We all come into this world with sealed orders, said 19th century philosopher Søren Kierkegaard. Although the great Dane lived at a time when much of science was still gauzy and life events were often ascribed to fate, the notion seems to hold true today. A quick scan of newborn babies snoozing in a maternity ward offers little hint of what their futures hold.
But medical researchers are now unsealing these orders by seizing on a simple clue — a newborn’s weight. Having established that being too small at birth carries health risks down the road, researchers are also finding that high birthweight comes with baggage.
A stream of evidence has upended the long-held assumption that a big baby is a healthy baby. Newborns pushing 9 pounds face an increased risk of obesity, diabetes, heart disease, cancer and even neurological problems over a lifetime. They are more likely to run afoul of these conditions than are babies born in the “sweet spot” — not too big and not too small.
That much is clear, but details of how the tipped scales lead to later disease are still being sorted out. “High birthweight, in a way, is a proxy for a whole bunch of things going on,” says David Hill, a physiologist at the Lawson Health Research Institute in London, Ontario. “It’s like a lighthouse. You can see the light, but where are the rocks?”
Scientists suspect that high birthweight is a marker for unwanted fetal programming. Studies in animals suggest that too much nutrition triggers a collage of changes in a fetus’ gene activation, organ function and production of insulin and other hormones. In a human pregnancy, these changes conspire to make a newborn too large for its own good.
CDC benchmark for low birthweight
CDC benchmark for high birthweight
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The good news is that some of the problem is preventable, ideally through good prepregnancy health, controlled weight gain and exercise. But that’s easier said than done. Many women still consider a big baby a sign of good health even as doctors are becoming more attuned to the risks of high birthweight.
Are the days of eating for two gone? “I certainly hope they are,” says Emily Oken, a physician at Harvard Medical School who works on women’s health issues. In many cases, she says, “we think they should be eating for 1.1.”
High birthweight is an informal classification that starts at 4 kilograms (8.8 pounds) for Western newborns, black or white, and, some suggest, 3.5 kilograms (7.7 pounds) for Asian babies. This doesn’t include big babies who are born to naturally big people. Doctors call these babies “constitutionally large,” says obstetrician Michael Ross of the UCLA School of Medicine. These infants are likely to be big-boned and long with plenty of muscle, he says. The high-birthweight babies to worry about are normal-sized newborns who carry extra fat mass, he says.
Of course, all women should gain some weight while pregnant. The Institute of Medicine, an advisory panel to the U.S. government, set down hard-and-fast ranges in 2009. Exceeding those ranges or carrying extra weight can distort mother-to-fetus communication.
“Fetus and mother are talking to each other through the placenta,” says endocrinologist David Phillips of the University of Southampton in England. Nutrients such as glucose, fats, protein components and a few hormones pass from mom to fetus. “The mother is giving clues to the fetus, which responds accordingly.”
This nutritional message includes lots of glucose, because all pregnant women experience some insulin resistance in the last two trimesters. Their cells resist insulin’s effects and become less efficient at processing glucose for energy, leaving more of it available to the fetus, says Patrick Catalano, an obstetrician at Case Western Reserve University and MetroHealth Medical Center in Cleveland.
Ideal weight gain
In 2009, the Institute of Medicine updated guidelines for weight gain during pregnancy, based on body mass index. The guidelines call for ample weight gain in thin or normal-sized women and less in heavier women.
Source: Institute of Medicine
Inflammation may also boost this insulin resistance, says Fernando Guerrero-Romero, an internist and research scientist at the Mexican Social Security Institute in Durango. In obese women, fatty tissues act as a source of immune proteins called cytokines, which are chronic inflammation signalers. Inflammation exacerbates insulin resistance in a pregnant woman, he says. Insulin and some cytokines are too big to cross the placenta barrier, but excess glucose does, leading to an overfed fetus.
Women who are already obese before pregnancy tend to deliver a nutritional mix that is high in fats, Ross says. In women who gain excess weight during gestation, it’s likely to be excess glucose. “With a diabetic mother,” he says, “it’s a little bit of everything.” Those extra nutrients sent through the placenta trip hidden switches in the offspring that can lead to higher rates of obesity much later. Some combination of this poor nutrient mix “results in offspring with increased appetite and increased predisposition to fat deposition,” Ross says. “They are just driven to store fat rather than break it down.”
It’s difficult to investigate how those changes happen in human fetuses, since invasive tests are out of the question. It’s also tricky to try to assign pregnant women to experimental diets. But studies in animals shed light on the impact of excess nutrition in utero.
Some show that a faulty nutritional mix can cause DNA modifications, known as epigenetic changes, that modify genes and cells, sometimes for the long term, Ross says. Being awash in glucose, for example, might alter stem cells in a fetus as they change from nascent cells to cells with a more clearly defined role. In animals, stem cells with the blueprints to develop into the brain’s neurons, for example, can be altered at key points, steering a neuron away from being one that induces satiety into one that provokes appetite.
