Markers of Fetal Onset Adult Diseases

R E V I E W A R T I C L E Markers of Fetal Onset Adult Diseases LATHA N AIR, MKC NAIR AND DS CHACKO From Child Development Centre, Medical College, Thiruvananthapuram 695 011, Kerala, India. Correspondence to: Dr MKC Nair, Professor of Pediatrics and Clinical Epidemiology and, Director, Child Development Centre, Medical College, Thiruvananthapuram 695 011, Kerala. India. E-mail: [email protected] The “fetal origins hypothesis”, proposes that non- gene hypothesis is that certain populations may have communicable diseases including coronary heart disease, genes that determine increased fat storage, which in times type 2 diabetes and hypertension originate through the of famine represent a survival advantage, but in a modern responses of a fetus to undernutrition, that permanently environment result in obesity and type 2 diabetes. The change the structure and function of the body. fetal origins theory is of greatest relevance to the Associations between low birthweight and disease in later developing world and the implications of this work for life have been widely studied in Europe and the USA. global health are enormous. To reduce chronic diseases, Studies in southern India have shown that babies who are we need to understand how the human fetus is nourished short and fat tend to become insulin deficient and have and how malnutrition changes its physiology and high rates of non-insulin dependent diabetes. These metabolism, so that interventions be implemented to limit findings have important public health implications as it the damage. The challenge for the next decade must be to suggests that associations with body size at birth discover the cellular and molecular mechanisms giving underestimate the contribution of intrauterine develop- rise to these associations. If this aim is accomplished, it ment to later disease, and also, that while the primary might be possible to devise strategies to reduce the impact prevention of coronary heart disease and non-insulin of these disabling chronic and expensive diseases. dependent diabetes may ultimately depend on changing the body composition and diets of young women. Keywords: Barker hypothesis, Fetal origins hypothesis, Therefore, more immediate benefit may come from Non-communicable diseases, Thrifty gene preventing imbalances between prenatal and postnatal hypothesis. growth among children. The basic premise of the thrifty he core of the theory of fetal origins of hypothesis was developed by linking records of disease is that nutritional deprivation of births in the early 20th century with health in later the fetus during critical periods of life from the Hertfordshire records(1-10). development forces the baby to resort to T adaptive survival strategies, which entail a resetting Associations between low birthweight and later of the normal course of metabolic, physiological, and disease have been widely replicated in studies in anatomical development(1). These adaptations Europe and the USA(11-13). The association between become maladaptive if the organism encounters low birth weight and coronary artery disease has been contrasting nutritional circumstances in later life. It confirmed in studies of men in Sweden(11), Helsinki, has also become clear that maternal constraint must Finland, and South Wales(14), and among 80 000 have a central role in fetal programming. Under such women in the American nurses study(12). The fetal circumstances, maternal uterine constraint becomes origins theory is of greatest relevance to the a dominant regulator of fetal growth. The proponent developing world, and the implications of this work of “fetal origins hypothesis” is a British for global health are enormous(15). Studies in epidemiologist David Barker. The fetal origin, southern India have shown that babies who are short INDIAN PEDIATRICS S48 VOLUME 46, SUPPLEMENT, JANUARY 2009 NAIR, et al. FETAL ONSET ADULT DISEASES and fat tend to become insulin deficient and have of young women, more immediate benefit may come high rates of non-insulin dependent diabetes(16). from preventing imbalances between prenatal and These findings were similar to those seen in Pima postnatal growth among children. Many chronic Indians and also with observations in Sheffield that disorders that manifest later in life may be related to showed an association between abdominal two seemingly opposing factors potentially present circumference at birth and death from coronary heart early in life; (i) poverty (i.e, malnourished mothers disease(17). Shortness and fatness are thought to be give birth to malnourished infants with low birth the result of maternal hyperglycaemia, with weight [LBW]), and (ii) prosperity (exposure of an consequent imbalance in the supply of glucose and infant with LBW phenotype to a high