1. Prenatal Exposures and Obesity Evidence from Epidemiologic Studies Colby College, October 14 th, 2011 Elizabeth E. Hatch Associate Professor of Epidemiology Boston University School of Public Health

2. Overview  Prenatal diethylstilbestrol (DES) exposure as a model for endocrine disruption  Critical periods for development of obesity  Time trends in birth weight and infant weight  Prenatal exposure to smoking and later obesity: causation or confounding?  Overview of recent epidemiologic studies of prenatal exposure to endocrine disrupting chemicals (EDCs) and obesity  Methodologic challenges in studying prenatal determinants of obesity in humans  Future directions

3. Diethylstilbestrol (DES)  Used in pregnancy from 1940s to 1971  Clinical trials in 1950s showed it was ineffective, but use continued  Linked to rare cancer in female offspring  Further follow-up found many other health effects

4. Current findings for DES Daughters Hoover RN, New England J Med, 10/6/2011

5. Lessons learned from DES  One prenatal exposure multiple adverse outcomes  Animal and human studies remarkably consistent  Model for ‘fetal origins of adult disease’ and potential effects of other endocrine disrupting chemicals in the environment  Without ‘signal’ cancer, other adverse effects of DES may never have been identified  Implications for other drugs/environmental exposures in pregnancy?

6. Lessons learned from DES  DES effects easier to study compared to environmental chemicals Caused a signal cancer Exposure status documented by medical records  Dose and timing of exposure available for many women in the study In contrast to environmental chemical exposures, DES exposure stopped at the end of pregnancy Difficult and expensive to measure environmental chemicals Difficult to pinpoint critical time period of exposure

7. DES and Obesity? One animal study suggested that DES is an obesogen, especially at low doses  Human data not yet reported  Early study suggested increase in anorexia

8. Critical periods of increased risk for development of obesity  Prenatal  Infancy  Early childhood  Puberty  Childhood obesity predicts adult obesity  Early life prevention critical  Treatment difficult and mostly ineffective

9. Increase in Infant Obesity?

10. Trends in Obesity Prevalence in Infants and Pre-school Children (U.S.) Kim J, Obesity, v. 14, 2006

11. Increasing Birth Weight over Time, Denmark Shack-Nielsen, 2006

12. Early life risk factors for development of overweight and obesity  Genetics  Maternal factors Pregnancy weight gain Pregnancy diet Gestational diabetes Smoking in pregnancy  Perinatal factors Birth weight (high and low) Breast feeding (protective) Timing of introduction of solid food

13. Early life risk factors for development of overweight and obesity  Early childhood growth patterns Rapid growth in infancy ‘Catch-up growth’ Timing of ‘adiposity rebound’  Childhood behaviors Sleep TV/sedentary behavior Medication use????

14. Early Life Factors and Risk of Obesity at Age 7 Risk FactorRelative Risk Birth weight (per 100 grams) 1.05 Maternal Smoking >20/day1.80 Parental obesity (both parents) 10.40 TV at age 3 (hours/day) < 41.00 4-81.37 >81.55 Sleep duration (hrs) age 3 <10.51.57 10.5-10.91.31 11-11.90.94 12 +1.00 *all results adjusted for maternal education

15. Early Life Factors and Risk of Obesity at Age 7 Risk FactorRelative Risk Early childhood weight Top quartile, 8 mos 3.03 Top quartile, 18 mos 3.71 Adiposity rebound Late (>61 mos)1.00 Early (by 61 mos)2.85 Very early (<43 mos) 12.00 Catch up growth2.21 Weight gain first 12 mos (per 100 gram increase) 1.07 *all results adjusted for maternal education Reilly JJ, British Medical Journal, 2005, results from ALSPAC cohort

16. Maternal smoking and offspring obesity  Over 20 studies have evaluated smoking in pregnancy and risk of offspring obesity  Consistent positive association  Risk of obesity ~50% higher among offspring of women who smoked in pregnancy  Dose-response evident with amount smoked  Increased risk up through age 33 (one study)  Potential confounding by SES related factors?

17. Meta-analysis of maternal smoking/obesity studies Oken, E, 2008

18. Body Mass Index by Maternal Smoking Status MalesFemales Suzuki K, Int J. Obesity, 2010

19. Possible Mechanisms for In Utero Smoking/Obesity Association  Mechanisms still largely unknown  Alterations in leptin, insulin or glucocorticord receptors?  Fetal growth restriction leading to early catch up growth?  Fetal programming may operate through maternal appetite suppression?

