Prenatal Exposures and
Obesity
Evidence from Epidemiologic Studies
Colby College, October 14th, 2011
Elizabeth E. Hatch
Associate Professor of Epidemiology
Boston University School of Public Health
Overview
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Prenatal diethylstilbestrol (DES) exposure as a model for
endocrine disruption
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Critical periods for development of obesity
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Time trends in birth weight and infant weight
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Prenatal exposure to smoking and later obesity: causation or
confounding?
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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
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Future directions
Diethylstilbestrol (DES)
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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
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Animal and human studies remarkably consistent

multiple adverse outcomes
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 DES
is 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
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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.)
14
12
Prevalence of Obesity
10
1980-1981
8
2000-2001
6
4
2
0
0-5.9
6-11.9
12-23.9
24-35.9
36-71.9
Age in Months
Kim J, Obesity, v. 14, 2006
Increasing Birth Weight over Time, Denmark
Shack-Nielsen,
2006
Early life risk factors for development of
overweight and obesity
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Genetics
Maternal factors
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Pregnancy weight gain
Pregnancy diet
Gestational diabetes
Smoking in pregnancy
Perinatal factors
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Birth weight (high and low)
Breast feeding (protective)
Timing of introduction of solid food
Early life risk factors for development of
overweight and obesity
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Early childhood growth patterns
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Rapid growth in infancy
‘Catch-up growth’
Timing of ‘adiposity rebound’
Childhood behaviors
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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
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Over 20 studies have evaluated smoking in
pregnancy and risk of offspring obesity
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Consistent positive association
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Risk of obesity ~50% higher among offspring of
women who smoked in pregnancy
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Dose-response evident with amount smoked
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Increased risk up through age 33 (one study)
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Potential confounding by SES related factors?
Meta-analysis of maternal
smoking/obesity studies
Oken, E, 2008
Body Mass Index by Maternal
Smoking Status
Males
Suzuki K, Int J. Obesity, 2010
Females
Possible Mechanisms for In Utero
Smoking/Obesity Association
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Mechanisms still largely unknown
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Alterations in leptin, insulin or
glucocorticord receptors?
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Fetal growth restriction leading to early
catch up growth?
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Fetal programming may operate through
maternal appetite suppression?
Studies of Developmental Exposure to
EDCs and Obesity
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Almost all studies focus on
persistent chemicals
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PCBs
DDT/DDE
HCB
INMA Study Design
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657 women enrolled in 1st trimester of
pregnancy, 2004-2006
Data collection:
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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
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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
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Prospective design
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High follow-up rates
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Early pregnancy blood collection
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Measured and adjusted for multiple chemicals
simultaneously
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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
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Measured growth rate over first 6 months—strong
predictor of future obesity
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Measured BMI at 14 months
Rapid Overview: Other Studies of
Developmental Exposure to EDCs and Obesity
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PCBs
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11 studies
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3 positive association with obesity
5 no effect
3 negative association with obesity
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A decidedly mixed picture!
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Some evidence for differences by dose
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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
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DDT/DDE
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9 studies
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5 positive
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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
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HCB
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3 studies
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1 positive association with obesity
2 no association
Other studies
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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 nonpersistent chemicals in relation to offspring obesity very
limited!
Methodologic challenges in studying
EDCs and obesity
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Actual exposure to fetus inferred through mother’s exposure
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Most studies use maternal serum in pregnancy
Critical time period of exposure for obesity risk uncertain
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Measurement taken in pregnancy often at convenient time—not necessarily
the ‘right’ time in terms of risk
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Single measurement of exposure may not accurately reflect true exposure,
especially for non-persistent chemicals
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Misclassification of exposure usually results in attenuation of effects
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What about mixtures of chemicals?
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High levels of one chemical often correlated with high levels of others
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How do we pinpoint which chemicals are most associated with risk?
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What if risks from chemicals interact synergistically?
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Animal/laboratory studies can provide guidance to human studies
More Challenges!
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Difficult to define and measure ‘obesity’
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Body Mass Index (BMI) most often used
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BMI mixes fat and lean mass
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Misclassifies people in terms of adiposity
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Most studies evaluate BMI at one point in time
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Skin-fold thickness/DXA scans would give more precise
measurement of outcome of interest
Growth patterns over time likely to be a better measure
Use of BMI and related measures does not elucidate
possible mechanisms
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For insights into mechanisms, animal/laboratory studies
essential
Still more challenges!
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Obesity has multiple contributing causes
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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?
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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
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Although prenatal time period crucial, let’s not
forget about later exposures
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Continue to mine existing cross-sectional data for
clues and insights into potential mechanisms of
obesogens
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Dramatic weight gain with certain medications
demonstrates potential for important effects after birth
NHANES
Evaluate obesity in special, high-exposure cohorts
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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
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Use on-going general cohort studies
(especially pregnancy cohorts) with stored
biological specimens
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Incorporate hypotheses for specific
environmental chemicals
Initiate new cohort studies: consider
preconception exposures and multiple
measurements if possible
Interdisciplinary collaboration!