The fetal origins of adult disease: no longer just a hypothesis and may be critically important in south Asia

British Medical Journal, Feb 17, 2001 by Roger Robinson

No longer just a hypothesis and may be critically important in south Asia
David Barker pioneered the idea that the 20th century epidemic of coronary heart disease in Western countries might have originated in fetal life.[1] Paradoxically, the epidemic coincided with improved standards of living and nutrition, yet in Britain its greatest impact was in the most deprived areas. Barker observed that early in the 20th century these areas had the highest rates of neonatal mortality and by inference the highest rates of low birth weight. He postulated that impaired fetal growth might have predisposed the survivors to heart disease in later life. The first world congress on the fetal origins of adult disease in Mumbai earlier this month provided an opportunity to assess the state of the hypothesis and consider its implications for future research and policy.

Barker's group originally examined cardiovascular mortality in men born in Hertfordshire, England, in the early decades of the century, on whom good records had been kept of size at birth and growth in infancy. Deaths from ischaemic heart disease were indeed commoner in men who had been small at birth and at 1 year. This kind of retrospective cohort study depends on anthropometric measurements in infancy having been preserved. At least seven such studies have shown that lower birth weight is associated with higher risks of later ischaemic heart disease and diabetes or impaired glucose tolerance. These and many other studies have shown that lower birth weight is associated with higher blood pressure in childhood and adult life (C Martyn(*)). However this effect is relatively small--2-3 mm Hg higher blood pressure for 1000 g less of birth weight. Neither the higher blood pressure nor other recognised risk factors account for the association of low birth weight with heart disease.

The evidence for the association of adverse adult outcomes with lower birth weight is strongest for blood pressure and impaired glucose tolerance (D Leon). Those outcomes can be measured earlier in life, and more data are available, including some prospective studies. Though fewer studies link heart disease to low birth weight, and some are confined to men, the evidence looks convincing. Barker's original hypothesis is confirmed. The few studies on stroke suggest the same association, particularly for haemorrhagic stroke (D Leon, J Rich-Edwards).
The effects of impaired fetal growth are modified by subsequent growth: the highest risks of heart disease and of type 2 diabetes, the insulin resistance syndrome, or impaired glucose tolerance (collectively referred to below as impaired glucose tolerance) are in those who were small at birth but became overweight adults. This led to the second part of the hypothesis proposed by Barker and Hales: the idea of the "thrifty phenotype."[2] As an adaptation to undernutrition in fetal life permanent metabolic and endocrine changes occur which would be beneficial if nutrition remained scarce alter birth. If nutrition becomes plentiful, however, these changes predispose to obesity and impaired glucose tolerance,

The congress heard a wide range of research that these hypotheses have stimulated. The patterns of prenatal and postnatal growth that predispose to the two major disease outcomes--ischaemic heart disease and impaired glucose tolerance--are complex (D J P Barker; J Eriksson and C Osmond). In general the most unfavourable growth pattern is smallness and thinness at birth, continued slow growth in early childhood, then acceleration of growth so that height and weight approach the population means. A continuing rise in body mass index above the mean is associated with impaired glucose tolerance. However, the patterns differ by sex and also by ponderal index (a rough measure of fatness) at birth. Whether or not the thrifty phenotype is the mechanism, low birth weight and high body mass index undoubtedly interact: their effects on blood pressure and impaired glucose tolerance are multiplicative (D Leon). Birth weight and ponderal index (as well as body mass index) are crude measures of how fatal nutrition has affected body composition and of the balance between lean body mass and fat, so the true size of the effect of fetal growth on later disease is hard to measure.
The hypothesis predicts that more heart disease and impaired glucose tolerance will be seen in a population that is undergoing transition from sparse to better nutrition. Holding the conference in Mumbai was therefore appropriate: the incidences of type 2 diabetes and ischaemic heart disease are rising rapidly in India, coinciding with increasing urbanisation and obesity. Indian babies are exceptionally small, with a mean birth weight of only 2700 g, and 30% have a birth weight of 2650 g or less (C S Yajnik). Their mothers are short and underweight, with a mean body mass index of only 18.

Furthermore, Yajnik's group in Pune find that these small babies have a low muscle mass, small viscera, and a relative excess of fat (C S Yajnik et al)--a body composition particularly likely to lead to insulin resistance. A cohort study by Yajnik's group showed that lower birth weight and higher body mass index in childhood are associated with impaired glucose tolerance in these children (A Bavdekar et al). The fetal origins hypothesis predicts high rates of type 2 diabetes for them later in life. The prevalence of diabetes in India is likely to go on increasing and to constitute a major health burden.