20. Studies of Developmental Exposure to EDCs and Obesity  Almost all studies focus on persistent chemicals PCBs DDT/DDE HCB

21. INMA Study Design  657 women enrolled in 1 st trimester of pregnancy, 2004-2006  Data collection: Questionnaires: baseline, 3 rd trimester, delivery, 6 months and 14 months postpartum Blood collected at first trimester visit  Measured DDT/DDE, HCB, ßHCH, ΣPCBs Birth outcomes—n=616 Infant growth data—n=518 BMI @14 months—n=502 Mendez, MA, Environmental Health Perspectives, 2011

22. INMA Study Results  24% of babies defined as ‘rapid growers’ in first 6 months of life  Babies who grew fast were 5 X more likely to have a high BMI compared to average/slow growers  Higher DDE level associated with 2 fold increase in risk of rapid growth among normal weight but not obese mothers  Higher DDE also associated with higher risk of elevated BMI at 14 months

23. Strengths of INMA Study  Prospective design  High follow-up rates  Early pregnancy blood collection  Measured and adjusted for multiple chemicals simultaneously Only DDE appeared related to growth after mutual adjustment  Accounted for numerous potential confounders such as prenatal smoking, gestational weight gain, maternal age and education, and parental overweight  Measured growth rate over first 6 months—strong predictor of future obesity  Measured BMI at 14 months

24. Rapid Overview: Other Studies of Developmental Exposure to EDCs and Obesity  PCBs 11 studies  3 positive association with obesity  5 no effect  3 negative association with obesity  A decidedly mixed picture!  Some evidence for differences by dose Lower dose generally related to higher risk of obesity Higher dose generally related to reduced risk of obesity  Some evidence for gender differences in effects

25. Studies of Developmental Exposure to EDCs and Obesity  DDT/DDE 9 studies  5 positive Including INMA--strong effect for rapid infant growth  4 no effect  Overall pattern of results is mixed but studies with positive findings tended to be of better quality

26. Studies of Developmental Exposure to EDCs and Obesity  HCB 3 studies  1 positive association with obesity  2 no association  Other studies Danish greenhouse workers: some evidence for heavier offspring in greenhouse workers exposed to pesticides in early pregnancy In utero exposure to PFCs associated with lower weight in early childhood, especially in boys (Andersen CS, 2010) Epidemiologic studies of developmental exposure to non- persistent chemicals in relation to offspring obesity very limited!

27. Methodologic challenges in studying EDCs and obesity  Actual exposure to fetus inferred through mother’s exposure Most studies use maternal serum in pregnancy  Critical time period of exposure for obesity risk uncertain Measurement taken in pregnancy often at convenient time—not necessarily the ‘right’ time in terms of risk Single measurement of exposure may not accurately reflect true exposure, especially for non-persistent chemicals  Misclassification of exposure usually results in attenuation of effects  What about mixtures of chemicals? High levels of one chemical often correlated with high levels of others How do we pinpoint which chemicals are most associated with risk? What if risks from chemicals interact synergistically? Animal/laboratory studies can provide guidance to human studies

28. More Challenges!  Difficult to define and measure ‘obesity’ Body Mass Index (BMI) most often used BMI mixes fat and lean mass Misclassifies people in terms of adiposity  Skin-fold thickness/DXA scans would give more precise measurement of outcome of interest Most studies evaluate BMI at one point in time  Growth patterns over time likely to be a better measure  Use of BMI and related measures does not elucidate possible mechanisms For insights into mechanisms, animal/laboratory studies essential

29. Still more challenges!  Obesity has multiple contributing causes In addition to role of prenatal exposure, early life exposures are important Studies should take into account potential early life factors that might contribute to or confound the associations between EDCs and obesity  Confounding, especially by diet? E.g. moms who eat more canned foods may have higher BPA, but possibly also higher weight gain or other dietary characteristics that ‘program’ offspring obesity

30. Future directions for epidemiologic studies of EDCs and obesity  Although prenatal time period crucial, let’s not forget about later exposures Dramatic weight gain with certain medications demonstrates potential for important effects after birth  Continue to mine existing cross-sectional data for clues and insights into potential mechanisms of obesogens NHANES  Evaluate obesity in special, high-exposure cohorts Agent Orange, PCB exposure cohorts, Seveso, DES, Russian cohorts, 3M cohorts with high exposure to PFCs, agricultural cohorts

31. Future directions for epidemiologic studies of EDCs and obesity  Use on-going general cohort studies (especially pregnancy cohorts) with stored biological specimens Incorporate hypotheses for specific environmental chemicals  Initiate new cohort studies: consider preconception exposures and multiple measurements if possible  Interdisciplinary collaboration!