Faculty Disclosure
Emily Oken, MD, MPH
Dr. Oken has listed no financial
interest/arrangement that would be considered
a conflict of interest.
Does Obesity Begin Before Birth?
Influence of the Intrauterine and Infant
Environment on Obesity and Metabolic Disease
Emily Oken, MD, MPH
Obesity Prevention Program
Department of Population Medicine
Harvard Medical School and
Harvard Pilgrim Health Care Institute
Does the health of mothers influence the health of
babies in the short and long term?
Prevalence of overweight, obesity and
Overweight
and obesity rising
extreme obesity among women 20-39* y old:
US, 1963-2004
in U.S. women
age 20-39
Proportion of women (%)
60
Overweight (BMI > 25 kg/m2)
Obese (BMI > 30 kg/m2)
Extreme obesity (BMI > 40 kg/m2)
50
NHANES
1999-2000,
2001-02
2003-04
40
30
NHANES
1963-65,
1966-70
NHANES
1976-80
20
NHANES
1971-74
NHANES
1988-94
10
0
1965
1975
1985
1995
2005
Year of survey
From: Health, United States, 2005 and Ogden CL, et al.
JAMA 2006;295:1549.
*Ages 20-35 through NHANES 1988-94
Obesity is also rising in infants
Prevalence of Overweight
15
12-23 months
24-71 months
10
5
0-11 months
0
1980
1985
1990
Year
1995
2000
Kim et al., Obesity 2006; 14(7):1107-12. ~500,000 well child visits in Mass.
Fetal growth parallels maternal BMI
Odds Ratio
2.5
3500
Odds of high birth weight
Mean birth weight
3429
3334
2.36
2
3281
1.5
3400
3300
3225
1.31
1
1.00
3200
0.5
0.52
3100
0
Underweight
Normal
Overweight
Maternal BMI
Adapted from Heslehurst, et al. Obesity Reviews 2008.
Meta-analysis of published cohort studies.
Obese
Mean birth weight (g)
3
Heavier babies remain heavier
Adult BMI (kg/sq m)
25
24.6
24.2
23.8
23.4
23
22.6
22.2
<2.5
2.5-3.0
3.0-3.5
3.5-4.0
4.0-4.5
>4.5
Birthweight (kg)
Danish conscripts 18-26 y.o. Sorensen, Gillman, et al., BMJ 1997;315(7116):1137.
Adjusted for gestational age, birth length, maternal factors
Odds ratio for child obesity
10
Odds of child obesity for obese vs.
normal weight mothers
5.1
4.1
4.3
4.3
3.1
1
Whitaker 2004
(age 4)
Li 2005 (ages
2-14)
Reilly 2005
(age 7)
Li 2007 (Ages Salsberry 2007
2-12, early
(ages 12-13)
onset)
Author, year, child age
Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77.
Offspring of obese mothers have
poorer cardio-metabolic status



At birth, higher body fat, reduced energy
expenditure, and more atherogenic lipid
profiles
In childhood, higher blood pressure, risk for
metabolic syndrome - even after adjustment
for attained BMI
In adulthood, increased risk of death from
coronary heart disease
Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77.
Gestational weight gain
Gestational weight gain
• Infant birth weight increases 16-23g
per 1kg increase in maternal weight
gain
– Greater risk for macrosomia, LGA
– Lower risk for low birth weight, SGA
Viswanathan M, et al. Outcomes of maternal weight gain. 2008. AHRQ Evidence Report.
http://www.ahrq.gov/downloads/pub/evidence/pdf/admaternal/admaternal.pdf
% gaining excessive weight
The prevalence of excessive weight gain
is also on the rise
50
45
40
35
30
25
1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003
Year
http://www.cdc.gov/pednss/pnss_tables/html/pnss_national_table16.htm
Distribution of GWG relative to 1990 guidelines
by prepregnancy BMI category (PRAMS, 2002-03)
120
Proportion (%) of women
< IOM
Within IOM
> IOM
63
36.3
100
19.5
38.4
80
60
49.9
40
41.1
26.8
20
0
30.2
30.6
20.5
10.3
23.5
Underweight
Normalweight
Overweight
Obese
Body mass index category (IOM criteria)
Gestational weight gain
and child weight
Child BMI z score .
0.8
0.6
0.47
0.52
0.4
0.2
0.17
0
Inadequate
Adequate
Excessive
Maternal weight gain per 1990 IOM Guidelines
Adjusted for maternal race/ethnicity, smoking, BMI, socio-demographics, gestational
diabetes; paternal BMI; child sex, gestation length, breastfeeding duration
Oken et al., Am J Ob Gyn 2007;196(4):322 e1-8.
Gestational weight gain
and adolescent weight
0.6
Change in child BMI z-score
Without adjustment for maternal BMI
0.4
0.29
With adjustment for maternal BMI
0.2
0.0
-0.2
-0.25
-0.4
-0.6
<10
Oken et al. 2008
10-14 15-19 20-24 25-29 30-34 35-39 40-44 >=45
Gestational weight gain (pounds)
What accounts for associations of
maternal weight with child weight?

