DEVELOPMENTAL (FETAL) ORIGINS OF ADULT DISEASES ( DOHaD )

2. DEVELOPMENTAL (FETAL) ORIGINS OF ADULT DISEASES (DOHaD) MAJID MOHAMMADIZADEH MD ISFAHAN UNIVERSITY OF MEDICAL SCIENCES DEPARTMENT OF PEDIATRICS DIVISION OF NEONATOLOGY

3. Chronic diseases are the greatest public health problem, because of: • direct cost to society and government • disability lasting for years • They include cardiovascular diseases, diabetes, cancer, osteoporosis, obesity, etc.

4. The burden of chronic diseases is rapidly increasing worldwide • Almost half of the total chronic disease deaths are attributable to cardiovascular diseases • Obesity and diabetes are also showing worrying trends

5. CONCEPT OF DOHaD

6. The concept of fetal origins of adult disease popularized by Barker arose from a robust association between small size at birth and the risk of chronic adult diseases, such as coronary artery disease, hypertension, stroke, type 2 diabetes mellitus, and osteoporosis • Example: 1944-1945 Dutch famine

7. These original epidemiologic observations have been extensively replicated by multiple groups in varying populations of different ethnicity employing birthweight as a surrogate for the intrauterine state • The culmination of all these epidemiologic associations is referred to as the "Barker hypothesis"

8. The concept of the "developmental programming" and DOHaD has become well accepted because of the compelling animal studies that have precisely defined the outcomes of specific exposures

9. IUGR has been widely used as a marker of poor fetal nutrition and health, but some antenatal nutritional disturbances can increase the risk of diseases later in life without affecting fetal growth • At the other extreme of weight, an infant of a diabetic mother who is LGA develops obesity and type 2 diabetes during late childhood

10. The health of the child and issues that will determine its appetite and metabolism, intelligence and temperament in life depend on: • the type and amount of nutrients that the baby receives in the womb • pollution, drugs and infections which it is exposed to before and after birth • the mental and physical health of the mother and her levels of stress and mental illness

11. Public health implications of DOHaD

12. DOHaD are now recognized to have major public health implications worldwide • WHO states: "The global burden of death, disability and loss of human capital as a result of impaired fetal development is huge and affects both developed and developing countries"

13. This statement advocates for a broader concept of maternal well-being and achieving an optimal environment for the fetus (and newborn) to maximize the potential for a full and healthy life • This concept has widened to include plasticity during childhood

14. Return to:CONCEPT OF DOHaD

15. Malnutrition during gestation that include macronutrients or micronutrients can potentially set the stage for adult-onset chronic diseases

16. Thrifty phenotype • Adaptive mechanisms combat an adverse nutritional or metabolic intrauterine environment by developing safeguards for the energy supply sometimes at the expense of growth, ensuring a reduced fetal demand • Additional nutritional or metabolic stressors encountered subsequently tip the finely crafted phenotypic balance toward a disease state

17. The conventional belief is that these phenotypic features are expressed mainly in aging adults • Given lifestyle changes toward an increased caloric intake and relative inactivity, some of these features are seen in childhood or during late teenage years

18. The molecular, cellular, metabolic, endocrine and physiological adaptations to intrauterine nutritional conditions result in permanent alterations of cellular proliferation and differentiation of tissues and organ systems, which in turn can manifest by pathological consequences or increased vulnerability to chronic diseases in adulthood

19. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood • In conditions of severe intrauterine deprivation, there is a capacity to lose structural units such as nephrons, cardiomyocytes, or pancreatic beta-cells within developing organ systems • These responses will result in the programming of a reduced functional capacity for life

20. Programmingis defined as a permanent or long term change in the physiology, morphology, or metabolism of a fetus in response to a specific insult or stimulus at a critical period in development • Any programming of an organism or tissue may be regarded as the consequence of an adaptation that is necessary to survive an insult

21. Developmental epigenetics is believed to establish adaptive phenotypes to meet the demands of the later-life environment • Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk

22. Prenatal and postnatal factors contributing to the development of diabetes mellitus

23. Sleep disorders during pregnancy influence the risk of insulin resistance and impaired glucose tolerance

24. A summary of the current mechanisms considered to underlie the developmental origins of adult disease

25. Potential consequences of environment-epigenetic interactions for the health of the next and subsequent generations

26. An overview of the developmental origins of adult health and disease

27. Although fetal growth and birthweight have served as surrogate markers of fetal nutrition and health, these are two distinct processes • Birthweight at both ends of the spectrum is associated with adult chronic diseases, but it is only a presenting feature • The relationship between prenatal nutritional status and metabolic diseases is shaped like a U as the risk increases at both ends of the birth weight curve i.e. in conditions of poor nutrition and excessive dietary intake

28. It is clear that fetuses subjected to nutritional perturbations with no resultant change in size or growth also develop adult chronic diseases • Examples: isolated glucose deficiency, certain essential amino acid deficiencies, and micronutrient deficiencies • On the other hand, growth can suffer in the presence of adequate nutrition because of multifactorial etiologies

