Faculty Disclosure Emily Oken, MD, MPH Dr. Oken has listed no financial interest/arrangement that...

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, MPHObesity Prevention Program

Department of Population MedicineHarvard 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 andextreme obesity among women 20-39* y old:

US, 1963-2004

Year of survey

1965 1975 1985 1995 2005

Pro

port

ion

of w

omen

(%

)

0

10

20

30

40

50

60Overweight (BMI > 25 kg/m2)Obese (BMI > 30 kg/m2)Extreme obesity (BMI > 40 kg/m2)

NHANES1963-65,1966-70

NHANES1971-74

NHANES1976-80

NHANES1988-94

NHANES1999-2000,2001-022003-04

From: Health, United States, 2005 and Ogden CL, et al. JAMA 2006;295:1549.*Ages 20-35 through NHANES 1988-94

Overweight and obesity rising in U.S. women age 20-39

0

5

10

15

Pre

vale

nce

of

Ove

rwei

ght

Year

24-71 months

0-11 months

12-23 months

1980 1985 1990 1995 2000

Obesity is also rising in infants

Kim et al., Obesity 2006; 14(7):1107-12. ~500,000 well child visits in Mass.

Adapted from Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies.

2.36

1.311.00

0.52

3225

3281

3429

3334

0

0.5

1

1.5

2

2.5

3

Underweight Normal Overweight Obese

Maternal BMI

Od

ds

Rat

io

3100

3200

3300

3400

3500

Me

an

bir

th w

eig

ht

(g)

Odds of high birth weight

Mean birth weight

Fetal growth parallels maternal BMI

Heavier babies remain heavier

Danish conscripts 18-26 y.o. Sorensen, Gillman, et al., BMJ 1997;315(7116):1137.Adjusted for gestational age, birth length, maternal factors

22.2

22.6

23

23.4

23.8

24.2

24.6

25

<2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 >4.5

Birthweight (kg)

Adu

lt B

MI (

kg/s

q m

)

Oken, Ob Gyn Clinics of N. America, 2009 Jun;36(2):361-77.

Odds of child obesity for obese vs. normal weight mothers

3.1

4.1 4.3

5.1

4.3

1

10

Whitaker 2004(age 4)

Li 2005 (ages2-14)

Reilly 2005(age 7)

Li 2007 (Ages2-12, early

onset)

Salsberry 2007(ages 12-13)

Author, year, child age

Od

ds

rat

io f

or

ch

ild o

bes

ity

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

The prevalence of excessive weight gain is also on the rise

25

30

35

40

45

50

1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003

Year

% g

ain

ing

ex

ce

ss

ive w

eig

ht

http://www.cdc.gov/pednss/pnss_tables/html/pnss_national_table16.htm

Distribution of GWG relative to 1990 guidelinesby prepregnancy BMI category (PRAMS, 2002-03)

Body mass index category (IOM criteria)

Under- Normal- Over- Obese

Pro

port

ion

(%)

of w

omen

0

20

40

60

80

100

120

weight weight weight

< IOM Within IOM > IOM

19.5

49.9

30.6

38.4

41.1

20.5

63

26.8

10.3

36.3

30.2

23.5

Oken et al., Am J Ob Gyn 2007;196(4):322 e1-8.

0.17

0.470.52

0

0.2

0.4

0.6

0.8

Maternal weight gain per 1990 IOM Guidelines

Ch

ild

BM

I z s

co

re

.

