Fetal Origins Hypothesis: Pros and Cons

1. Fetal Origins Hypothesis:Pros and Cons Kate E. Pickett, PhD University of Chicago Dept. of Health Studies & Dept. of Obstetrics and Gynecology

2. Life course approach to disease • Risk factors accumulate over a lifetime • Current risk factors may be biologically implausible causes of current disease • Early events may be as or more important than later events and/or may interact with later factors

3. Do you think the fetal origins hypothesis has been confirmed? Can you think of other factors that provide a plausible alternative explanation? What future research might be needed to help establish the truth (or otherwise) of the fetal origins hypothesis? What are the implications of the hypothesis for MCH public health practice? Questions to bear in mind

4. The Fetal Origins or “Barker” Hypothesis • Pioneered by David Barker in the early 1990s • Painstaking development of historical birth cohort studies in England • Part 1: Impaired fetal growth causes adult disease • Part 2: “Thrifty phenotype” - impaired fetal growth permanently changes the body’s structure and physiology • Adaptive for compromised nutrition • Maladaptive for over-nutrition • Potential mechanisms include blood pressure, fibrinogen concentration & glucose tolerance From: Keith M Godfrey and David JP Barker Fetal nutrition and adult disease Am J Clin Nutr 2000 71: 1344S-1352S.

5. A digression: DES and clear cell carcinoma of the vagina and cervix • DES is a synthetic estrogen widely prescribed during pregnancy in the 1950s and 1960s. • Fetal exposure to DES was linked to later occurrence of a very rare cancer in daughters in the early 1970s

6. Longer-term effects of DES • Increased breast cancer among mothers, RR=1.30 • Increased autoimmune disease and other cancers among daughters? • Increased testicular cancer among sons? • Collateral effects: increased heart disease and osteoporosis among daughters afraid to use HRT? • Third-generation effects?

7. Radiation Heavy alcohol use Heavy metals Nutrient deprivation Cigarette smoke Cocaine ? Note also that nutrition in the immediate post-partum has profound effects on long-term health Breastfeeding: Cognitive function Obesity Cardiovascular dx Birthweight has now been associated with: Cardiovascular disease Heart disease Hypertension Stroke Mental health Anti-social personality disorder Cognitive/behavioral problems Reproductive health Infertility PCOS Marriage Diabetes Birthweight of next generation Other fetal exposures with long-term effects

8. Methodological criticisms • Scientific approach Not stated as refutable hypotheses • Selection bias in study samples Study samples are a tiny fraction of the original birth cohorts • Exposure measurement Is birthweight a good measure of fetal nutrition? • Alternative explanations Long list of possible confounding factors • Inference Inconsistent no reformulation of hypotheses, do not explain temporal or international trends in CVD

9. Deductive Develop refutable hypothesis Plan challenge Test hypothesis Either refute (discard) or accept and reformulate new tests Inductive Scientific hypotheses/conclusions derived from observations Accumulation of “weight of evidence” 1. Scientific Approach

10. 1.Paneth and Susser’s proposed “ordeals” for the fetal origins hypothesis • Results should also hold in cohorts with adequate follow-up • As twins are growth-restricted in utero, they should have a higher incidence of CVD than singletons • Results should hold when adjustment is made for other fetal exposures (e.g., maternal smoking) and for other factors associated with both low birth weight and CVD (e.g., SES over the life course)

11. 2. Selection Bias • Subjects form a very small proportion of the original birth cohort, losses due to: • Death • Migration • Loss to follow up • Some analyses were performed on less than 5% of the original cohorts

12. 3. Does birthweight measure fetal nutrition? • Birthweight represents both fetal growth and length of gestation • Fetal growth seems to be protected under quite adverse circumstances • Role of micronutrients may be quite different from that of macronutrients • Reverse causality? • Other environmental factors (associated with later disease) cause, rather than result from, impaired fetal growth

13. 4. Alternative explanations • A long list….. • Genetic factors which affect fetal metabolism • Environment over the life-course • Socioeconomic status over the life-course • Behavior over the life course • Maternal health factors • Behaviors • Disease • Infection

