The complex nature of prenatal programming of obesity

i-8489e523508b983eb19a97c395a445c0-fat mouse ccs.jpgThis article struck my eye because all of the literature I was familiar with said the opposite. The authors looked a weight gain in the mother during pregnancy and found that the children of the mothers who gained too much or even normal amounts of weight -- by the existing standards -- were more likely to be overweight at 3 years old:

Pregnant women who gain excessive or even appropriate weight, according to current guidelines, are four times more likely than women who gain inadequate weight to have a baby who becomes overweight in early childhood. These findings are from a new study at the Department of Ambulatory Care and Prevention of Harvard Medical School and Harvard Pilgrim Health Care and are published in the April issue of the American Journal of Obstetrics and Gynecology.

"Maternal weight gain during pregnancy is an important determinant of birth outcomes," says lead author Emily Oken, MD, MPH, instructor in the Department of Ambulatory Care and Prevention. "These findings suggest that pregnancy weight gain can influence child health even after birth and may cause the obstetric community to rethink current guidelines."

Oken and colleagues examined data from 1,044 mother-child pairs in Project Viva, a prospective study of pregnant women and their children based at the Department of Ambulatory Care and Prevention's Obesity Prevention Program. The authors studied whether pregnancy weight gain within or above the recommended range increased the risk of a child being overweight at age 3 years.

In 1990, the Institute of Medicine (IOM) published guidelines for gestational weight gain ("Nutrition During Pregnancy") that were motivated by evidence that low weight gain in pregnant women may cause low birth weight. These guidelines call for smaller gains in mothers with a higher body mass index (BMI) and generally permit greater gains than previous recommendations.

The IOM report remains the standard for clinical recommendations regarding gestational weight gain. However, some have questioned whether evidence is sufficient that greater gains promote better birth outcomes in modern developed nations. More weight gain may cause undesirable birth outcomes, such as increased rates of babies born at high birth weight and cesarean section, and is associated with higher postpartum weight retention and later risk of maternal obesity.

In this study, 51 percent of women gained excessive weight, 35 percent gained adequate weight, and 14 percent gained inadequate weight, according to the IOM guidelines. Women with adequate or excessive gain were approximately four times more likely than those with inadequate gain to have an overweight child, as measured at age 3. The authors defined overweight as a BMI greater than the 95th percentile for the child's age and sex. (Emphasis mine.)

This is interesting because I had actual heard of the opposite effect. After examining a cohort of children born to mothers who were pregnant during the Dutch famine of 1944, researchers had shown that prenatal malnutrition increases the rates of obesity later in life.

This led researchers to conclude that there was a "thrifty hypothesis" that governed physiological set-points for weight as determined prenatally. Basically, the fetus looks at the nutritional environment that it can reasonable expect outside the womb as determined by the nutritional environment prenatally. The fetus then establishes set-points for things like hunger and satiety -- all of which can make an individual more prone to obesity if they are not correct.

However, the results of the Harvard study -- and other work I have realized -- show that prenatal nutrition may have a "U" effect on obesity later in life, with outliers at either extreme resulting in a higher rate of obesity.

Novak et al published an excellent review on the subject of prenatal nutrition and obesity:

Obesity is a complex disorder, influenced strongly by both genetics (i.e., melanocortin 4 receptor mutations) and environment. The influence of birth weight on subsequent adult obesity represents a 'J' or 'U' shaped curve, with an increased incidence at both extremes. In the human, obese mothers are more likely to deliver relatively large infants who have a significant risk of subsequent obesity. Paradoxically, infants born small also have an enhanced risk of subsequent obesity. Indeed, a variety of work has demonstrated that human infants born small who during childhood gain weight rapidly ('catch-up' growth) are at greater risk of developing central obesity and metabolic syndrome as they age.

The 'thrifty hypothesis' posits that suboptimal early nutrition results in fetal/neonatal metabolic adaptations designed to allow the organism to develop efficiently in a nutrient-poor environment. Subsequent exposure to a nutrient-rich environment postnatally then results in untoward consequences, including the development of type 2 diabetes and the metabolic syndrome. Indeed, women exposed in utero to famine early in gestation had a higher incidence of obesity at age 50 than did those not exposed to nutrient deprivation. The increasing incidence of obesity in developing nations as they are exposed to western diet lends further credence to the thrifty hypothesis, however, the mechanisms underlying it are uncertain.

Studies of growth-restricted animals are beginning to provide insights into contributory mechanisms. Guinea pig pups born to malnourished mothers, while smaller than their control counterparts, have relatively larger stores of adipose tissue, suggesting that propensity toward obesity begins in utero. Similar findings have been reported in human infants born small. Expression profiling performed in visceral adipose tissue derived from 130 d/o male offspring of protein deprived dams demonstrates up-regulation of genes involved in carbohydrate, protein, and lipid metabolism as compared to controls; similar results have been demonstrated in fetal sheep after nutrient deprivation. Postnatally, obvious potential factors include abundance of food, enhanced appetite, and diminished postnatal activity. Rats undernourished in utero are less active and, if exposed postnatally to hypercaloric diets, more prone to subsequent obesity than are their well nourished counterparts, suggesting that, as in the human, diminished energy expenditure/activity may play an important role in the development of obesity.

