In short, the backbone of the theory has graduated from hypothesis to accepted biology even though the details remain controversial. One of the central tenets of the early programming theory is that the effects are most pronounced when there is a mismatch between early nutritional deprivation and later nutritional affluence. In the West this is manifest in the fact that the detrimental effects of intrauterine growth retardation are most clearly seen in populations that have become overweight and obese in adult life 1 , 4.
The great majority of low-birth-weight babies, and, by inference, of growth-restricted fetuses, are born in developing countries 5. This might not be of great significance if these populations remain lean, fit and frugal, because studies under such conditions show very few risk factors for chronic diseases hyperinsulinemia, hypertension, hyperlipidemia and no detectable association with maternal nutrition during pregnancy e.
However, with increasing affluence the obesity pandemic is now penetrating into many developing countries, especially in urban areas 7. Until this newfound affluence feeds through to produce larger mothers and larger babies, a process likely to take several generations, it is suggested that these developing-country settings are where the fetal origins theory is most relevant.
It was for this reason that the Society for International Nutrition Research SINR convened a symposium at EB in San Diego to take a critical look at the evidence and explore the experimental paradigms that will be required to reach a better understanding of the basic biology, and hence of the health implications.
From frugal origins to affluent futures: human metabolism stressed by excess Poor peoples in developing countries can be viewed as having been exposed to four phases in which nutritional deprivation may have imprinted itself on their metabolic makeup: an evolutionary phase with frequent famines selecting what J.
Neel termed a thrifty genotype 8 ; an intergenerational phase in which the failure of women to grow to their full genetic potential imposes uterine restraint on the developing fetus; a fetal phase; and a postnatal phase. Any of the latter three phases might create what Hales and Barker have termed a thrifty phenotype in which the metabolic and endocrine control systems are tuned to expect a meager substrate supply and are ill-adapted for later nutritional excess 9. In the twentieth century most natural famines i.
This might be the case, but is not necessarily so, because an examination of the earlier historical record shows that all of humanity has been regularly challenged by famine to a surprising degree 12 ; it may therefore be misleading to impute a greater genetic thriftiness in people from the developing countries of today.
It is noteworthy that Neel's original speculation about the thrifty genotype arose from observations in relation to fetal overgrowth in mothers with gestational diabetes. The original concept was of a fetal thriftiness, even though many of the later interpretations have tended to focus on the idea that thriftiness was selected for by the ability of adults to survive starvation c.
In fact a close look at the statistics of when during the life cycle most Darwinian selection occurs yields the surprising finding that most selection occurs prenatally see Fig.
This may have important implications for our understanding of how genetic factors may contribute to the observed associations among size at birth, later growth and adult disease, and must be factored into our thinking 13 , The intergenerational cycle of fetal growth restriction The early breeding studies of Walton and Hammond, in which dwarf Shetland ponies were crossed with Shire horses several times their size, showed conclusively the importance of the maternal uterine environment in constraining fetal growth so that the mother can deliver an appropriately sized offspring Such effects also operate in humans, with small mothers especially in southern Asia producing small babies 16 , The effects have complex modes of transmission from generation to generation, but, aside from the subtleties, it is clear that several cycles of good nutrition are required to ameliorate them.
Until this has happened, populations of small mothers pose a real dilemma in terms of how rapidly and aggressively we should try to intervene with supplementary feeding initiatives, because there is some concern that acute interventions in pregnant women may exacerbate a problem described as the thin-fat baby phenomenon, in which the extra nutrients may drive the development of an inappropriate fat mass, which is associated with insulin resistance from very early life 17 , Fetal growth restriction and the thrifty phenotype The possibility that fetal growth restriction may create a thrifty phenotype disadapted to later affluence has been described and discussed at length elsewhere and so requires little amplification here.
Postnatal growth restriction and the thrifty phenotype Most of the discussion of the early-life theory of adult disease has concentrated on fetal growth restriction, although even some of the earliest publications described associations with weight at 1 y of age The subsequent interest in postnatal growth has tended to focus on rapid growth as a risk factor for later disease, especially where there is a pronounced divergence between fetal and postnatal growth trajectories 4 , 20 — In many areas of the developing world, the combination of poor diet, persistent gastroenteropathy and infections leads to serious growth faltering in whole population groups and life-threatening malnutrition in a substantial subset.
Figure 2 shows some fairly typical growth trajectories, in this case in rural Gambian children. This implies that the postnatal stresses are actually greater than the prenatal stresses.
It may be that such stresses have less impact on longer-term metabolic function because the great majority of the cell divisions required to create the fully differentiated organism occur prenatally; however, there may be plenty of remaining scope for entraining endocrine systems.
The later consequences of this early growth failure merit closer examination to determine the extent to which they may contribute to the development of a thrifty phenotype. Values represent sd scores. Poor nurture during pregnancy can worsen the hand that nature has dealt. When a significant situation, disaster, or event occurs across a given population, it can be assumed that the entire population is affected, thus generalizing findings across all demographics in a given group.
Certain historical events provide epidemiological support for the developmental origins of health and disease, including the Dutch Hunger Winter and the Holocaust.