14. Growth of a body of evidence? Inconsistencies in studies of the Barker group through 1995

15. Ordeal #1: Evidence from studies with better follow-up • Nurses’ Health Study: • Study cohort = 121,700 women followed since 1976 • Sample cohort = 70,297 (58%), excluded were women who did not provide retrospective information on birthweight • Effect most pronounced at extremes of birthweight • Confirmed in Scandinavian birth cohorts with > 97% follow-up, able to look at fetal growth rates

16. Ordeals #2 & #3: New Zealand cohort study • Twins had lower birth weight and lower blood pressure at ages 9 and 18 years • Infants of smokers had lower birth weight and higher blood pressure • Birthweight effects are small From: Twins and maternal smoking: ordeals for the fetal origins hypothesis? A cohort study Sheila Williams and Richie Poulton BMJ 1999; 318: 897.

17. Correlation or causation? • To what extent can we infer causality from existing findings? • Is it fetal nutrition?

18. Temporality Strength of association Consistency Specificity Experimental evidence Biological plausibility Dose response Consideration of alternative explanations Coherence Epidemiologic criteria for inferring causality

19. 1. Temporality • Obvious • What if some other factor, which will later cause adult disease, causes low birth weight? BUT 

20. 2. Strength of Association • Relative risks for lowest birth weight category vs. highest • ~ 2 for CHD • ~ 6 for non-insulin dependent diabetes • ~ 18 for metabolic syndrome • Blood pressure 2-3 mmHg higher with every 1000 g less birth weight 

21. 3. Consistency • Diverse study designs and populations • Retrospective and prospective • Cross-national • Some findings are conflicting ~

22. Growth of a body of evidence? Inconsistencies in studies of the Barker group through 1995

23. 4. Specificity • Specific to a number of diseases linked by metabolic-nutritional underpinnings BUT • Associations are found with: • Mental illness • Cognitive function • PCOS - high birthweight 

24. Psychological and mental disorders • Much work predates Barker • Early work focused on brain injury in utero or at delivery • Even more resistance to idea of programmed behavior or disease of the mind than to programmed disease of the body • Case in point: smoking and behavior disorders

25. 5. Experimental evidence • Not really been tested-difficult to do Fetal Growth/ Infant metabolism Nutrition intervention ?? Long-term growth monitoring and follow-up for disease Randomize pregnant women Usual care 

26. 6. Biologic Plausibility • Fetal programming of metabolism • “thrifty phenotype” • Genetic determination of insulin resistance • “fetal insulin hypothesis” • Programming of the hypothalamic-pituitary-axis (HPA), which controls growth and development • Animal studies 

27. Biological mechanisms

28. Maternal vs. fetal nutrition

29. 7. Dose Response • Linear trends demonstrated in most studies BUT • Should we expect them? 

30. 8. Consideration of alternate explanations • Association not explained by obvious confounding (maternal and offspring): • Smoking • employment • Alcohol consumption • Exercise BUT • Measurement is an issue • Potentially large role of genetic confounding ~

31. Non-smoker 669 Non-smoker 685 4 18 9 10 Smoker 257 Light smoker 46 Light smoker 45 9 2 14 Moderate smoker 39 Moderate smoker 27 7 5 8 Heavy smoker 172 Heavy smoker 169 13 20 Smoking status at baseline Smoking status in late pregnancy

32. 9. Coherence • Association of prenatal insults with other health outcomes is well-known • Radiation • Heavy alcohol use • Heavy metals • Nutrient deprivation • Cigarette smoke 

33. Temporality  Strength of association  Consistency ~ Specificity  Experimental evidence  Biological plausibility  Dose response  Consideration of alternative explanations ~ Coherence  Epidemiologic criteria for inferring causality

34. Do you think the fetal origins hypothesis has been confirmed? Can you think of other factors that provide a plausible alternative explanation? What future research might be needed to help establish the truth (or otherwise) of the fetal origins hypothesis? What are the implications of the hypothesis for MCH public health practice? Questions to bear in mind

35. Implications for MCH practice • Affirming, not revolutionary • Increased attention to maternal nutrition rather than weight gain • Increased attention to breastfeeding, smoking • Increased support for nutrition-related programs? • How long would it take to see results?