The Developmental Origins of Health and Disease: Another Legacy From Your Grandmother

"No progress without paradox."—Niels Bohr "… but Alice had got so much into the way of expecting nothing but out-of-the way things to happen, that it seemed quite dull and stupid for life to go on in the common way."—Lewis Carroll, Alice in Wonderland The fetal origins of adult disease theory brings new meaning to the word "environment." In this paradigm, more recently named the developmental origins of health and disease (DOHaD) theory, environmental influences occur from preconception to adulthood and transcend generations to alter our risk of metabolic disease in adult life (1.Gluckman P.D. Cutfield W. Hofman P. et al.The fetal, neonatal and infant environments—the long term consequences for disease risk.Early Hum Dev. 2005; 81: 51-59Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 2.Kuzawa C.W. Fetal origins of developmental plasticity: Are fetal clues reliable predictors of future nutritional environments?.Am J Hum Biol. 2005; 17: 5-21Crossref PubMed Scopus (292) Google Scholar, 3.Adair L.S. Prentice A.M. A critical evaluation of the fetal origins hypothesis and its implications for developing countries.J Nutri. 2004; 134: 191-193PubMed Scopus (48) Google Scholar). In other words, the intrauterine environment that your grandmother provided for your mother could affect your risk of type 2 diabetes and cardiovascular disease (CVD). One of the earliest observations of this phenomenon was described in an ongoing study of the long-term health outcomes of the children born in Amsterdam from 1943 to 1947, during World War II. Individuals whose mothers were subjected to harsh, Nazi-imposed rations for 5 months during the winter of 1945 before, during or after pregnancy became the Dutch Famine Birth Cohort (4.Painter R.C. Roseboom T.J. Bleker O.P. Prenatal exposure to the Dutch famine and disease in later life: An overview.Reprod Toxicol. 2005; 20: 345-352Crossref PubMed Scopus (556) Google Scholar). They provide a unique cohort to study the effects of extreme starvation at different times during pregnancy on health of offspring in adult life. The starvation occurred preconception, early gestation, mid-gestation, late gestation and after birth. Those individuals who were exposed to maternal starvation in early gestation had higher rates of obesity, coronary heart disease, and lipid and clotting abnormalities; those exposed in late gestation had higher rates of type 2 diabetes. This birth cohort illustrates the enormous complexity of interpreting associations between birth weight and long-term outcomes (5.Painter R.C. Roseboom T.J. Bossuyt P.M. et al.Adult mortality at age 57 after prenatal exposure to the Dutch Famine.Eur J Epidimiol. 2005; 20: 673-676Crossref PubMed Scopus (80) ). Further evidence from other birth cohorts showed a similar, inverse relationship between birth weight and adult obesity, type 2 diabetes and CVD in adult life. The hypothesis developed by Barker and colleagues suggests that undernu- trition at critical times during fetal life induces permanent adaptive metabolic programming that is compatible only with lifelong undernutrition. When this individual with the "thrifty phenotype" is exposed to nutritional excess, a mismatch occurs, resulting in disease states. Barker and colleagues proposed that altered development in response to intrauterine compromise was a more important risk factor than unhealthy adult behavioural patterns in predicting adult CVD and type 2 diabetes. The Barker theory has been challenged, because birth weight is the result of a complex set of fetal and maternal factors, including uterine size, placental sufficiency, maternal health, maternal nutrition, drugs, gestational age, fetal anomalies and the mechanistic evidence underlying these relationships has been lacking. More recently, however, the DOHaD hypothesis has matured to encompass a complex set of epigenetic phenomena: information that is passed to offspring without changing DNA. Undernutrition at one or more critical periods of development along the life spectrum from preconception, periconception, early gestation, late gestation, early infancy, childhood to adolescence, can have permanent effects on how the organism and its progeny respond to the environment. "Developmental plasticity" may be thought of as the ability of a genotype to produce ≥1 phenotype in response to different environmental conditions and that these permanent adaptations can be passed on through generations. This plasticity is influenced by genotype that will result in different effects on the future health of specific populations. The DOHaD theory has significant implications for early infant feeding practices, since one of the critical periods of exposure to nutritional excess appears to be the first weeks of life. There has been unbridled enthusiasm to optimize the nutrition of babies with intrauterine growth retardation (IUGR) in neonatal units over the past 20 years. If rapid weight gain in the first week of life in an IUGR baby is associated with future obesity and type 2 diabetes, this aggressive nutritional approach may, paradoxically, be detrimental. Another unique population that may be affected by the DOHaD theory is the progeny conceived by in vitro fertilization, in which the peri- conception environment is altered dramatically. The infant of a mother with diabetes is exposed to a unique abnormal metabolic environment. One of the seminal observations was the increased rate of obesity and type 2 diabetes in adolescent offspring of Pima Indian mothers with gestational diabetes mellitus. At the time, it was thought that the adolescent obesity was more likely related to long-term effects of fetal macrosomia or the postnatal nutritional environment, rather than directly related to the maternal diabetes. Most of the early literature from 1970 to 1990 regarding the effect of maternal diabetes on offspring focussed on perinatal morbidity of infants of mothers with type 1 diabetes. Long-term sequelae of birth asphyxia and hypoglycemia were a major concern. Permanent metabolic programming by the intrauterine environment was a novel concept. Much of the evidence on long-term metabolic outcome of the offspring is limited by a lack of recognition of the unique characteristics of maternal obesity, gestational diabetes, prepregnancy type 1 diabetes and, in the past decade, prepregnancy maternal type 2 diabetes. The mechanisms for DOHaD are controversial and include reduced number of islet cells, impaired insulin secretion, altered insulin sensitivity and gene imprinting. The first studies in fetal programming were related to obesity, type 2 diabetes and CVD. Evidence is increasing about the impact of fetal programming on other systems, including cancer, osteoporosis, mental health and neurodegenerative disorders. Knowledge translation of the DOHaD theory in the development of healthy public policy involves reducing maternal obesity and promoting breastfeeding as the keys to reducing the burden of CVD and type 2 diabetes in the developed and developing world. The DOHaD paradox is that intervention during pregnancy is probably too late for the current offspring but may have an impact on the grandchildren. The International Society for DOHaD was formed 5 years ago by scientists eager to encourage collaboration. The first 2 congresses on Fetal Origins of Adult Disease were held in Mumbai, India (2001), and Brighton, United Kingdom (2003). The third congress was held in Toronto in November 2005. This meeting had an emphasis on the implications of DOHaD for developing countries. There were 4 main themes: exposures, outcomes, mechanisms and interventions. Other new themes addressed at the congress were evolutionary biology, developmental plasticity, influences of social hierarchies, effects of prematurity and populations in transition. A remarkable feature of the DOHaD congress was the lack of industry presence. Most of the sponsors were academic research organizations, including the Canadian Institutes of Health Research and the National Institutes of Health. There were no company-sponsored satellite symposia and no free gifts or meals, save for a luncheon served during the annual business meeting, which was covered by the registration. But that is a subject for a future editorial.

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