1. Effects of maternal obesity on fetal growth
and metabolic health of the offspring
Emily Oken, MD, MPH
Obesity Prevention Program
Department of Population Medicine
Harvard Medical School and Harvard Pilgrim Health Care Institute

2. 0
5
10
15
PrevalenceofOverweight
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.

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

4. ‘Fetal Origins’ hypothesis
David Barker.
Mothers, Babies, and
health in later life.

5. ‘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 >4.5
AdultBMI(kg/sqm)
Birthweight(kg)

6. 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
Percentage
Overweight (BMI >= 25.0)
Obese (BMI >= 30.0)

7. Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies.
2.36
1.31
1.00
0.52
3225
3281
3429
3334
0
0.5
1
1.5
2
2.5
3
Underweight Normal Overweight Obese
Maternal BMI
OddsRatio
3100
3200
3300
3400
3500
Meanbirthweight(g)
Odds of high birth weight
Mean birth weight
Maternal weight predicts fetal growth

8. 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

9. Stillbirth
2.07 (1.59, 2.74)

10. NICU treatment
Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies.
1.35 (1.22, 1.49)

11. Neonatal outcomes
Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies.
1.5
2.1 2.1
1.6
1.0 1.0
0.1
1
10
Low 1m
Apgar
Low 5m
Apgar
Fetal
compromise
Meconium Shoulder
dystocia
Jaundice
OddsRatio(95%CI)
n=3 n=4 n=4 n=5 n=9 n=4

12. 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
1.3
1.5 1.5
1
10
Incubator
requirement
Respiratory
distress
Resuscitation Fetal heart
rate
abnormalities
Tube feeding
required
Birth trauma
OddsRatio(95%CI)

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

14. Outcomes in childhood and beyond

15. 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 (ages
2-14)
Reilly 2005
(age 7)
Li 2007 (Ages
2-12, early
onset)
Salsberry 2007
(ages 12-13)
Author, year, child age
Oddsratioforchildobesity

16. 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.

17.  Genes
What accounts for associations of
maternal weight with child weight?

18. 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

19. The uterus
is the environment of the fetus

20.  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?

21.  Genes
 Shared behaviors
 Mediators
 Fetal growth
 GDM
 Breastfeeding
 Infant diet quality and feeding
interactions
What accounts for associations of
maternal weight with child weight?

22. 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)
ChangeinchildBMIz-score
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 guid
by prepregnancy BMI category (PRAMS, 2
Body mass index category (IOM criteri
Under- Normal- Over- Obese
Proportion(%)ofwomen
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)

23.  Genes
 Shared behaviors
 Mediators
 Confounders
 SES
 Smoking
What accounts for associations of
maternal weight with child weight?

24. 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

25.  Genes
 Shared behaviors
 Mediators
 Confounders
 Direct effect of “obese” intrauterine
environment
What accounts for associations of
maternal weight with child weight?

26. Maternal diet
0.1
1
10
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
OddsRatio
Maternal prenatal diet and child ow/obesity at age 5
% Saturated Fat % Sugar
Murrin et al. EJCN 2013
Donahue et al. AJCN 2011

27. 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
1.59
1.46
1.18
Odds of obesity for black vs. white children in the US
Adjusted for
sociodemographic
characteristics
Adjusted for
prenatal &
perinatal
factors
• Pre- and peri-natal
factors explain
most of the
disparity in obesity

28. 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

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

30. 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

31. Weight(g)
Age (weeks)
Food restriction during weeks 0-3
results in sustained lower body weight
(and food excess in higher weight)
21 day period of food restriction
weaning

32. Timing is important
weaning
Weight(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

33. 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 dams
Offspring of control dams
Offspring of obese dams
Offspring of control dams

34. …higher fat mass…
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
OC – Offspring of control dams
OO – Offspring of obese dams

35. …higher energy intake…
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
Offspring of obese dams
Offspring of control dams
Offspring of obese dams
Offspring of control dams

36. …and adverse cardio-metabolic profiles
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
OC – Offspring of control dams
OO – Offspring of obese dams

37. Pathways linking maternal weight
with child outcomes
Maternal
pre-pregnancy
size
Gestational
weight
gain
Child
adiposity
Birth
weight
Disease
outcomes
Fetal
growth
Gestation
length
Shared genes and behaviors
Gestational
Diabetes
Infant
feeding &
growth
Oken, E. In “Influence of Pregnancy weight on maternal and child health.” IOM 2007.

38. The microbiome and obesity
Huh et al. Arch Dis Child 2012.
Dominguez-Bello et al. Proc Natl Acad
Sci USA. 2010;107[26]:11973.)

39. „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?

40. Epigenetics
Genes = hardware
Epigenetic markers = software

41. The Placenta
Al Wasel et al., Placenta 2010

42. Diet
Extrauterine
environment
Mom’s own
intrauterine
and childhood
experiences
Mom’s
prenatal
health
Fetal
and placental
metabolism
Child growth
and behaviors

43. 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

44. Air pollution and obesity
Fleisch et al. Submitted.
Fleisc
h
Et
al
0.1
1
10
1 2 3 4 5
Black Carbon
Traffic Density
Quintile
Overweightat6m

45. Built environment
Air Pollution
Social stressors
Overnutrition
Which comes first?

46. Taveras et al. Arch Ped Adol Med 2012.
What can you do after birth?
• Watch out for
accelerated
postnatal growth

47. 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
OddsRatio
BMI < 25
BMI >= 25
Gestational Diabetes
0.1
1
10
<-1 -1 to <1 1 to <2 2 to <3 >= 3
Change in BMI
OddsRatio
BMI < 25
BMI >= 25

48. 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
Cases
Controls
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.