Postnatal Growth and Later Risk of Disease

Small body size in childhood may reflect nutritional insufficiency that may program adult disease in ways similar to that observed in the fetal period. Independent of birth weight, low weight at 1 year of age has been associated with increased risk of cardiovascular disease in adult men. Similarly, poor childhood growth manifested as short stature has been linked with insulin resistance.

More attention has recently been paid to the effects of rapid childhood growth in height and weight. The observation in much of the fetal programing literature that effects of birth size emerge or are strengthened when current body size (typically represented as BMI) is taken into account suggests an important role for postnatal growth in the origins of adult disease. Individuals who are born small, but who end up relatively large (taller or heavier than their peers) have clearly experienced more rapid growth at some point between birth and when health outcomes and current size are assessed. Whether rapid growth is an independent risk factor or whether it confers increased risk only in individuals with a history of intrauterine growth restriction is a question requiring further research. Moreover, even when strong associations of growth rate and chronic disease risk are found, it is unclear whether the association is causal or whether growth serves as a marker for other underlying causal processes.

Postnatal growth is clearly related to prenatal growth. Some metabolic changes associated with prenatal nutritional sufficiency may affect postnatal physiology and behavior that, in turn, affect growth. In addition, there is intriguing evidence from animal studies that prenatal nutritional restriction alters appetite and induces hyperphagia, and also reduces physical activity in adult animals (see Figure 2). If true in humans, this would be an important pathway by which disease risk is affected. Suggestive evidence comes from human infants whose cord blood leptin levels at birth were inversely related to weight gain in the first 4 months of life, independent of birth

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Figure 2 Locomotor behavior and food intake in Wistar rats as a consequence of a normal or adverse fetal environment (n = 6-8/ group). (A) Food intake (kcal per gram body weight per day over a 5-day period) in females at day 145; P< 0.005 for effect of fetal programing, P < 0.05 for postnatal hypercaloric diet. (B) Locomotor activity at 14months in males and females; P<0.005 for effect of fetal programing and gender. Data analyzed by factorial ANOVA, and data are shown as means ±SE. (Reproduced from Vickers MH, Breier BH, McCarthy D, and Gluckman PD (2003) Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. American Journal of Physiology. Regulatory Integrative and Comparative Physiology 285(1): R271-273 with permission from the American Physiological Society.)

weight. Leptin may relate to subsequent growth by affecting appetite and energy intake.

Depending on the outcome under study, there are differences in whether linear growth or growth in weight, particularly weight relative to height, matters. Most often, more rapid weight gain is the risk factor, owing to the fact that excess adiposity is an important risk factor for many chronic diseases of adulthood. Another key issue concerns the timing of effects. There is controversy about whether early infancy compensatory growth following intrauterine growth restriction confers risk, or whether it is only later growth that matters.

Where many potential adverse outcomes might be affected by postnatal growth, the following sections focus on adiposity, blood pressure and coronary heart disease, insulin resistance and diabetes, and cancer.

Adiposity and Obesity

Early undernutrition followed by later overnutrition as well as early overfeeding independent of prior growth restriction are thought to increase risk of later obesity. Rapid postnatal weight gain occurs in a significant proportion of infants who are born small for gestational age. Prospective studies in US, South African, and British cohorts show that rapid growth in early infancy increases later risk of overweight. Longitudinal data from the US National Perinatal Collaborative study show that, independent of birth weight, one-third of obesity at age 20 is attributable to rapid weight gain in the first 4 months of life. In a Bristol, UK cohort, nearly one-third of children had an increased weight standard deviation (SD) score of more than 0.67units from birth to age 2 years, and these children remained fatter, having more central fat distribution at age 5 years compared to children with lower early growth rates. Similarly, data from the South Africa Birth to Ten cohort showed that children with rapid weight gain in infancy were significantly lighter at birth and significantly taller, heavier, and fatter throughout childhood.

Early postnatal growth rates may program insulin-like growth factors, IGF-I and IGF-II. Figure 3 illustrates this point with data on 5-year-old children from Bristol, UK in whom IGF levels were strongly related to current body size, but also that, independent of current size, children who had experienced catch up growth (change in Z-score >0.67 SD) from birth to age 2 had higher IGF levels. Childhood IGF levels are important as determinants of later linear growth and timing of puberty, and are associated with later risk of hormone-dependent cancers.

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Figure 3 Hormone levels at age 5years by change in weight Z-score from birth to 2years of children in the ALSPAC cohort: means and 95% confidence intervals of IGF-I and IGF-II, adjusted for fat mass and fat-free mass. (Drawn from data from Ong K, Kratzsch J, Kiess W, Dunger D, and ALSPAC Study Team (2002) Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate. Journal of Clinical Endocrinology and Metabolism 87(3): 1041-1044.)

Cancer

A large body of literature relates adult height to cancer risk, with the largest volume of evidence on breast, prostate, and colorectal cancers. In each case, risk of disease is increased with taller stature. A role for accelerated childhood growth is inferred, since taller individuals have experienced more linear growth. Possible mechanisms fall into two categories: childhood growth as a marker for other exposures that influence risk (fetal exposures, infections, timing of puberty, and energy intake) or growth as a mediator of risk (effects of growth promoting hormones such as IGF-I and IGF-II).

Few studies have directly addressed the effects of childhood growth, owing to lack of longitudinal data. Based on data from the UK Boyd Orr cohort, a one SD difference in height was associated with a 42% higher risk of overall cancer mortality in later life among males, but no effects were found in females. In another UK birth cohort, risk for breast cancer was elevated among women who were large at birth and tall at age 7. Based on data from the US Nurse's Health Study, rapid adolescent growth was associated with an increased risk of both pre- and postmenopausal breast cancer.

Blood Pressure and Coronary Heart Disease

Blood pressure is the one of the most well-studied outcomes in the context of fetal programing, with fairly consistent findings of a modest inverse relationship of birth weight to adult systolic blood pressure that increases with age. Substantial evidence demonstrates a synergistic relationship of fetal growth restriction with rapid postnatal growth. Figure 4 presents the classic picture for systolic blood pressure: the highest pressure is found among adolescent males who were relatively thin at birth, but relatively heavy as adolescents. Current BMI is typically the strongest anthropometric predictor of blood pressure, but at the same BMI, those with a history of fetal growth restriction have higher mean blood systolic pressure and increased risk of having high blood pressure.

Owing to the existence of good longitudinal growth data in Scandinavia, child growth trajectories can be traced for individuals with and without hypertension or other adverse outcomes such as coronary heart disease. As shown in Figure 5, though initially smaller, adults with hypertension diverged in their BMI trajectory and were relatively heavier after age 7 compared to those without hypertension.

There remains controversy about the age at which higher growth rates pose risk of later disease. Some studies show elevated blood pressure in association with rapid weight gain in infancy, while other studies show no effect, or a protective effect (infants with larger weight increments have lower blood pressure

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