Genes
What accounts for associations of
maternal weight with child weight?

Genes

Dad weight is also associated with child weight
Exposure
Mom
Dad
Reilly,
2005
BMI >=30
4.25 (2.86, 6.32)
2.54 (1.72, 3.75)
Li,
2009
Per 1 kg/m2 1.57 (1.26, 1.95)
1.45 (1.03, 2.05)
What accounts for associations of
maternal weight with child weight?

Genes

Dad weight is also associated with child weight



but associations not as strong
Identified obesity genes only account for a small
proportion of risk
Other factors matter, even when genetic risk is
high
Even in Pima Indians,
it’s not just the genes
80%
70%
70%
Mexico
United States
60%
50%
38%
40%
30%
20%
10%
7%
13%
0%
Type 2 Diabetes
Obesity
Schultz et al. Diabetes Care 2006;29(8):1866-71
What accounts for associations of
maternal weight with child weight?


Genes
Shared behaviors

Parents and children tend to share diet, physical
activity habits (Oliveria et al, AJCN, 1992)
What accounts for associations of
maternal weight with child weight?



Genes
Shared behaviors
Mediators

Fetal growth & body composition at birth
Size at birth and body composition
larger babies: more muscle and more fat
smaller babies: less muscle, but not less fat
MUA muscle area z score
Large for gestational age
Hediger et al, Pediatrics, 1998
Small for gestational age
Age (months)
What accounts for associations of
maternal weight with child weight?



Genes
Shared behaviors
Mediators


Fetal growth & body composition
GDM
Offspring of mothers with DM in
pregnancy are heavier at 14-17 years
27
26
Mean BMI (kg/m2)
26
25
24.6
24
23.6
23
22
20.7
21
20
Gestational
Diabetes
Pre-gestational
diabetes
All maternal DM NCHS reference
combined
Silverman et al., Diabetes Care, 1998
What accounts for associations of
maternal weight with child weight?



Genes
Shared behaviors
Mediators



Fetal growth & body composition
GDM
Breastfeeding
Breastfeeding
• Observational studies
suggest small benefit for
child obesity (but
confounded)
Breastfeeding and child overweight
Parsons et al (33)
Poulton and Williams (26)
Tulldahl et al (16)
Kramer (15)
Kramer (15)
Elliot et al (15)
Gillman et al (12)
Sung et al (11)
Toschke et al (6-14)
Liese et al (10)
Frye and Heinrich (10)
Maffeis et al (10)
Li et al (8)
Eid (8)
Strbak et al (1-7)
Richter (7)
Wadsworth et al (6)
von Kries et al (6)
Bergmann et al (6)
Scaglioni et al (5)
O'Callaghan et al (5)
Neyzi et al (5)
Hediger et al (4)
Grummer-Strawn and Mei (4)
Armstrong & Reilly (3)
Thorogood et al (1)
Dewey et al (1)
Yeung et al (0.5)
Taitz (0)
0.87 (95% CI 0.85, 0.89)
Combined
Breast feeding better
Owen et al, Pediatrics, 2005
.5
Odds of obesity
1 Formula feeding
1.5 better
Large RCT: no differences at 6.5 years
(but all infants breastfed )
4
Cluster-adjusted difference*
3
2
1
0.7
0.3
0.1
0
-0.4
0
0.2
0.2
-1
-2
-3
*Difference > 0 indicates higher value in experimental group
-4
Height, cm
BMI, kg/m2
Waist
Triceps SF, Subscapular Systolic BP, Diastolic BP,
circumference,
mm
SF, mm
mm
mm
cm
Outcome at age 6.5 years
Kramer et al. Am J Clin Nutr. 2007 Dec;86(6):1717-21
What accounts for associations of
maternal weight with child weight?