Can fetal growth be improved in pregnancies at risk for fetal growth retardation? Improving the mother's growth and nutrition before pregnancy is the ideal strategy, but animal studies show that more than one generation of improved maternal nutrition may be needed to optimise fetal growth. Later marriage and childbearing would allow Indian mothers to start pregnancy better grown (W P T James and J M Wallace). Only limited evidence exists that nutritional supplements in pregnancy improve fetal growth in undernourished mothers (AM Prentice). Furthermore, the effects of supplements vary according to the stage of pregnancy: giving them early in pregnancy may even worsen fetal growth.

The thrifty phenotype is a paradigm that has stimulated animal as well as human research on fetal growth retardation; its neuroendocrine and metabolic effects; and the possible mechanism by which metabolism, body composition, and growth may be permanently affected. It was widely if not universally accepted by the congress as a model to explain the link between fetal growth retardation and later diseases. Of the existence of that link there is no doubt, and in the 21st century it may matter most in the Indian subcontinent.
Roger Robinson associate editor, BMJ

The BMJ provided financial support to the congress. RR wrote an introductory chapter to Fetal and infant origins o[ adult disease.[1]

(*) Papers presented at the congress are indicated here by their authors' names in parentheses. Abstracts will be published in a supplement to Pediatric Research, July 2001.

[1] Barker DJP, ed. Fetal and infant origins of adult disease. London: BMJ Books, 1992.
[2] Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992;35:595-601,

Roger Robinson "The fetal origins of adult disease: no longer just a hypothesis and may be critically important in south Asia". British Medical Journal. FindArticles.com. 07 Apr, 2010.

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Type 2 diabetes in children: exemplifies the growing problem of chronic diseases

British Medical Journal, Feb 17, 2001 by Anne Fagot-Campagna, K M Venkat Narayan

Exemplifies the growing problem of chronic diseases
Type 2 diabetes mellitus in children is an emotionally charged issue and an emerging public health problem.[1 2] Until recently most children with diabetes mellitus had type 1, one of the most common[3] and increasingly prevalent[4] chronic diseases in children. Increasingly, however, type 2 diabetes is being reported in children from the United States, Canada, Japan, Hong Kong, Australia, New Zealand, Libya, and Bangladesh.[5]

The prevalence of type 2 diabetes in children ranges from 4.1 per 1000 12-19 year olds in the US to 50.9 per 1000 15-19 year old Pima Indians of Arizona.[1 2] Between 8% and 45% of recently diagnosed cases of diabetes among children and adolescents in the United States is type 2, and the magnitude of this disease may be underestimated.[1 2] The prevalence of the disease is on the rise in North America, and its incidence almost doubled in Japan between 1976-80 and 1991-5--from 7.3 to 13.9 per 100 000 junior high school children.[5] These trends coincide with the rising prevalence of overweight and physical inactivity world wide.[5 6-8]

Among US children the mean age at diagnosis of type 2 diabetes is between 12 and 14 years, corresponding with puberty; the disease affects gifts more than boys, predominantly people of non-European origin, and is associated with obesity, physical inactivity, a family history of type 2 diabetes, exposure to diabetes in utero, and signs of insulin resistance.[1 2] At diagnosis the affected child may present with weight loss, ketosis, and acidosis.[1 2] Insulin and C peptide levels are often raised and antibodies absent, which may help differentiate type 1 from type 2 diabetes, but insulin secretion may well be blunted at diagnosis.[1] Haemoglobin [A.sub.1c] levels may range from 10% to 13%, and a sizeable proportion of patients have hypertension, hypertriglyceridemia, albuminuria, sleep apnoea, and depression,[2] and these factors may worsen over time.[9] However, treatment protocols vary considerably, and several of the drugs used for glycaemic, blood pressure, and lipid control are not approved for use in children.[1 2]

To respond to this emerging problem, the American Diabetes Association and the American Academy of Pediatrics issued a joint consensus statement, and the Committee for Native American Child Health is developing treatment guidelines based on expert opinion. The National Institutes of Health and the Centers for Disease Control and Prevention have each embarked on new research programmes to improve gaps in our knowledge. So, what do we need to know and do?

Firstly, we need to develop case definition(s) that will differentiate between types of diabetes in children, and will be suitable for estimating the magnitude of the disease in populations[2] and for clinical diagnosis.[1] Case definitions for public health surveillance and clinical purposes should involve simple low cost tests, an issue of importance to poor countries and communities.

