Post on 18-Dec-2014
description
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.
‘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)
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
Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies.
1.35 (1.22, 1.49)
Neonatal outcomes
Heslehurst, et al. Obesity Reviews 2008. Meta-analysis of published cohort studies.
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)
What accounts for associations of maternal weight with child weight?
Genes Shared behaviors Mediators
Fetal growth GDM Breastfeeding Infant diet quality and feeding
interactions
What accounts for associations of maternal weight with 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)
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
What accounts for associations of maternal weight with child weight?
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
What accounts for associations of maternal weight with child weight?
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
Offspring of obese damsOffspring of control dams
…higher fat mass…
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
OC – Offspring of control damsOO – Offspring of obese dams
…higher energy intake…
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
Offspring of obese damsOffspring of control dams
Offspring of obese damsOffspring of control dams
…and adverse cardio-metabolic profiles
Samuelsson, A.-M. et al. Hypertension 2008;51:383-392
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
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.