Prenatal Exposures and Obesity
Evidence from Epidemiologic Studies
Colby College, October 14th, 2011
Elizabeth E. HatchAssociate Professor of EpidemiologyBoston University School of Public Health
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
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
Current findings for DES Daughters
Hoover RN, New England J Med, 10/6/2011
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?
DES and Obesity?
One animal study suggested that DESis an obesogen, especially at low doses
Human data not yet reported
Early study suggested increase in anorexia
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
Increase in Infant Obesity?
Trends in Obesity Prevalence in Infants and Pre-school Children (U.S.)
Kim J, Obesity, v. 14, 2006
0
2
4
6
8
10
12
14
0-5.9 6-11.9 12-23.9 24-35.9 36-71.9
Age in Months
Pre
vale
nce
of
Ob
esit
y
1980-1981 2000-2001
Increasing Birth Weight over Time, Denmark
Shack-Nielsen,2006
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
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????
Early Life Factors and Risk of Obesity at Age 7
Risk Factor Relative Risk
Birth weight (per 100 grams) 1.05
Maternal Smoking >20/day 1.80
Parental obesity (both parents) 10.40
TV at age 3 (hours/day)
< 4 1.00
4-8 1.37
>8 1.55
Sleep duration (hrs) age 3
<10.5 1.57
10.5-10.9 1.31
11-11.9 0.94
12 + 1.00*all results adjusted for maternal education
Early Life Factors and Risk of Obesity at Age 7
Risk Factor Relative 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 growth 2.21
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
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?
Meta-analysis of maternal smoking/obesity studies
Oken, E, 2008
Body Mass Index by Maternal Smoking Status
Males Females
Suzuki K, Int J. Obesity, 2010
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?
Studies of Developmental Exposure to EDCs and Obesity
Almost all studies focus on persistent chemicals
PCBs DDT/DDE HCB
INMA Study Design
657 women enrolled in 1st trimester of pregnancy, 2004-2006
Data collection: Questionnaires: baseline, 3rd 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
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
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
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
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
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!
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
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
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
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
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!