Inadequate Adequate Excessive

Adjusted for maternal race/ethnicity, smoking, BMI, socio-demographics, gestationaldiabetes; paternal BMI; child sex, gestation length, breastfeeding duration

Gestational weight gain and child weight

0.29

-0.25

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

<10 10-14 15-19 20-24 25-29 30-34 35-39 40-44 >=45

Gestational weight gain (pounds)

Cha

nge

in c

hild

BM

I z-s

core

Without adjustment for maternal BMI

With adjustment for maternal BMI

Oken et al. 2008

Gestational weight gain and adolescent 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)


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

Schultz et al. Diabetes Care 2006;29(8):1866-71

Even in Pima Indians, it’s not just the genes

7%

38%

13%

70%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Type 2 Diabetes Obesity

Mexico

United States

Genes Shared behaviors

Parents and children tend to share diet, physical activity habits (Oliveria et al, AJCN, 1992)


Genes Shared behaviors Mediators

Fetal growth & body composition at birth


Size at birth and body composition larger babies: more muscle and more fatsmaller babies: less muscle, but not less fat

MU

A m

usc

le a

rea

z sc

ore

Age (months)

Small for gestational age

Large for gestational age

Hediger et al, Pediatrics, 1998

http://pediatrics.aappublications.org/content/vol102/issue5/images/large/pe1183449001.jpeg






Fetal growth & body composition GDM


Silverman et al., Diabetes Care, 1998

Offspring of mothers with DM in pregnancy are heavier at 14-17 years

26

23.6

24.6

20.7

20

21

22

23

24

25

26

27

GestationalDiabetes

Pre-gestationaldiabetes

All maternal DMcombined

NCHS reference

Mea

n B

MI (

kg/m

2)


Fetal growth & body composition GDM Breastfeeding


Breastfeeding

• Observational studies suggest small benefit for child obesity (but confounded)

Breastfeeding and child overweight

Odds of obesity.5 1 1.5

Combined

Taitz (0)

Yeung et al (0.5)

Dewey et al (1)

Thorogood et al (1)

Armstrong & Reilly (3)

Grummer-Strawn and Mei (4)

Hediger et al (4)

Neyzi et al (5)

O'Callaghan et al (5)

Scaglioni et al (5)

Bergmann et al (6)

von Kries et al (6)

Wadsworth et al (6)

Richter (7)

Strbak et al (1-7)

Eid (8)

Li et al (8)

Maffeis et al (10)

Frye and Heinrich (10)

Liese et al (10)

Toschke et al (6-14)

Sung et al (11)

Gillman et al (12)

Elliot et al (15)

Kramer (15)

Kramer (15)

Tulldahl et al (16)

Poulton and Williams (26)

Parsons et al (33)

Breast feeding better Formula feeding better

0.87 (95% CI 0.85, 0.89)

Owen et al, Pediatrics, 2005

Large RCT: no differences at 6.5 years(but all infants breastfed )

0.70.1 0.3

-0.40 0.2 0.2

-4

-3

-2

-1

0

1

2

3

4

Height, cm BMI, kg/m2 Waistcircumference,

cm

Triceps SF,mm

SubscapularSF, mm

Systolic BP,mm

Diastolic BP,mm

Outcome at age 6.5 years

Clu

ste

r-a

dju

ste

d d

iffere

nce

*

*Difference > 0 indicates higher value in experimental group

Kramer et al. Am J Clin Nutr. 2007 Dec;86(6):1717-21

Genes Shared behaviors Mediators Confounders

SES Smoking


Maternal prenatal smoking and child overweight – meta-analysis

Odds Ratio.5 1 5

Combined

von Kries, 2002

Wideroe, 2003

Whitaker, 2004

Toschke, 2003

Toschke, 2002

Salsberry, 2005

Reilly, 2005

Power, 2002 M

Power, 2002 F

Oken, 2005

Dubois, 2006

Chen, 2006 M

Chen, 2006 F

Bergmann, 2003

Al Mamun, 2006

Adams, 2005

OR 1.50, 95% CI: 1.36, 1.65

Oken, et al. Int J Obes (Lond) 2008; 32(2):201-10

Pathways linking maternal weight with child outcomes

Maternal pre-pregnancysize

Gestationalweightgain

Child adiposity

Birth weight

Diseaseoutcomes

Fetalgrowth

Gestationlength

Shared genes and behaviors

GestationalDiabetes

Infant feeding &growth

Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.