caloric diet). other nutrients to the fetus. Studies in Preston These factors contribute to the biological showed that babies whose placentas are phenomenon of developmental plasticity, or the disproportionately large in relation to their own ability of a genotype to produce multiple forms and weight tend to have raised blood pressure (18). behaviors in response to environmental conditioning(19). The Fetal origin hypothesis is These findings have important public health summarized in Fig.1(19). implications, as it suggests that associations with body size at birth underestimate the contribution of Four birth phenotypes associated with later intrauterine development to later disease. While the disease have been identified; (a) babies who are thin primary prevention of coronary heart disease and at birth; (b) babies who are short at birth; (c) babies non-insulin dependent diabetes may ultimately short and fat at birth, and (d) babies born with a large depend on changing the body composition and diets placenta(19). Babies that are thin tend to be insulin Maternal malnutrition Leads to fetal malnutrition Leads to the following Other organs Disease of Insulin Abnormal vascular malfunction (liver) beta cell mass resistance development Hyperlipdemia Diabetes Hypertension These three constitute THE INSULIN RESISTANCE SYNDROME FIG. 1 Fetal origins hypothesis. INDIAN PEDIATRICS S49 VOLUME 46, SUPPLEMENT, JANUARY 2009 NAIR, et al. FETAL ONSET ADULT DISEASES resistant as children and adults, and are therefore described this phenomenon as the “thrifty liable to develop the insulin resistance phenotype”(29-31). The basic premise of the thrifty syndrome(20). It could be that the thin baby has gene hypothesis is that certain populations may have adapted to under-nutrition through endocrine and genes that determine increased fat storage, which in metabolic changes. Babies that are short in relation times of famine represent a survival advantage, but to their head circumference, and babies that have a in a modern environment, result in obesity and type- reduced abdominal circumference, tend to have 2 diabetes(32,33). Intrauterine growth retardation persisting abnormalities of liver function, including (IUGR) or clinically abnormal thinness at birth raised serum LDL cholesterol and plasma fibrinogen strongly predicts the subsequent occurrence of concentrations(21,22). Babies that have a small hypertension, hyperlipidemia, insulin resistance, abdominal circumference in relation to their head type 2 diabetes and ischemic heart disease. circumference can result from “brain sparing” circulatory adaptations by which cardiac output is The concept of fetal programming during diverted to the brain at the expense of the trunk(23). development has been proposed to explain these findings. Fetal undernutrition, during middle THE THRIFTY GENOTYPE AND THE THRIFTY gestation in particular, raises the risk of later disease PHENOTYPE by the programming of blood pressure, cholesterol metabolism, blood coagulation and hormonal The prospective studies by Yajnik, et al.(24) in Pune settings(1). One third of Indian babies have a low in India are therefore notable and deserve attention. birthweight, on average they weigh around 2.7kg. Caroline Fall from David Barker’s Medical This makes them highly susceptible to conditions Research Council group in Southampton along with mentioned earlier when they are older. The thinness Yajnik and his team have used anthropometric of Indian babies is due to poor muscle mass and measurements of babies to describe their small abdominal viscera and is due to the “thrifty morphology at birth(25). According to Yajnik, phenotype” of Indian babies, which enhanced maternal uterine constraint becomes a dominant survival in subsistence conditions in the past, but regulator of fetal growth in order to protect the becomes detrimental in a modern context of plentiful mother from having to deliver an inappropriately food and reduced physical activity(34). Yajnik also large baby. In rural villages mothers average about showed that in the babies of urban mothers in Pune, 44 kg in mid-gestation, with a height of 152 cm and insulin concentrations in the blood of the cord seem body mass index of 18 kg/m2(25). This leads to fetal raised compared with British babies and were malnutrition, which may be a major component in correlated with subscapular skin-fold thickness(35). the susceptibility to coronary heart disease and non- Indian babies are much smaller than those in insulin-dependent diabetes. Southampton in all respects except measures of body fat-especially central fat as judged by the In the words of J V Neel, the initial proponent of subscapular skin-fold thickness. They describe this the thrifty genotype hypothesis, the

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