1. Early programming hypothesis Wilfried Karmaus Reproductive Epidemiology EPI 824

2. Assumption A number of chronic diseases in adulthood have their origin before birth. Examples are:Examples are: –

3. Biological basis The basis of these epidemiological observations is proposed to be that of programming: An event operating at a critical or sensitive period results in a long-term changes in the structure or function of the organism.An event operating at a critical or sensitive period results in a long-term changes in the structure or function of the organism. Programming is a well-established biological phenomenon.

4. Time pattern of cause and effects Exposure ---------------------------------------------------  Disease Disease --------------------  Immediate effect Delayed effect  latency period

5. Time pattern of early programming Exposure in utero Marker of exposure: birth characteristics Immediate effect Delayed effect  latency period Disease --------------------  Epidemiological studies. Early childhood marker

6. Since programming involves a critical time window in early life, this phenomenon is proposed to lead both to changes in –Birth characteristics (marker of exposure) and –Altered homeostatic mechanism such as blood regulation, insulin sensitivity etc. (marker of disease) We can therefore detect associations between birth characteristics and adult diseases (not causal).

7. Role of nutrition Experimental animal studies Famine: - Dutch hunger period - Siege of Leningrad - Folic acid and prevention of malformation Maternal diet Maternal metabolism Placental transport & metabolism Fetal metabolism

8. Genetic and epigenetic effects Genes play a central role in fetal growth. –The surviving small baby hypothesis. However: Half-sibling studies: stronger correlation of birth weights among half siblings who share the mother than the father. Epigenetic phenomena: molecular basis of heritability of treats by non-genetic mechanisms (influence of maternal metabolism).

9. Endocrine effects Transplacental: –Maternal thyroid hormones and neurodevelopment of the child –DES and cancer in childhood –Maternal stress, cortisol Boys with low birth weight had higher cortisol levels and blood pressure. –Birth weight as a marker of estrogen exposure in utero and as a risk factor for breast cancer (among female twins with male co-twin)

10. Placental is impermeable to other polypeptides (e.g. growth hormones)  fetus & placenta = autonomous unit –Adaptation to external challenges result in a new endocrine balance that persist throughout life.

11. Environmental effects Infection during pregnancy (rubella) Lead level in utero and mental development (IQ) Exposure to polychlorinated biphenyls and other organochlorines in utero and via breastfeeding and neurodevelopment. In utero exposure to allergens and childhood asthma

12. Summary The early programming hypothesis is a challenge for ‘classical’ epidemiologic research as the focus may change from prevention in adulthood to improvement of pregnancy conditions. To understand early programming, we need to conduct follow-up studies that start with conception.