Genes Shared behaviors Mediators Confounders Direct effect of the intra-uterine environment


Pathways linking maternal weight with child outcomes

Maternal pre-pregnancysize

Gestationalweightgain

Child adiposity

Birth weight

Diseaseoutcomes

Fetalgrowth

Gestationlength

Shared genes and behaviors

GestationalDiabetes

Infant feeding &growth

Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.

• 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!!


• Randomized trials• Observational human studies

– Statistical adjustment for measured factors


Maternal BMI associated with child weight even after adjustment

0.1

1

10

< 18.5 18.5-24.9 25-29.9 30-39.9 >= 40

Maternal 1st trimester BMI (kg/m2)Ad

jus

ted

od

ds

of

ch

ild

o

ve

rwe

igh

t

2 year olds

3 year olds

4 year olds

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

3.77 4.35

Inadequate Adequate ExcessiveMaternal weight gain per IOM recommendations

Od

ds R

ati

o .

10

Odds of child overweight according to maternal gestational weight gain

Adjusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestationaldiabetes; 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

4.33.4

4.2 4.2

1

10

100O

dd

s ra

tio

Excessive gain vs inadequate gain

GDM, BF

+ fetal growth

+ child diet & activity

+ mom diet & activity

Also djusted for maternal race/ethnicity, smoking, BMI, sociodemographics, gestationaldiabetes; paternal BMI; child sex, gestation length, breastfeeding duration

• Randomized trials• Observational human studies• Sibling studies


Weights of children born before (BMS, n=45) and after (AMS, n=172) maternal weight-loss surgery

0%

10%

20%

30%

40%

50%

60%

Underweight Normal weight Overweight Obese

BMS

AMS

Kral JG, et al. Pediatrics. 2006 Dec;118(6):e1644-9

Dabelea et al., Diabetes 2000. 19 Pima families/58 sibs

• Randomized trials• Observational human studies• Sibling studies• Animal studies


Animal studies suggested early energy intake can permanently program body size

75 days: Weights 86g, 230g21 days: Weights 14g, 60g

Widdowson and McCance, 1960

Wei

ght (

g)

Age (weeks)

Food restriction during weeks 0-3results in sustained lower body weight (and food excess in higher weight)

21 day period of food restriction

weaning

Timing is important

Timing is important

weaning

Wei

ght (

g)

Later food restriction (weeks 9-12) –rats quickly regain and (perhapsovershoot) body weight

Age (weeks)

Widdowson and McCance, 1963 21 day period of food restriction

Offspring of overfed mother rats have higher body weight …

Samuelsson, A.-M. et al. Hypertension 2008;51:383-392

Male offspring Female offspring

Offspring of obese damsOffspring of control dams


…higher fat mass…


OC – Offspring of control damsOO – Offspring of obese dams

…higher energy intake…




…and adverse cardio-metabolic profiles


OC – Offspring of control damsOO – Offspring of obese dams

What are the mechanisms?

Altered AppetiteRegulation

High NeonatalAdiposity

Altered AdipocyteMetabolism

Wu Q. and M. Suzuki. Obes Rev. 2006 May;7(2):201-8

Experiment 3: Maternal high fat diet before gestation with embryo transfer after conception

Peri-conceptional exposure only


0

50

100

150

200

250

300

350

Body Weight Gain (g)

HF LF



0

5

10

15

20

Food Consumption(MJ rat-1)

Food Effiency (gMJ-1)

Abdominal AdiposeTissue

Plasma InsulinConc (ng Ml)

Plasma LeptinConc (ng Ml)

HF LF


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 3%

Obtain nutrition referral 14%

Herring SJ. Journal of Women’s Health, 2010.

