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!