Changes in the hypothalamus of the brain during late pregnancy are involved “in the programming of appetite and metabolism toward establishing an elevated body weight set point,” Paul Taylor and Lucilla Poston of Kings College London suggested in Experimental Physiology in 2007.
Regardless of how overfeeding in utero causes problems into adulthood, the consequences are becoming clear.
In adults ages 24 to 45 in Finland who were part of a health study, those born big were twice as likely to become obese as those of average birthweight, scientists report in Arteriosclerosis, Thrombosis and Vascular Biology in May. Another study shows that being born heavy, even without an obese mom, increases an adolescent’s risk of obesity by 46 percent — implicating weight gain in pregnancy.
Birthweight is also tied to diabetes risk. Researchers at the University of Leipzig in Germany found in an analysis of 1,117 children with diabetes that these children had birthweights that were strikingly higher or lower than those of about 54,000 kids without diabetes.
Too much glucose
This chart shows birthweights of children and adolescents in relation to their diabetes status. The zero horizontal line marks a healthy birthweight, which is where nondiabetic children clustered. Kids who developed diabetes were more likely to have been born big or small. (click chart to enlarge)
Source: V. Kuchlbauer et al/Pediatric Diabetes 2013; Credit: E. Otwell
The finding suggests that access to too much or too little glucose in utero contributes to type 1 diabetes. What’s more, women who were born big are roughly twice as likely to develop gestational diabetes during pregnancy as women who weren’t, a Swedish team found in 2012.
The result of overnutrition in utero is measurable almost immediately. When scientists at the University of Chile in Santiago examined 84 infant girls, they found that high-birthweight girls had lower levels of adiponectin in the blood than those with average birthweights. This hormone helps to regulate glucose levels and break down fats. Low adiponectin is linked with insulin resistance in animals and people.
In Mexico, scientists examined 107 newborns and found that the 22 who were large, averaging about 9 pounds, were more apt to have higher blood levels of insulin, a sign of high blood glucose and insulin resistance, than average-weight babies, says Guerrero-Romero, who reported the findings in 2012 in BMC Pediatrics.
The impact of high birthweight goes beyond metabolic problems to include neurological predispositions that might be long-lasting. Tests in animals have shown that an adverse prenatal environment, whether due to overnutrition, undernutrition or other events such as psychological stress in the mother, can affect how the brain develops.
Phillips in the U.K. teamed with researchers in Finland in 2007 and found that adults who were born at either high or low birthweight had lower cortisol production during stress tests than normal-birthweight people. Cortisol is a powerful hormone with both beneficial and deleterious effects. Out-of-balance cortisol levels could be a sign of poor fetal programming, Phillips says.
He and his colleagues also tested elderly Britons for stress reactivity. In a 2013 study, they gave hundreds of people a standard stress test, asking how they would react in uncertain social situations. Answers to the questions can reveal how a person is hardwired to react to stress, with choices such as “I generally stay cool” or “I often feel warm.” After accounting for other stressors in the volunteers’ lives — recent and past — the researchers found that both low- and high-birthweight people reacted more strongly to stress in old age than those born within the normal weight range.
The ramifications of high birthweight might stretch beyond stress to schizophrenia. In another Finnish study, people born at high-birthweight were 68 percent more apt to be diagnosed with schizophrenia than others their age, according to the 2011 report in Psychiatry Research. The authors suggest that a difficult delivery might play a role, but they also note that gestational diabetes could have been a contributing factor.
Cancer and heart disease
Scientists have known about a link between high birthweight and childhood leukemia since the 1960s. Other malignancies now tied to high birthweight include brain, colon, breast and prostate cancers in adulthood.
Less clear is the biology underpinning it all; insulin may play a role here as well. Twenty years ago Belgian researchers assessed fetal levels of an insulin building block called C-peptide and two growth factors called IGF-1 and IGF-2. Tests of umbilical cord blood from newborns showed some excess IGF-1 and C-peptide and very high levels of IGF-2 in high-birthweight babies. That report appeared in the American Journal of Obstetrics and Gynecology.
In lab animals, increased IGF-1 hikes colon cancer risk. Meanwhile, high insulin levels in the blood show up in cancer patients, and insulin itself seems able to promote tumor growth.
Fraction of U.S. women who enter pregnancy overweight
Fraction of U.S. women who enter pregnancy obese
Fraction of pregnant women worldwide with gestational diabetes
High birthweight might also contribute to cancer risk by adding to an individual’s “stem cell burden.” Because stem cells are self-renewing and long-living, the stem-cell burden hypothesis holds, having greater numbers of stem cells would increase the odds of cancerous changes arising at some point. Cristina Capittini and her colleagues at the IRCCS Policlinico San Matteo Foundation in Pavia, Italy, looked at stored umbilical cord blood samples from 1,037 full-term infants and tallied the population of stem cells, identifiable by the protein CD34. Writing in Maturitas in 2011, they reported that heavier babies had substantially more stem cells than average-weight or low-weight newborns.
But in some ways the cancer link to high birthweight appears to be an effect in search of a cause. “Birthweight is a marker for something,” cancer epidemiologist Julie Ross of the University of Minnesota Medical School in Minneapolis asserted in a 2012 editorial in Pediatric Blood & Cancer. She suspects IGFs getting activated in fetuses, and possibly altered levels of adiponectin and other hormones, account for some of it.