Clinician Knowledge of BMI categories

Maternal BMI Correct response % Correct

Underweight < 18.5 kg/m2 48%

Normal >= 18.5 kg/m2

< 25 kg/m2

41%57%

Overweight >= 25 kg/m2

< 30 kg/m2

76%57%

Obese >= 30 kg/m2 60%

Please indicate the body mass index (BMI) that reflects each weight status listed below:

Herring SJ. Journal of Women’s Health, 2010

Postpartum weight loss is key

Gestational Diabetes

0.1

1

10

<-1 -1 to <1 1 to <2 2 to <3 >= 3

Change in BMI

Odd

s R

atio

BMI < 25BMI >= 25

Large for Gestational Age

0.1

1

10

<-1 -1 to <1 1 to <2 2 to <3 >= 3

Change in BMI

Odd

s R

atio

BMI < 25BMI >= 25

Villamor, Lancet 2006;368:1164-70

Modifiable postpartum behaviors and PPWR

Oken et al., AJPM 2007; 32(4):305-311.

0.50

0.23

0.95

0.1

1

10

Od

ds

Rat

io (

95%

CI) ThreeTwoOneNone

Number of beneficial postpartum behaviors

TV viewing < 2 h/day, walking > 30 min/day, trans fat < median

Physical activity before, during, and after pregnancy

2.2

5.4

2.3

9.8

1.5

5.1

0.7

7.2

1.4

5.8

1.3

8.4

0

2

4

6

8

10

12

Light-moderate

Walking forexercise

Vigorous Total activity

hour

s / w

k

Prepregnancy (n=1895)

2nd trimester (n=1623)

6 mo postpartum (n=1124)

Pereira et al, AJPM, 2007

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

0.1

1

10

<= 5 6 7 8

Hours of sleep

Od

ds r

ati

o (

95%

CI)

.

3.1

Gunderson, et al. AJE 2007

Substantial PPWR >= 5 kg at 1 year by sleep at 6 mo postpartum

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.

Childhood

• Beware of ‘catch up growth’

Infant weight gain

0

2

4

6

8

10

12

14

Pre

va

len

ce

o

ve

rwe

igh

t a

ge

7

ye

ars

WG5 WG3 WG1B

W1

BW

2

BW

3

BW

4

BW

5

Early infancy weight gain categories

Birth weight categories

Stettler N, Pediatrics 2002

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 & MeStudy 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 Intervention

Usual Care

P-value

N (%) or Mean (SD)

Change in weight-for-length (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 ownintrauterine

and childhoodexperiences

Mom’s peri-

conceptionalhealth

Utero-placental blood flow,placental function

Diet duringpregnancy

Fetalmetabolism

IDM = infants of mothers with GDM

Boloker et al., Diabetes 2002;51(5):1499-506.

Intergenerational influences

http://diabetes.diabetesjournals.org/content/vol51/issue5/images/large/db0520363002.jpeg

http://diabetes.diabetesjournals.org/content/vol51/issue5/images/large/db0520363002.jpeg

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

Mom’s ownintrauterine

and childhoodexperiences

Mom’s peri-

conceptionalhealth

Utero-placental blood flow,placental function

Diet duringpregnancy

Fetalmetabolism

Extrauterine environment

SGA and LGA trends since 1990

Oken et al. Obstet Gynecol. 2010 Feb;115(2 Pt 1):357-64

0.9

-2.2

-3

-2

-1

0

1

2

3

1990 1995 2000 2005Year

Ch

an

ge

in %

SG

A o

r L

GA

fro

m 1

990 Small for Gestational Age,

Low-Risk Subgroup

Large for Gestational Age,Low-Risk Subgroup

SGA and LGA trends since 1990


0.9

-2.2

-3

-2

-1

0

1

2

3

1990 1995 2000 2005Year

Ch

an

ge

in %

SG

A o

r L

GA

fro

m 1

990 Small for Gestational Age,

Low-Risk Subgroup

Large for Gestational Age,Low-Risk Subgroup

SGA

LGA

Birth weight trends since 1990


-51

-79

-100

-80

-60

-40

-20

0

1990 1995 2000 2005Year

Ch

ang

e in

Bir

th W

eig

ht

(g)

fro

m 1

990

All Births

Low Risk Subgroup

Questions?“Anything on women of pre-childbearing age?”

Faculty Disclosure Emily Oken, MD, MPH Dr. Oken has listed no financial interest/arrangement that...

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