Genes
Shared behaviors
Mediators
Confounders


SES
Smoking
Maternal prenatal smoking and
child overweight – meta-analysis
Adams, 2005
Al Mamun, 2006
Bergmann, 2003
Chen, 2006 F
Chen, 2006 M
Dubois, 2006
Oken, 2005
Power, 2002 F
Power, 2002 M
Reilly, 2005
Salsberry, 2005
Toschke, 2002
Toschke, 2003
Whitaker, 2004
Wideroe, 2003
von Kries, 2002
OR 1.50, 95% CI: 1.36, 1.65
Combined
.5
1
Odds Ratio
5
Oken, et al. Int J Obes (Lond) 2008; 32(2):201-10
Pathways linking maternal weight
with child outcomes
Gestational
Diabetes
Gestational
weight
gain
Gestation
length
Fetal
growth
Infant
feeding &
growth
Child
adiposity
Birth
weight
Maternal
pre-pregnancy
size
Disease
outcomes
Shared genes and behaviors
Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.
What accounts for associations of
maternal weight with child weight?





Genes
Shared behaviors
Mediators
Confounders
Direct effect of the intra-uterine environment
Pathways linking maternal weight
with child outcomes
Gestational
Diabetes
Gestational
weight
gain
Gestation
length
Fetal
growth
Infant
feeding &
growth
Child
adiposity
Birth
weight
Maternal
pre-pregnancy
size
Disease
outcomes
Shared genes and behaviors
Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.
How to study whether maternal weight
status programs offspring weight?
• Randomized trials
How to study whether maternal weight
status programs offspring weight?
• Randomized trials
– None of pre-pregnancy interventions
– Few studies to prevent excess gestational weight
gain
• Most not powered to study weight at birth
• None with f/u after early infancy
– Stay tuned!!
How to study whether maternal weight
status programs offspring weight?
• Randomized trials
• Observational human studies
– Statistical adjustment for measured factors
Adjusted odds of child
overweight
Maternal BMI associated with child weight
even after adjustment
10
2 year olds
3 year olds
4 year olds
1
Maternal 1st trimester BMI (kg/m2)
0.1
< 18.5
18.5-24.9
25-29.9
30-39.9
>= 40
8494 children in WIC Ohio. Adjusted for maternal, race/ethnicity, parity, smoking,
education, marital status, age; gestational weight gain, and child sex, fetal growth
and birth year
Whitaker, Pediatrics 2004;114(1):e29
Odds Ratio .
Odds of child overweight according to maternal
gestational weight gain
10
3.77
4.35
Inadequate
Adequate
Excessive
Maternal weight gain per IOM recommendations
Adjusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestational
diabetes; paternal BMI; child sex, gestation length, breastfeeding duration
Oken et al., Am J Ob Gyn 2007;196(4):322 e1-8.
GWG and child weight gain associations persist
after adjustment
100
Odds ratio
Excessive gain vs inadequate gain
10
4.3
3.4
4.2
4.2
+ child diet
& activity
+ mom diet
& activity
1
GDM,
BF
+ fetal
growth
Also djusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestational
diabetes; paternal BMI; child sex, gestation length, breastfeeding duration
GWG and child weight gain associations persist
after adjustment
100
Odds ratio
Excessive gain vs inadequate gain
10
4.3
3.4
4.2
4.2
+ child diet
& activity
+ mom diet
& activity
1
GDM,
BF
+ fetal
growth
Also djusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestational
diabetes; paternal BMI; child sex, gestation length, breastfeeding duration
GWG and child weight gain associations persist
after adjustment
100
Odds ratio
Excessive gain vs inadequate gain
10
4.3
3.4
4.2
4.2
+ child diet
& activity
+ mom diet
& activity
1
GDM,
BF
+ fetal
growth
Also djusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestational
diabetes; paternal BMI; child sex, gestation length, breastfeeding duration
GWG and child weight gain associations persist
after adjustment
100
Odds ratio
Excessive gain vs inadequate gain
10
4.3
3.4
4.2
4.2
+ child diet
& activity
+ mom diet
& activity
1
GDM,
BF
+ fetal
growth
Also djusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestational
diabetes; paternal BMI; child sex, gestation length, breastfeeding duration
How to study whether maternal weight
status programs offspring weight?
• Randomized trials
• Observational human studies
• Sibling studies
Weights of children born before (BMS, n=45)
