Metabolic Imprinting by Prenatal, Perinatal, and Postnatal Overnutrition

A Review

Jennifer Shine Dyer, M.D., M.P.H.; Charles R. Rosenfeld, M.D.

Disclosures

Semin Reprod Med. 2011;29:266-276. 

In This Article

Abstract and Introduction

Abstract

Epidemiological studies have suggested that metabolic programming is one of the critical factors contributing to the etiology of obesity as well as concurrent increase in related chronic diseases (e.g., type 2 diabetes and cardiovascular disease). Metabolic programming is the phenomenon whereby a nutritional stress/stimulus applied during critical periods of early development permanently alters an organism's physiology and metabolism, the consequences of which are often observed much later in life. The idea of metabolic programming originated from the fetal origins hypothesis proposed by Barker in which he suggested that disproportionate size at birth of the newborn due to an adverse intrauterine environment correlated well with an increased risk of adult-onset ill health outcomes (type 2 diabetes, hypertension, and cardiovascular disease). The fetal origins hypothesis, proposed by Barker, suggests that adequate nutrition during fetal development is critical. Overnutrition is a form of malnutrition that has increased in the United States over the past several decades in which nutrients are oversupplied relative to the amounts required for normal growth, development, and metabolism. Evidence for the effects of maternal obesity and overnutrition on metabolic programming is reviewed during critical prenatal, perinatal, and postnatal periods.

Introduction

Overnutrition, i.e., the delivery of nutrients in excess of the needs required for normal growth, development, and metabolism, has increased in the United States over the past several decades. Consequently, the prevalence of obesity has doubled for children 2 to 5 years of age, almost tripled for youth 6 to 19 year of age, and has disproportionately affected minorities.[1–3] Given the high prevalence of obesity across ages and ethnicities, children and adolescents with diabetes have also been affected,[4,5] particularly with an increase in the prevalence of pediatric type 2 diabetes.[6–11]

It is now apparent that genetic predisposition, sedentary lifestyles, and high caloric food intake alone do not account for the explosive increase in obesity observed over the last three decades. Current data (Fig. 1]) show proportions of obesity as high as 39% among low-income children 2 to 5 years of age enrolled in federally funded health programs, suggesting that obesity in U.S. children begins in early life.[12] Obese children have elevated levels of inflammatory biomarkers as early as 3 years of age that have been linked to heart disease manifested later in life.[13] Relative insulin resistance, an early pathogenic event in the development of type 2 diabetes, is notable in the newborn macrosomic or large for gestational age (LGA) neonate suggesting that abnormalities of metabolism may occur before birth.[14]

Figure 1.

Prevalence of overweight and obesity among low-income U.S. children 2 to 5 years of age who are enrolled in federally funded health programs. Overweight is defined as a body mass index (BMI, defined as the weight in kilograms divided by the square of height in meters) at the 85th to <95th percentile for age. Obesity is defined as a BMI ≥95th percentile. Data are from the Centers for Disease Control and Prevention (CDC) 2008 Pediatric and Pregnancy Nutrition Surveillance Systems (program-based surveillance systems that monitor the nutritional status of low-income infants, children, and women in federally funded maternal and child health programs). Data are based on BMI percentiles for children ≥2 years of age from CDC growth charts from 2000. The Ohio data are from the Ohio Department of Health's Women, Infants, and Children division; the prevalence according to the Ohio Department of Health's Bureau of Child and Family Health Services is higher (33.1%).[12]

Metabolic programming, as evidenced in epidemiological studies, appears to be a critical factor contributing to the etiology of obesity as well as concurrent increase in related chronic diseases (e.g., type 2 diabetes and cardiovascular disease). Metabolic programming is the phenomenon whereby a nutritional stress/stimulus applied during critical periods of early development permanently alters an organism's physiology and metabolism, the consequences of which are often observed much later in life. The idea of metabolic programming originated from the fetal origins hypothesis proposed by Barker in which he suggested that disproportionate size at birth of the newborn due to an adverse intrauterine environment correlated well with an increased risk of adult-onset ill health outcomes (type 2 diabetes, hypertension, and cardiovascular disease).[15] The fetal origins hypothesis, proposed by Barker, suggests that adequate nutrition during fetal development is critical. These findings have been replicated in similar studies performed in numerous countries and thus are not thought to be the result of confounding variables or peculiar to the initial population studied by Barker. Although the initial fetal origins hypothesis experiments dealt primarily with undernutrition and malnutrition, recent epidemiological and animal studies have begun to examine the effects of overnutrition during crucial periods of fetal development and the offspring's subsequent risk of developing the same chronic diseases associated with fetal growth restriction. These studies originated in response to the strong associations noted between large birthweights >90th centile for gestational age (i.e., LGA and the development of diabetes in the offspring of Pima Indians). Notably, this macrosomia was largely explained by a high incidence of gestational diabetes in this population.[16,17] The Helsinki Birth Cohort Study suggests there may be two separate patterns of growth leading to type 2 diabetes: one among children with below-average birthweights and minimal weight gain during infancy who developed obesity in later childhood and another among children with above-average birthweights who developed obesity in earlier childhood.[18]

The incidence and prevalence of diabetes are now being examined within the context of the fetal origins theory. A collective U-shaped risk curve involving term and near-term neonates born at the extremes of the birthweight spectrum has evolved from the contributions of extensive epidemiological studies of adults with type 2 diabetes over the past 20 years.[19–21] Therefore, birthweight has become a surrogate for summing the perinatal interaction between environmental and genetic influences during development. In addition to noted influences during the perinatal period, a strong relationship between later cardiovascular disease and slow weight gain during infancy has evolved suggesting that nutrition during the first year of life also influences metabolic programming independent of birthweight.[22] Furthermore, human and animal studies have demonstrated that mere macrobiotic differences in the quality of the diet involving changes in protein, carbohydrate, and fat during pregnancy and in early life correlate with the subsequent development of chronic disease in the offspring. Thus the existence of macrobiotic overnutrition in addition to caloric overnutrition has evolved as factors that might influence imprinting.[23] Prepregnancy obesity may also act as a factor influencing metabolic imprinting of the offspring's risk for later disease development, demonstrating that preconceptional factors as well as perinatal and postnatal factors may contribute to alterations in developmental programming.[24]

In the United States, overnutrition is generally agreed to be the pivotal environmental factor contributing to the rapidly increasing cases of maternal obesity, and therefore it is considered to be a primary contributor to noted trends of increased gestational diabetes and macrosomia.[25] Recent changes in Institute of Medicine (IOM) maternal weight gain guidelines reflect these observations and new concerns with perinatal maternal obesity and overnutrition.[26] Evidence for the effects of maternal obesity and overnutrition on metabolic programming is reviewed during critical prenatal, perinatal, and postnatal periods. The evidence is presented in the order of the history of discoveries beginning first with the original patterns noted during the perinatal period followed by important discoveries during the postnatal period and concluding with recent evidence regarding the prenatal or preconceptual period.

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