1. Fetal Origins of Disease Hypothesis Grace M. Egeland, Ph.D. University of Bergen

2. Lecture Objectives This lecture provides a basic review of the Fetal Origins of Disease Hypothesis and the status of the current literature.

3. “What exactly is the fetal origins of disease hypothesis ? “

4. Prevalence of non-insulin dependent diabetes and impaired glucose tolerance in men by their birth weight (N=370) Fetal and infant growth and impaired glucose tolerance at age 64. Birth weight ( lbs. ) < 5.5 > 9.5 Hales CN, et al. BMJ 1991;303:1019-22.

5. Effects of birth weight and adult weight on the metabolic syndrome in women. Birth weight Adult BMI Yarbrough DE, et al. Diabetes Care 1998; 21:1652-1658.

6. Childhood and Adolescents Studies among children, and adolescents have shown a similar direction in their results, ….BUT….. overall the evidence is not as consistent or as strong as studies among middle-aged and older adults;

7. Birth weight and systolic blood pressure among children Law CM, et al. IJE 2000;29:52-59.

8. Pregnancy Certain pregnancy-related complications predict future chronic disease occurrence; Pregnancy is a stress test for conditions considered to be precursors to NIDDM, CVD, and the adult insulin resistance syndrome.

9. Prevalence rate and adjusted odds ratios for gestational diabetes by women’s own birth weight B. Weight OR (95% CI) < 2,500g 1.8 (1.1 -3.0) 2,500 - 2,999 1.6 (1.1 -2.3) 3,000 - 3,499 1.4 (1.0 -2.0) 3,500 -3,999 1.1 (0.8 -1.5) 4,000 -4,500 1.0 > 4,500g 1.4 (0.7 - 2.8) Rate per 1,000 women Birth weight group Egeland GM, et al. BMJ 2000; 321:546-547.

10. “What about prematurity? May be its just babies born too early and not necessarily intrauterine growth retardation ? ”

11. Prevalence rate and adjusted odds ratios for gestational diabetes by women’s gestational age Gestational Age OR (95%CI) < 34 weeks 1.6 (0.8 -3.3) 35-36 0.9 (0.5 -1.7) 37-39 1.0 (0.8 -1.2) 40 (referent) 1.0 41-42 1.1 (0.9 - 1.4) 43-44 1.1 (0.7 - 1.7) Egeland GM, et al. BMJ 2000; 321:546-547. * *

12. Odds ratios for preeclampsia by women’s own gestational age and birth weight Birth weight (lbs.) Gestational age (weeks) < 3443-46< 4.5>8.5 Innes KE, et al. Epidemiol 1999;10:153-160.

13. Any questions so far?

14. “Earlier you said the fetal origins of disease hypothesis states that nutrition plays a role in fetal programming … ….what evidence supports this ?”

15. Animal Studies BIRTH Reduced size of offspring at birth. ADULTHOOD Elevated blood pressure and glucose intolerance in offspring in adulthood. Reduced Protein in Diet of Pregnant Rats Dahri S, et al. Diabetes 1991;40:115-20. Langley SC, et. al. Clin Sci 1994;86:217-22.

16. Observations among humans Dutch Hunger Winter -- some evidence; Siege of Leningrad -- no evidence; Nutrition epidemiologic studies --mixed evidence.

17. “What is the role of socioeconomic status in contributing to the associations observed in all of these studies? Do we have a confounder here? ”

18. The role of socioeconomic status Sub-optimal nutrition smoking obesity Physical activity Other factors Covariates of socioeconomic status Adulthood Chronic Diseases Intrauterine growth restriction Prenatal care

19. Crude and SES adjusted rate ratios for mortality from ischaemic heart disease by birth weight: Cohort from Uppsala, Sweden. Birth weight (kg) Leon DA, et al. BMJ 1998;317:241-5. *adjusted for SES-related factors

20. “How important is birth weight relative to other risk factors ?”

21. “Could there be an alternative hypothesis to that of the fetal programming of adult diseases that could explain the associations observed ?

22. Low Birth Weight Infants Adulthood Insulin Resistance Genetic Influences Alternative Hypothesis: Genetic Influences Hattersley AT, Tooke JE. Lancet 1999;353:1789-92.

23. Fetal Insulin Hypothesis Maternal glucose concentrations Glucose sensing by fetal pancreas Insulin secretion by fetal pancreas Insulin-mediated growth Infant’s birth weight Fetal genetically determined responses

24. Integrating hypotheses Fetal programming genetics Prenatal Nutrition and other factors Adulthood nutrition and other risk factors Adult Chronic Diseases

25. Summary Consistent evidence among adults that markers of fetal growth are inversely associated with the later development of CVD, NIDDM, and IRS; Good evidence of nutritional fetal programming from animal studies; Good evidence of an interaction between birth weight and adult measures of obesity; and

26. Summary SES is not likely to explain the associations observed; Determining the optimal maternal diet is difficult in epidemiologic studies; Fetal insulin hypothesis also has merit.

27. Recommendations Research should explore ways to integrate the fetal programming hypothesis with that of the genetic fetal insulin hypothesis;

28. Recommendations Publications should provide information in a more meaningful public health framework, such as –the % variation in disease associated with the exposure (r 2 ), or –the population attributable fraction.

29. Recommendations Further evaluation of potential effect modifiers, such as breastfeeding, is important, particularly in terms of identifying prevention strategies; Maternal nutrition campaigns and universal prenatal health care should be promoted world-wide.