Reversing Fetal Undernutrition by Kick-Starting Early Growth

The relationship between poor maternal nutritional status and enhanced chronic disease risk in the offspring is now abundantly established in both experimental models and in epidemiological data from human populations worldwide. The classic studies of Barker et al (1), demonstrating a relationship between low birth weight (LBW) and increased risk of cardiovascular disease, hypertension, and dyslipidemia, paved the way for extensive research into the influence of the intrauterine environment on development of chronic diseases. In these original studies, men in their sixties who were smallest at birth had a 3-fold higher death rate from ischemic heart failure compared with those with high birth weights (1). Likewise, incidence of type 2 diabetes and glucose intolerance was also significantly higher in men with LBWs (2). To add to an expanding list of ailments, it is now well accepted that the propensity to develop obesity, type 2 diabetes, immunologic dysfunction, insulin resistance and related metabolic diseases is, in part, influenced by the maternal in utero environment (3). The focus of many investigations on LBW and conditions that lead to small babies arises from the fact that environmental factors and nutrient supply play an important role in determining birth weight and alterations in birth weight represent a gross deviation in the fetal experience. Nonetheless, changes in birth weight should not be confused to be a sine quo non in developmental programming, because it is quite evident that longterm alterations in risk occur well below the threshold of alterations in body weight at birth. Over the last decade and half, an explosion of studies using a variety of approaches has shown that developmental programming occurs in the contexts of both maternal undernutrition and overnutrition (3). Although one’s genetic makeup, postnatal diet, and lifestyle factors such as physical activity indisputably are important proximate causes of obesity, the influence of gestational experiences is evident in the Uor J-shaped relationship between birth weight and later obesity risk, suggesting that both extremes of nutritional environments lead to detrimental changes in the offspring. Certainly, this is relevant to the current global epidemic of obesity and ubiquitous consumption of calorically dense diets, high in fat and simple sugars both before and during pregnancy (4, 5). The conceptual framework provided by the developmental origins of health and disease hypothesis posits that unfavorable prenatal and postnatal environments, specifically during sensitive periods in development, lead to permanent alterations in organ structure and function that may confer increased risk towards a variety of chronic diseases (6). As elaborated in the predictive adaptive response hypothesis (7, 8), these adaptive changes, facilitated by the process of developmental plasticity are designed to be beneficial in ensuring short-term survival and preparing for a “predicted” postnatal environment. However, when presented with a highly discrepant postnatal environment, mismatch ensues and these changes may prove disadvantageous or maladaptive, thereby increasing predisposition to disease. Evidence from follow up of individuals affected during the Dutch Hunger Winter famine during the latter part of the Second World War and the Chinese famine (1959–1961) lend strong support to this hypothesis (9, 10). Furthermore, high rates of obesity and diabetes in populations where poor maternal nutrition is historically prevalent in combination with current trends of urbanization, as evidenced in many developing nations, also presents an ongoing natural experiment. Despite