Appetite is a complex phenomenon, but there is clear evidence that it can be regulated or 'programmed' by pre- and perinatal nutriture. Indeed, food acquisition (orexia) is a primary physiologic function of all multicellular animal life forms, representing the major route for energy acquisition. Orexigenic (appetite stimulatory) function and regulation develop in utero in precocial species (e.g., human, sheep). Programming of orexigenic mechanisms in response to an altered pregnancy/newborn environment may influence infant, childhood, and ultimately adult appetite 'set points'. Dysfunctional appetite may thus result from maternal environmental influences during critical windows of development. In response to in utero undernutrition, offspring demonstrate hyperphagia as compared to controls, suggesting that enhanced appetite is an important mechanism by which obesity is induced postnatally. In fact, a variety of work in several different animal models has consistently demonstrated that nutritional deprivation in utero, whether involving total calories or protein, is capable of producing small offspring which, if allowed to gain weight rapidly in the postnatal period through the use of cross-fostering or provision of high-calorie diets will gain weight in excess of control animals. Restriction of intake throughout gestation and lactation delays 'catch-up' growth, and seems to prevent most characteristics of the human 'metabolic syndrome'. In utero exposure to nutritional deprivation may also impact food selection. All alterations appear to vary with the timing and duration of nutritional insult, as well as, potentially, with the sex of the offspring, thematically concordant with changes noted in offspring of women pregnant during the Dutch famine winter of 1944-1945. Of great interest, lifespan of animals malnourished in utero and re-fed early is diminished, while slow re-feeding (and weight gain) is protective.

Importantly, humans have well-developed orexigenic mechanisms. Conversely, satiety pathways are markedly less functional. Although anorexigenic (promoting anorexia) factors contribute to cessation of food intake, numerous factors including food availability, the sight and smell of food, and social behavior may augment food intake beyond maintenance levels. Thus, self-motivated dietary weight loss is extremely difficult. Should gestational programming and/or newborn catch-up growth further reduce the efficacy of satiety mechanisms, obesity may result. (Citations removed.)

If you have access to it, I recommend you read the whole review.

Anyway, what makes all of this evidence particularly difficult to interpret in humans are the social factors lumped on top of the physiological issues. For example, say the mother gained a large quantity of weight during her pregnancy. Does this suggest that she has a tendency to obesity herself, and that her infant may be overfed during the first several years of life? It isn't clear to me how you can adequately control for factors of that nature.

Furthermore, I am not certain that age three is an adequate end-point for studies of this nature. What you would really like is some sort of global measure of obesity throughout life, but I am not aware of any such measure.

This is interesting research to watch because the more we understand about the mechanisms of satiety in the human brain, the more easily we can manipulate these mechanisms to improve human health.

Here is some information about what the current recommendations for weight gain in pregnancy are.


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Did they control for economic status / quality of diet? Did they control for levels of physical activity?

Both of those have a strong correlation to weight, and both are likely to be an environmental factor in the upbringing of the children in question (as opposed to a pre- or peri-natal biochemical factor).

By Craig Helfgott (not verified) on 02 Apr 2007 #permalink

This review sounds convincing and comprehensive. I am tempted to agree with most of the points raised by this particular research. However, i still feel its NOT conclusive though and more controlled human feeding studies are required to be able to finalise on the overall mechanisms that are involved in the programming of orexigenic and anorexigenic pathways in human subjects (Obesity and metabolic syndrome).

Matsungo TM (Mr)
Nutritionist/Physiologist (Zimbabwe)

By Tonde Matsungo (not verified) on 02 Apr 2007 #permalink

How do they control for the fact that mothers and their offspring are genetically related, and that there's a genetic component to obesity? It seems possible to me that women who gain more than the recommended amount of weight during pregnancy may have a genetic predisposition to obesity themselves, which their offspring might inherit. I don't get why so many studies of this type ignore the genetic connection (aside from the fact that it's difficult to study), but maybe there's something I'm missing.

By Elizabeth Reid (not verified) on 03 Apr 2007 #permalink

The Harrison Hypothesis from the early 90's showed that women who gained less than 20 lbs during pregnancy risked higher rates of heart disease and diabetes for their children. This seems to suggest that too much weight gained is equally bad for baby. Maybe moderation in all things is the way to go.

By Joseph T. Young (not verified) on 05 Apr 2007 #permalink

There's no link to the data; all I can find anywhere are press releases. I understand your concerns, given that the press release doesn't mention the possibility of a genetic link, which is, I thought, firmly established in obesity. But also, if the percentage of three-year-olds scoring in the 95th percentile is so high, doesn't it suggest that the BMI charts are wrong for three-year-olds?

There's an excellant post at Junkfood Science with more information on the study.

While all of the focus was on the 9% of toddlers considered overweight, the 31% of children who were underweight or low-weight were not even mentioned!