and after (AMS, n=172) maternal weight-loss surgery
60%
BMS
AMS
50%
40%
30%
20%
10%
0%
Underweight
Normal weight
Overweight
Kral JG, et al. Pediatrics. 2006 Dec;118(6):e1644-9
Obese
Dabelea et al., Diabetes 2000. 19 Pima families/58 sibs
How to study whether maternal weight
status programs offspring weight?
•
•
•
•
Randomized trials
Observational human studies
Sibling studies
Animal studies
Animal studies suggested early energy intake
can permanently program body size
21 days: Weights 14g, 60g
75 days: Weights 86g, 230g
Widdowson and McCance, 1960
Weight (g)
Timing is important
weaning
Food restriction during weeks 0-3
results in sustained lower body weight
(and food excess in higher weight)
Age (weeks)
21 day period of food restriction
Weight (g)
Timing is important
weaning
Later food restriction (weeks 9-12) –
rats quickly regain and (perhaps
overshoot) body weight
Age (weeks)
Widdowson and McCance, 1963
21 day period of food restriction
Offspring of overfed mother rats have
higher body weight …
Male offspring
Offspring of obese dams
Offspring of control dams
Female offspring
Offspring of obese dams
Offspring of control dams
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
…higher fat mass…
OC – Offspring of control dams
OO – Offspring of obese dams
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
…higher energy intake…
Offspring of obese dams
Offspring of control dams
Offspring of obese dams
Offspring of control dams
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
…and adverse cardio-metabolic profiles
OC – Offspring of control dams
OO – Offspring of obese dams
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
What are the mechanisms?
Altered Appetite
Regulation
High Neonatal
Adiposity
Altered Adipocyte
Metabolism
Peri-conceptional exposure only
Experiment 3: Maternal high fat diet before gestation with
embryo transfer after conception
Wu Q. and M. Suzuki. Obes Rev. 2006 May;7(2):201-8
Peri-conceptional exposure only
HF
LF
350
300
250
200
150
100
50
0
Body Weight Gain (g)
Wu Q. and M. Suzuki. Obes Rev. 2006 May;7(2):201-8
Peri-conceptional exposure only
HF
LF
20
15
10
5
0
Food Consumption
(MJ rat-1)
Food Effiency (g
MJ-1)
Abdominal Adipose
Tissue
Plasma Insulin
Conc (ng Ml)
Wu Q. and M. Suzuki. Obes Rev. 2006 May;7(2):201-8
Plasma Leptin
Conc (ng Ml)
Epigenetic imprinting
Wu Q and M Suzuki. Obes Rev. 2006 May;7(2):201-8.
A vicious cycle?
Catalano PM. JCE&M 2003, 88(8):3505-3506.)
What is the overall impact?
Summary – maternal obesity and offspring
outcomes
• Maternal obesity and GWG
– Increasing in prevalence
– Excesses of each are associated with
increased risks for the child during
pregnancy and at birth
– Associated with child weight
• Probably not just genes
• Can we reverse the cycle?
• When/how to intervene?
Clinician advice matters
How frequently do you…when you see an
obese woman at her initial prenatal visit?
% almost
always
Tell woman she is overweight or obese
40%
Discuss risks associated with obesity
41%
Recommend a specific range of weight gain
74%
Recommend regular physical activity
74%
Discuss her diet
64%
Order GTT testing in 1st trimester
26%
Obtain anesthesia referral
Obtain nutrition referral
Herring SJ. Journal of Women’s Health, 2010.
3%
14%
Clinician Knowledge of BMI categories
Please indicate the body mass index (BMI) that reflects
each weight status listed below:
Maternal BMI
Correct response
% Correct
Underweight
< 18.5 kg/m2
48%
>= 18.5 kg/m2
< 25 kg/m2
41%
57%
Overweight
>= 25 kg/m2
< 30 kg/m2
76%
57%
Obese
>= 30 kg/m2
60%
Normal
Herring SJ. Journal of Women’s Health, 2010
Postpartum weight loss is key
Gestational Diabetes
Odds Ratio
10
BMI < 25
BMI >= 25
1
Large for Gestational Age
0.1
<-1
-1 to <1
1 to <2
2 to <3
Change in BMI
>= 3
Odds Ratio
10
BMI < 25
BMI >= 25
1
0.1
<-1
-1 to <1
1 to <2
2 to <3
Change in BMI
Villamor, Lancet 2006;368:1164-70
>= 3
Modifiable postpartum behaviors and
PPWR
Odds Ratio (95% CI)
10
Number of beneficial postpartum behaviors
None
1
One
Two
Three
0.95
0.50
0.23
0.1
TV viewing < 2 h/day, walking > 30 min/day, trans fat < median
Oken et al., AJPM 2007; 32(4):305-311.