Secondly, epidemiological data on the magnitude of the problem, its secular trends, and follow up of incident cases are needed for several at risk populations.[1 2] Limited data are available in selected populations such as the American Indians, but few data exist for several parts of the world where the disease is prevalent.

Thirdly, adult studies have shown efficacious interventions for type 2 diabetes, but their safety and efficacy in children is not known. Also needed are well coordinated, multicentre trials testing the feasibility of multiple risk factor reduction in children and its benefits for practical health outcomes, such as the early stages of vascular disease,

Fourthly, despite efficacious treatments, the quality of care for adults with type 2 diabetes remains suboptimal.[10] This situation is likely to be worse for children and adolescents[1 2] because this is a new problem for clinicians; adolescents may be particularly reluctant to make behavioural changes, manage their disease, and accept follow up; and access to health care may be inadequate. Carefully conducted studies of quality of care and of potential interventions among children are needed.

Finally, type 2 diabetes in children offers some unique opportunities to understand the causes of the disease and of insulin resistance[1 2] and to plan primary prevention. Early onset of diabetes may be due largely to genetic factors, which would mean that identification of genetic mechanisms might be profitably pursued in children. On the other hand, all societies worldwide are undergoing changes that are leading to major behavioural and environmental modifications. Among adults type 2 diabetes is highly related to behavioural and environmental factors[11]; the effect of these factors on children needs to be understood.

The emergence of the disease in young people embodies the growing problem of chronic diseases worldwide and their extension to youth. The rising prevalence of obesity and type 2 diabetes in children is also the unforeseen consequence of worldwide industrialisation. To fight type 2 diabetes as a paediatric disease will require use of recent medical advances but will also require understanding and questioning the unwanted changes from industrialisation. Gaps still exist in our knowledge of disease classification, magnitude and trends, causes, treatment efficacy and safety, quality of care, and behavioural and environmental factors. Thus, we need worldwide cooperation and collaboration to develop studies in each of these areas using standardised protocols. In the meantime primary care workers should watch out for type 2 diabetes in children.

Anne Fagot-Campagna medical epidemiologist K M Venkat Narayan chief, diabetes epidemiology section (kav4@cdc.gov)

Giuseppina Imperatore medical epidemiologist Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Mailstop K-68, Atlanta, GA 30341, USA

[1] American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381-9.

[2] Fagot-Campagna A, Pettitt DJ, Engelgau MM, Rios Burrows N, Geiss LS, Valdez R, et al. Type 2 diabetes among North American children and adolescents: an epidemiological review and a public health perspective. J Pediatr 2000;136:664-72.

[3] LaPorte RE, Matsushima M, Chang YE Prevalence and incidence of insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiher GE, Bennett PH, eds. Diabetes in America. 2nd ed. Washington, DC: National Institutes of Health, NIDDK, 1995:37-46.

[4] Onkamo P, Vaananen S, Karnoven M, Tuomilehto J. Worldwide increase in incidence of type 1 diabetes: the analysis of the data on published incidence trends. Diabetologia 1999:42:1395-403.

[5] Fagot-Campagna A. Emergence of type 2 diabetes mellitus in children: the epidemiological evidence. J Pediatr Endocrinol Metabol (in press).

[6] Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents. The National Health and Nutrition Examination Surveys, 1963 to 1991. Arch Pediatr Adolesc Med 1995;149:1085-91.

[7] Ingram M. British children are getting fatter and many are dangerously overweight. What can be done? Times 2000;21 Jul.

[8] Bursaux E. Le nombre d'enfants obeses a double au cours des dix dernieres annees. Le Monde 2000;21 Jun.

[9] Fagot-Campagna A, Knowler WC, Pettitt DJ. Type 2 diabetes in Pima Indian children: cardiovascular risk factors at diagnosis and 10 years later. Diabetes 1998;47(suppl 1):A155.

[10] Narayan KMV, Gregg EW, Fagot-Campagna A, Engelgau MM, Vinicor F. Diabetes--A common, serious, costly, and potentially preventable public health problem. Diab Res Clin Pract 2000;50 (suppl 2)::77-84.

[11] Rewers M, Hamman RF. Risk factors for non-insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiher GE, Bennett PH, eds. Diabetes in America. 2nd ed. Washington, DC: National Institutes of Health, NIDDK, 1995:179-220.

Anne Fagot-Campagna "Type 2 diabetes in children: exemplifies the growing problem of chronic diseases". British Medical Journal. FindArticles.com. 07 Apr, 2010. http://findarticles.com/p/articles/mi_m0999/is_7283_322/ai_71350524/