Oken o&p2013

Effects of maternal obesity on fetal growth and metabolic health of the offspring

Emily Oken, MD, MPHObesity Prevention Program

Department of Population MedicineHarvard Medical School and Harvard Pilgrim Health Care Institute

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 increasing not only in adults and children, also in infants

Kim et al., Obesity 2006; ~500,000 well child visits in Mass.

Lancet. 2010 May 15; 375(9727): 1737–1748.

‘Fetal Origins’ hypothesis

David Barker. Mothers, Babies, and health in later life.

http://ije.oxfordjournals.org/content/34/6/1234/F1.large.jpg

‘Developmental Origins’ and obesity

Hediger et al., Pediatrics, 1998; Sorensen et al., BMJ 1997; Innes et al. JAMA 2002

21

22

23

24

25

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

t BM

I (kg/

sq m

) Birthweight (kg)

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

Oken, Ob Gyn Clinics of N. America, 2009; NHANES data

Maternal obesity

0

10

20

30

40

50

60

1960-1962 1971-1974 1976-1980 1988-1994 1999-2002 2005-2008

Pe

rce

nta

ge

Overweight (BMI >= 25.0)

Obese (BMI >= 30.0)

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

Maternal weight predicts fetal growth

Birth defects – meta-analysis• Infants of obese mothers at increased risk for:

– neural tube defects (OR 1.87; 95% CI, 1.62-2.15)– spina bifida (OR 2.24; 95% CI, 1.86-2.69)– cardiovascular anomalies (OR 1.30; 95% CI, 1.12-1.51)– septal anomalies (OR 1.20; 95% CI, 1.09-1.31)– cleft palate (OR 1.23; 95% CI, 1.03-1.47)– cleft lip and palate (OR 1.20; 95% CI, 1.03-1.40)– anorectal atresia (OR, 1.48; 95% CI, 1.12-1.97)– hydrocephaly (OR 1.68; 95% CI, 1.19-2.36)– limb reduction anomalies (OR 1.34; 95% CI, 1.03-1.73)

• Lower risk for:– gastroschisis (OR 0.17; 95% CI, 0.10-0.30).

Stothard KJ, et al. JAMA 2009;301(6):636-650

Stillbirth

2.07 (1.59, 2.74)

NICU treatment


1.35 (1.22, 1.49)

Neonatal outcomes


1.5

2.1 2.11.6

1.0 1.0

0.1

1

10

Low 1mApgar

Low 5mApgar

Fetalcompromise

Meconium Shoulderdystocia

Jaundice

Od

ds R

atio (

95%

CI)

n=3 n=4 n=4 n=5 n=9 n=4

Other neonatal outcomes

Heslehurst, et al. Obesity Reviews 2008. Non meta-analysis results.

No association: asphyxia, hyperbilirubinemia, hypoglycemia, cord pH<7.2

1.6 1.7 1.8

1.31.5 1.5

1

10

Incubatorrequirement

Respiratorydistress

Resuscitation Fetal heartrate

abnormalities

Tube feedingrequired

Birth trauma

Od

ds

Ra

tio (

95

% C

I)

Infant death

Chen A, et al. Epidemiology 2009;20:74-81.

Outcomes in childhood and beyond

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.

Genes

What accounts for associations of maternal weight with child weight?

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

Environment matters, too

7%

38%

13%

70%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Type 2 Diabetes Obesity

Mexico

United States

The uterus is the environment of the fetus

Genes Shared behaviors

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


Genes Shared behaviors Mediators

Fetal growth GDM Breastfeeding Infant diet quality and feeding

interactions


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)

Change in c

hild

BM

I z-s

core Without adjustment for maternal BMI

With adjustment for maternal BMI

IOM 2009;Oken et al., AJOG 2008

Gestational weight gain

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

Body mass index category (IOM criteria)

Under- Normal- Over- Obese

Pro

portio

n (%

) of w

om

en

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

(25-35 lb)

(15-25 lb)

(12-20 lb)

(28-40 lb)

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

Genes Shared behaviors Mediators Confounders Direct effect of “obese” intrauterine

environment


Maternal diet

0.1

1

10

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Odd

s Rati

o

Maternal prenatal diet and child ow/obesity at age 5

% Saturated Fat % Sugar

Murrin et al. EJCN 2013

Donahue et al. AJCN 2011

Obesity disproportionately affects racial/ethnic minority children

• In 2010: 14% of white, 24.3% of Black, and 21.2% of Hispanic children 2-19 years were obese

• Overall rates are stubbornly high; racial/ethnic disparities are starting early and appear to be widening

Ogden et al. JAMA 2012.Weden et al. AJPH 2012.

0

5

10

15

20

25

Non-Hispanic White

Non-Hispanic Black

Hispanic

1.591.46

1.18

Odds of obesity for black vs. white children in the US

Weden et al. AJPH 2012;102(11) 2057-2067.

Adjusted for sociodemographic

characteristics

Adjusted for prenatal & perinatal

factors

• Pre- and peri-natal factors explain most of the disparity in obesity

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

Animal studies suggested early energy intake can permanently

program body size

75 days: Weights 86g, 230g

21 days: Weights 14g, 60g

Widdowson and McCance, 1960

Weig

ht

(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

weaning

Weig

ht

(g) 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 …

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

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.

The microbiome and obesity

Huh et al. Arch Dis Child 2012.Dominguez-Bello et al. Proc Natl AcadSci USA. 2010;107[26]:11973.)

‘Agouti’ mice - Genetic cause for obesity first identified >100 years ago

These mice are identical twins!

How do you get from here

back to here?

Epigenetics

Genes = hardwareEpigenetic markers = software

The Placenta

Al Wasel et al., Placenta 2010

Diet

Extrauterine environment

Mom’s ownintrauterine

and childhoodexperiences

Mom’s prenatalhealth

Fetal and placental

metabolism

Child growth and behaviors

Inter- and trans-generational influences

Kaati et al. European Journal of Human Genetics (2007) 15, 784–790

Excess early nutrition

in grandmother (pink line) results

in shorter lifespan in grandchild

Innes et al,. JAMA 2002

Longevity of grandchild

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

Air pollution and obesity

Fleisch et al. Submitted.

FleischEt al

1 2 3 4 51

10 Black CarbonTraffic Density

Quintile

Ov

erw

eig

ht

at

6 m

Built environment

Air Pollution

Social stressors

Overnutrition

Which comes first?

Taveras et al. Arch Ped Adol Med 2012.

What can you do after birth?

• Watch out for accelerated postnatal growth

What can you do after birth?

• Watch out for accelerated postnatal growth

• Promote postpartum weight loss

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

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

Dabelea D, et al. Diabetes Care 2008;31(7):1422-6. 79 youth aged 10-22y with Type 2 DM and 190 nondiabetic controls

% exposed to maternal diabetes % exposed to maternal obesity

CasesControls

What is the impact?Overall, 47.2% (95% CI 30.9–63.5) of type 2 diabetes in youth could be attributed to intrauterine exposure to maternal diabetes and obesity.

http://care.diabetesjournals.org.ezp-prod1.hul.harvard.edu/content/31/7/1422/F1.large.jpg



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Oken o&p2013

Health & Medicine

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