Physical activity before, during, and after pregnancy
12
hours / wk
10
Prepregnancy (n=1895)
2nd trimester (n=1623)
6 mo postpartum (n=1124)
9.8
8.4
8
7.2
5.4 5.1
6
5.8
4
2.3
2.2
2
1.5 1.4
0.7
1.3
0
Lightmoderate
Walking for
exercise
Pereira et al, AJPM, 2007
Vigorous
Total activity
Sleep and PPWR
• Chronic sleep curtailment is associated with
– Higher prevalence of obesity and weight gain in
young adults
– CAD and type 2 DM in women
– Higher mortality
• The postpartum period is characterized by
sleep deprivation
Substantial PPWR >= 5 kg at 1 year by sleep at
6 mo postpartum
Odds ratio (95% CI) .
10
3.1
1
0.1
<= 5
6
7
8
Hours of sleep
Adjusted for race/ethnicity, marital status, education, age, parity pre-pregnancy BMI, gestational weight gain (IOM
categories), postpartum behaviors (dietary fiber intake, PA, inactivity, dieting and breastfeeding.
Gunderson, et al. AJE 2007
Childhood
• Beware of ‘catch up growth’
Infant weight gain
12
10
8
WG5
WG3
WG1
Early infancy weight gain
categories
Stettler N, Pediatrics 2002
BW4
0
BW2
2
BW3
4
BW5
6
BW1
Prevalence
overweight age 7
years
14
Birth weight
categories
Childhood
• Beware of ‘catch up growth’
• Promote healthy postnatal and child
behaviors
– Breastfeeding
– Less TV, fast food, sugar sweetened
beverages
– More physical activity
• Engage mothers & families
First Steps for Mommy and Me
First Steps for Mommy & Me
Study Aims
•
Develop and test feasibility of an
intervention to promote healthy eating
and physical activity behaviors among
mother-infant pairs in the first 6
months of life
Breastfeeding Promotion
Preliminary Results –
Feeding and Media Exposure
• At 6-months of age, compared to usual
care participants:
– fewer intervention participants had been
introduced to solid foods (57% v. 82%; p=0.04)
– intervention infants viewed less screen media
(median 0.5 v. 1.0 h/d; p= .07)
– no differences in breastfeeding duration
Preliminary Results – Sleep
• At 6-months of age, compared to usual
care participants, intervention
participants:
– Had fewer nighttime awakenings (median 1.0
v. 2.0 times per night; p=.05)
– Had longer duration of nighttime sleep
(median increase 24 minutes v. 10 minutes;
p=.03)
– Intervention mothers reduced time spent
putting their infants to sleep at night (median
reduction 19.0 v. 0 min; p=.03)
Preliminary Results – Weight for Length
Anthropometric
Outcomes
Overall
Intervent
ion
Usual
Care
Pvalue
N (%) or Mean (SD)
Change in weight-forlength (WFL-Z), birth to
6-months
0.33
(1.5)
0.24 (1.5)
0.50
(1.4)
0.09
WFL >85th percentile at
6-months, N (%)
13 (15.5)
7 (11.7)
6 (25.0)
0.18
Highest quartile of WFL
at 6-months, N (%)
23 (27.4)
13 (21.7)
10 (41.7)
0.04
Intrauterine nutrition is not only about
maternal behavior in pregnancy
Mom’s own
intrauterine
and childhood
experiences
Mom’s
periconceptional
health
Diet during
pregnancy
Utero-placental
Fetal
blood flow, metabolism
placental
function
Intergenerational influences
IDM = infants of
mothers with
GDM
Boloker et al., Diabetes 2002;51(5):1499-506.
Mom’s own birth weight is associated
with her risk for GDM
Innes et al., JAMA, 2002
Intrauterine nutrition is not only about
maternal behavior in pregnancy
Extrauterine environment
Mom’s own
intrauterine
and childhood
experiences
Mom’s
periconceptional
health
Diet during
pregnancy
Utero-placental
Fetal
blood flow, metabolism
placental
function
Change in % SGA or LGA from 1990
SGA and LGA trends since 1990
3
Small for Gestational Age,
Low-Risk Subgroup
2
Large for Gestational Age,
Low-Risk Subgroup
1
0.9
0
-1
-2
-2.2
-3
1990
1995
2000
Year
Oken et al. Obstet Gynecol. 2010 Feb;115(2 Pt 1):357-64
2005
Change in % SGA or LGA from 1990
SGA and LGA trends since 1990
3
Small for Gestational Age,
Low-Risk Subgroup
2
Large for Gestational Age,
Low-Risk Subgroup
1
0.9
SGA
0
-1
-2
-2.2
-3
1990
1995
2000
Year
Oken et al. Obstet Gynecol. 2010 Feb;115(2 Pt 1):357-64
2005
LGA
Change in Birth Weight (g) from 1990
Birth weight trends since 1990
0
-20
-40
-51
-60
All Births
-80
Low Risk Subgroup
-79
-100
1990
1995
2000
Year
Oken et al. Obstet Gynecol. 2010 Feb;115(2 Pt 1):357-64
2005
Questions?
“Anything on women of pre-childbearing age?”