29. Form of compromises to the fetus which can set the stage for the subsequent onset of chronic diseases: • Malnutrition • Reduced blood flow • Hypoxia • Other stressors such as drug exposure, toxins, infections, and inflammation which has the propensity of perturbing the fetal hormonal-metabolic milieu

30. Factors that adversely affect the gestational and early postnata l environment • Maternal diseases and their treatments: • Psychiatric neurologic disorders • Diabetes • Asthma • Sleep related breathing disorders • Anemia • Maternal lifestyle and environment: • Maternal behavior, interpersonal stress and psychosocial trauma • Smoking in pregnancy • Home • Environmental pollutions • Maternal nutrition and micronutrients

31. Factors that adversely affect the gestational and early postnata l environment • Perhaps less well appreciated is that some environmental agents like gamma irradiation and thalidomide also can cause functional disorders that persist postnatally and into adult life • This seems to be true also for hormones that when present in non-physiological concentrations during ‘critical periods’ of perinatal life can act as ‘endogenous functional teratogens’ • Example: perinatalhyperinsulinism

32. Many human teratogens elicit their deleterious effects through mechanisms involving the generation of reactive oxygen species and oxidative stress • Since many antioxidant regulation enzymes are not well expressed early in organogenesis, it may explain why embryos, in earlier periods of development, are more susceptible to teratogen-induced dysmorphogenesis and functional teratogenesis

33. The origin of chronic diseases is considered to be related to four relevant factors in fetal life: • Intrauterine growth retardation (IUGR) • Premature delivery of a normal growth for gestational age fetus • Overnutrition in utero • Intergenerational factors

34. POSTNATAL AND EARLY CHILDHOODGROWTH

35. Findings such those during the Leningrad Siege suggest that postnatal manipulation of nutrition may have a protective effect on the trajectory of fetal origins of adult disease • More recent investigations have revealed that in girls and boys, low BW with a slow growth pattern between 0 and 2 years followed by exponential growth between 2 and 8 years led to increased mortality secondary to cardiovascular events, and an increase in glucose intolerance and type 2 diabetes mellitus

36. These findings are of particular interest to neonatology: • There is an ongoing dilemma as to: • what is ideal postnatal growth • whether this growth rate should be the same for infants of varying birthweight ranges and differing presentations

37. SGA infants • Metabolic and endocrine changes in infants who are SGA include: • reduced insulin sensitivity, lipid profile aberrations, metabolic syndrome, premature adrenarche, and polycystic ovarian syndrome

38. SGA infants • Most of the phenotypic changes seem to be due to insulin resistance, although the site of insulin resistance seems to be an imbalance between hepatic insulin resistance and pancreatic ß-islet cell production of insulin • The reduction of insulin sensitivity is magnified with fat mass deposition and a faster "catch-up" growth pattern, which is associated with disease attributable to insulin resistance • This early growth during childhood that is sustained through adolescence predetermines who goes on to develop type 2 diabetes mellitus as an adult

39. Premature infants • Premature infants, particularly those with VLBW, although distinctly different in presentation at birth, tend to mimic infants with IUGR in the final phenotype • This similarity may be related to the nutritional compromise and stressors (that invoke endogenous glucocorticoid surges and intermittent exposure to hypoxia) encountered during the early postnatal phase of life

40. After the early postnatal period when complete oral feedings are established, a significant catch-up growth phenomenon is realized in most infants with increasing caloric provision • Long term follow-up investigations of infants with VLBW reveal a higher systolic blood pressure, central adiposity by 19 years of age, and emergence of premature pubarche in 24% of these children

41. This presentation in infants with VLBW is reminiscent of what was encountered in infants with IUGR who faced an adverse in utero environment • In both cases, the postnatal catch-up growth leads to disease presentations secondary to insulin resistance

42. CATCH- UP GROWTH

43. Definition • It is a normal tendency by the body to compensate after a nutritionally restricted period, showing rapid growth

44. Consequences • Short-term benefits: • Survival • protecting the reproductive capacity

45. Consequences • It tends to favor: • nutrient deposition in white adipose tissue resulting in adiposity, particularly visceral adiposity • a rearrangement of skeletal muscle mitochondria • increased oxidative injury • These changes set the stage for metabolic syndrome, diabetes mellitus, and coronary artery disease as the child matures into an adult • This catch-up growth results in a shortened life span with changes in the telomeric length

46. Consequences For "short-term gain ", catch-up growth results in "long-term pain"

47. Rapid postnatal growth, whether superimposed on LBW or normal birthweight, seems to have a similar effect in producing adult chronic diseases

48. Should postnatal catch-up growth not be fostered? If postnatal nutrition matches intrauterine nutrition,can adult chronic diseases be curbed and result in longevity?

49. The absence of catch-up growth, while resulting in glucose tolerance, lean body composition, and reduced coronary artery disease with longevity, may negatively affect cognition and reproductive capacity • Avoidance of rapid postnatal catch-up growth within a short period may be beneficial if replaced with moderate long-term growth • Postnatal nutrition results in walking a fine line between guarding against "nutritional excess" while ensuring adequate energy for the developing brain

50. LGA infants • In infants who are LGA, postnatal intervention consisting of breast feeding versus bottle feeding led to a decline in obesity during childhood • This intervention represents a "catch-down" mechanism at work