Any review of prenatal programing must begin with due recognition of the pioneering contributions of Dr. David Barker. He and his colleagues conducted the first large-scale epidemi-ological studies that systematically documented the strong associations between birth weight and adult disease (Barker, 1998). Their analyses showed that in both industrialized countries of northern Europe and rural regions of India, there is a high concordance between the geographic patterns and historic trends in birth weight and the prevalence of cardiovascular, respiratory disease, and type 2 diabetes. Infants born premature or very small had long been known to be at greater risk for many diseases, but the Barker papers provided compelling evidence for a more general association across the full continuum of weight in full-term babies and the extent of risk for adult disease later in life.
While evident at the population level for infants of all sizes, the influence of birth weight is certainly most pronounced in those born small-for-gestational age (SGA) (Dunger and Ong, 2005). Moreover, a number of researchers have argued further that there is added significance if a baby evinces signs of asymmetrical somatic growth, born with a relatively large head and a stunted body (Fergusson et al, 1997). The lack of proportionality in the lower body may connote an acute period of deprivation late in pregnancy, beyond just the slow growth sustained across the entire pregnancy, which would result in a small, but more symmetrical baby. A similar interpretation about the significance of asymmetry has been proposed when the placen-tal size is relatively large with respect to a baby's low weight, suggesting a compensatory increase in response to a compromised pregnancy.
Analyses of neonatal appearance and fetal growth restriction following a period of under-nutrition or placental insufficiency during pregnancy heralded what has become known today as the 'thrifty phenotype.' That is, when confronted with limited resources during pregnancy, the developing fetus re-programs its growth rate and metabolism in a manner that will facilitate adaptation to further nutrient shortages after birth. Assuming that the prenatal prophecy is correct, such a shift toward a slower growth rate could be advantageous for the baby presenting with a thrifty phenotype. Perhaps enabling it to survive in an adverse world by maximizing the uptake and efficient use of limited nutritional resources.
However, if subsequently there is a mismatch and the growing child now has abundant resources, the altered metabolism and coveting of nutrients can result in a propensity for obesity. Such a scenario sometimes occurs after adoption of a young infant from an impoverished setting to an affluent country. These children are then at greater risk for becoming overweight and developing the metabolic syndrome with glucose intolerance and atherogenic dyslipidemia and are more prone to cardiovascular disease. Clinical tests indicate that these individuals also have prothrombotic and proinflammatory profiles. In addition to the human studies supporting this line of reasoning, numerous reports on rodent and sheep models have begun to delineate the hormone mechanisms and metabolic pathways accounting for these long-term effects (Murphy et al, 2006; Wintour et al, 2003). These experiments indicate that the physiological programing includes changes in the kidney, with decreases in nephron number and/or size, which contribute to the later hypertension in adulthood (Moritz et al, 2009).
Beyond the obvious relevance for many regions of the world where food supplies are inadequate for pregnant women, these observations have proven to be germane to understanding long-lasting changes in population health after acute periods of deprivation during wars and environmental disasters. The best-documented example is certainly the decade-long effects of the Dutch Hunger famine in 1944 when the Netherlands was subjected to extreme food rationing during World War II (Ravelli et al, 1976). Food intake for many pregnant women was reduced to 500-800 calories per day for several months. When the deprivation occurred late in gestation, the neonates were of smaller size and grew up to be at greater risk for obesity and diabetes (Ravelli et al, 1998). For the pregnant women who experienced food restriction earlier in pregnancy and subsequently had access to a better diet, their babies were born at a larger size, but continued to be more likely to develop cardiovascular disease by 50 years of age (Roseboom et al, 2000).
Beyond the impact of stunted fetal growth during periods of social strife and turmoil, it is known that even under normal circumstances, infants who are born small and then undergo a period of rapid postnatal growth also have distinctive physiological profiles. This type of catch-up growth has the additional effect of placing high demands on iron reserves, increasing the likelihood of the infant becoming anemic during the first year of life (see Section 8 on risk factors for iron deficiency anemia).
While most clinical attention has been focused on premature and SGA babies, there is a complementary literature indicating that excessive fetal growth can present a different set of problems. With large-for-gestational age babies (LGA), there is a significant increase in obstetrical complications and need for caesarian delivery (Gregory et al, 1998). In addition, these infants are more likely to continue on the path toward obesity during childhood and adulthood, especially after diabetic pregnancies (Law et al, 1992). Longitudinal studies show they are predisposed to have poorer glucoregu-lation and to develop type 2 diabetes as adults. Here too, basic science studies in animals have provided considerable support for these associations and revealed several critical mediating pathways linking accentuated growth rates and later disease. For example, pregnant dams fed a high caloric diet will gestate offspring with a distinctive insulin response and altered pancreatic size and renal functioning. In addition, providing young rat pups with a period of over-nutrition right after birth changes how their leptin and thyroid hormones are regulated in a manner that will permanently alter appetite and energy metabolism into adulthood (Rodrigues et al, 2009).
Obesity early in life thus seriously increases risk for many ailments, but especially for the Big Three: metabolic syndrome, diabetes, and cardiovascular disease. It is perhaps less well known that large babies and overweight children are also more likely to develop allergies and asthma (Pekkanen et al, 2001). In fact, if one were to compare the odds ratios of developing asthma in small neonates versus in large babies over 10 pounds, the greater pediatric concern would have to be for the bigger infants, especially in the heaviest ones gestated beyond 40 weeks postconception.
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