In the United States, the average lifespan dropped by 12 years per person. The study concluded an It is also notable that those who were already born but young between the ages of 1 and 5 during exposure did not have a noticeable increase in coronary heart disease or kidney disease.
Being exposed to the pandemic while in utero would lead to an average loss of 0. These effects were much higher or lower depending on the district of Italy.
In a recent[ when? It has been hypothesized that a definite link exists between influenza-induced stress on the fetus and schizophrenia. Where food was previously plentiful, supplies immediately were cut off in November , resulting in a period of starvation that lasted until spring of Analyses of the orderly health records from this time period allow for a systematic comparison of the effects of fetal starvation.
Individuals who were in utero during the Hunger Winter were subject to different outcomes depending on the period of time in which they were conceived. Those who were in the first trimester during the three-month siege were likely to be born normal size, having caught up with typical development. However, these normal size babies developed high blood pressure, diabetes, and obesity. Contrary to this group, those who were in the third trimester during the siege, who presumably had been well nourished up until the last few months of gestation, were born small.
But, these small babies stayed small their entire lives, and did not develop higher rates of obesity or disease. Surprisingly, effects continued to be seen in the offspring of the individuals who were fetuses at the time of the famine.
This fasting usually entails abstaining from food or drink for the daylight hours of the month. There are groups that are automatically exempt from having to participate such as the young, sick and old but the list of exemption does not officially include pregnant women though they are most often allowed exemption.
The majority of pregnant women however, choose to participate despite the hardship due to cultural and personal pressure. These outcomes were as numerous as a change in birth weight to the long term health of the affected. The studies were conducted primarily in Uganda and Iraq but had some smaller sections in Michigan and other places for control groups or specific studies.
The effects on birth weight are negatively correlated with Ramadan fasting. Arab Muslim pregnancies that overlap with the Ramadan fast experienced a lower birth weight of 18 grams per child. The effect was slightly larger at a lower birth weight of grams if Ramadan fell somewhere in the first or second trimester of the pregnancy. Though the measure for disability differs by country the effect is still noticeable. For those born 9 months after Ramadan the likelihood of disability is higher than the surrounding population.
The mean rate of disability in Uganda is 3. A similar effect can be observed in Iraq where the mean rate of disability is 1. The effects of exposure to the Ramadan fast can even be observed in mental disorders.
In a study conducted in Uganda it was concluded that exposure to the fast, early in a pregnancy effectively doubles the likelihood of a person having a cognitive disorder of some kind. The reported signs of Anemia among the old were higher for those exposed during mid gestation, all other points in the gestation period were found to be insignificant. Anemia is caused by damage to the kidneys so the findings are consistent that the effect is noticeable during mid gestation when the kidneys are being developed.
This finding shows that gene expressions can be altered via stressful experiences and then passed down to children through prenatal conditions. While the children of the Holocaust survivors had not themselves experienced Nazi inflicted trauma, they experienced the physiological and emotional trauma as if they had.
When compared to Jewish families who were living outside of affected areas of Europe, the findings continued to stand: "The gene changes in the children could only be attributed to Holocaust exposure in the parents. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. April Learn how and when to remove this template message Pollution may affect the health of the mother, or cross over the placenta and enter the developing fetus.
Beate Ritz, a professor at UCLA, found significantly higher rates of heart malformations and valve defects in the children born to women living in highly polluted areas of Los Angeles.
Such effects also operate in humans, with small mothers especially in southern Asia producing small babies 16 , Anemia is caused by damage to the kidneys so the findings are consistent that the effect is noticeable during mid gestation when the kidneys are being developed. There are groups that are automatically exempt from having to participate such as the young, sick and old but the list of exemption does not officially include pregnant women though they are most often allowed exemption. Their children, also, had lower basal cortisol levels than those not exposed to extreme prenatal stressors. First, they point to the importance of intergenerational influences on chronic disease.
For example, broadening the target population to women who might get pregnant would reduce the set of policies which are cost effective.
Comparisons between the children who were in gestation during the flu pandemic and those in gestation immediately before or after the health crisis show marked differences between the two groups on census data.
He finds support for this hypothesis in the case of low density lipoprotein cholesterol in Filipino adolescent males. As perhaps the most well-known fetal risk, It wasn't until that fetal alcohol syndrome was first formally diagnosed, and not until that the United States government began requiring warning labels directed at pregnant women to be in place on all alcoholic beverages for sale. Kuzawa 25 reminds us that although the central tenet of the fetal origins hypothesis involves nutritional programming, research in humans is most often based on birth size, which is a flawed indicator of prenatal nutrition. Epidemiological and epigenetic support[ edit ] Epigenetics refers to the study of the behavior of genes, and how gene expression can be altered by the environment without changes made in DNA. Beate Ritz, a professor at UCLA, found significantly higher rates of heart malformations and valve defects in the children born to women living in highly polluted areas of Los Angeles. Their ideas were initially described as the fetal origins of adult disease hypothesis and, in spite of the existence of a significant body of earlier animal data pointing to the existence of early life programming, were met with much skepticism 2.