Although the cancer danger is real, the overall risk is low. The added risk of childhood leukemia resulting from high birthweight is around 25 percent, Julie Ross notes. Since the risk of developing childhood leukemia is minuscule, she calculates that high birthweight probably accounts for an extra 8 cases per million people per year.
Heart disease is a lot more common than leukemia, and it might also get a leg up in utero. Heavy newborns grow up to have slightly thicker carotid artery walls, a risk factor for cardiovascular disease, than those with a normal birthweight, Michael Skilton, a vascular physiologist at the University of Sydney, and colleagues in Finland report in May in Arteriosclerosis, Thrombosis and Vascular Biology. Regardless of whether the adults were normal weight or overweight, if they were born big they were more likely to have more vessel thickening than if they weren’t.
Having large babies has little precedence in humans, says Michael Ross, because delivering them safely was harder before the advent of modern medicine. “Looking back over evolution, if you had too large a baby, you and your baby died.”
The problem for thousands of years was more likely too little nutrition, not too much. That may be why the impact of obesity and high birthweight shows up glaringly in cultures that historically faced food shortages but have recently run headlong into a Western diet and lifestyle. Ontario’s David Hill points to studies of native peoples in the Canadian north who have seen obesity levels soar in a generation or two.
High birthweight can be a sign of altered fetal programming that can sabotage health later in several ways:
Credit: E. Otwell
“You hear accounts of the day the satellite dish came to town,” Hill says. “Before that, kids ran about and played, then went home tired and slept.” Now, adults and children alike watch television and consume foods that are often less healthy than what they had before. This lifestyle change is coinciding with higher birthweights in Cree Indian babies in Northern Canada, who are naturally big. A survey published in the January/February 2011 American Journal of Human Biology found that nearly 37 percent of Cree Indian newborns were high birthweight, higher than the 30 percent rate found in 1969.
A generational effect shows up in Cree girls. Those born at high birthweight in recent decades have been more likely to grow up obese and remain that way during their pregnancies, Hill says. They are more apt to develop gestational diabetes when they get pregnant and more likely to pass metabolic risks to their offspring.
Studies of the Pima Indians in Arizona show a similar trend. In the past, they led a spartan life with long stretches of scant food, Catalano says. The people who survived passed on their “thrifty genes,” he says, which store fat efficiently for hard times — but can be detrimental in a modern world of abundance.
“It’s a vicious cycle,” says Guerrero-Romero. When he and his colleagues did their study in Mexico testing infants’ umbilical cord blood, they had to enroll 800 pregnant women to find 150 who were normal weight. “Obesity is a problem in Mexico,” he says, “and I don’t think there is a simple answer to the problem of high birthweight.”
What’s a mother to do?
High birthweight would seem an implacable foe, “sealed orders” that can’t be rescinded. But moms-to-be have some degree of control over their children’s fate. Michael Ross suggests that women lose weight in anticipation of pregnancy. But he acknowledges that roughly half of the pregnancies in the United States are unplanned, and prepregnancy counseling is uncommon.
That leaves controlling weight gain during gestation and exercising. When 47 pregnant women were randomly assigned to spend up to 40 minutes a day on a stationary bicycle as part of a trial in New Zealand, the children born to the cycling women were slightly smaller (but not underweight) than babies born to 37 pregnant women not given a stationary bike. The babies of the exercising mothers also scored better on tests of IGF-1 and IGF-2 than the other babies, according to the 2010 report in the Journal of Clinical Endocrinology & Metabolism.
Adults who were born at high birthweight have thicker carotid vessel walls, regardless of their current weight. A thicker intima-media, the innermost two layers of the vessel, is a warning sign for heart disease.
Credit: E. Otwell
To protect offspring from arterial thickening that can lead to heart disease, Skilton suggests that pregnant women control their cholesterol as much as possible, ideally by diet rather than with medication. For very obese women, pre-pregnancy bariatric surgery can lead to weight loss, lower blood glucose and even an end to type 2 diabetes (SN: 9/10/11, p. 26). While drastic, such an approach has been shown to benefit offspring. A U.S.-Canadian team compared the school-age weights of children born to 113 obese women who had undergone bariatric surgery. The women had a total of 45 children before surgery and 172 after the operations. The kids born post-surgery were half as likely to be obese during their school years as the others, the researchers reported in Pediatrics in 2006.
“The majority of women are very receptive to the idea that they are responsible for the future health of their babies,” Hill says. But some don’t understand the risks. A 2013 report from Australia found that women had poor knowledge of the risks of being overweight in pregnancy. In a survey of pregnant women delivering at MetroHealth in Cleveland, Catalano found that at least half of overweight and obese women were gaining more than the IOM recommended amounts.
Education can help break this cycle, Hill says. “You can set a whole generation on a good trajectory.” Intervention before and during pregnancy would help, he says, “but how effective you will be probably depends on how early you start.”