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Fetal Origins of Adult Disease
M. Bardett Fausett MDOrigin Health-Maternal Fetal Care
1. It’s not all genetic2. The uterine environment has a profound effect3. What we do makes a difference
A Bridge Too FarSeptember 1944 Arnhem Holland
German retaliation for Dutch participation in the resistance
Average caloric intake dropped from 1,500 cal/day to 450 cal/dayfrom Sept 1944 to May 1945
20,000 Deaths
Overall effects of the Hunger Winter
Clement Smith - American PediatricianMaternal weight gain as low as 4 lbsSignificant drop in birth weight and height (250 grams)
The Effect of Malnutrition on Pregnancy
Pregnancy prior to or following the hunger winter
Starvation only during first trimester - pregnant in spring 1945
Starvation only during the third trimester - birth late 1944BIGGEST BABIES
SMALLEST BABIES
Effects of Starvation on Growth
50 Days 100 Days Birth
Kg
1
2
3
Placental Weight
Baby’s Weight
Long-term EffectsAdult Obesity
N = 300,000 at 19 years old
0.00
0.75
1.50
2.25
3.00
Before First Half Second Half After
% affected
DJP Barker, MD
General Practitioner, ER1966-”Low Intelligence; Its Relation to Length of Gestation and rate of Foetal Growth”
Low birthweight and prolonged pregnancy associated with low intelligence
Clues in old maps
High Infant Mortality 1901-1910
Death from CAD in men aged 35-74 in 1959-1978
Is CAD a disease of affluence?
LONDON
Interpretation
Babies less well-prepared during fetal development were more prone to suffer from high incidence of neonatal death and CAD later in life
It is who you know
Hertfordshire CountyMidwife visits 1911--Birthweight, diet, illnessesWeight at 1 year
More Birth RecordsPreston
1934-1943Placental weight
Hospital, Sheffield, Yorkshire1907--birth proportionslengthabdominal and chest circumference
Adult RecordsKnocking on doors
Current measurementsTissue samples
National Health ServiceMen easier than womenBP measurementsProblem list
Studies linking Birthweight to CADBirth Characteristics
Small headsThin and ShortHigh Placenta : Birthweight ratios
PopulationsUK, India, China, Finland, USA
%Affected
5
10
15
Birth Weight
Coronary Artery Disease
Barker Hypothesis
2000 g 3000 g
Heart Disease40 Million in US with CAD60 Million with HTN80 Million with high Cholesterol1.5 Million MI/year
The Modern Fix
TobaccoDiet
ExerciseStress
The Origins of Health and Disease: Fetal Programming
Principles of Fetal Programming
1. Critical Periods of vulnerabilityToo much or too little
HormoneNutrientVitamin
Abnormal chemicalsAbnormal physical forces
Principles of Programming
2. Programming haspermanent affects
3. Development proceeds in an ordered fashion
Principles4. Structural changes in
varied organsCell numberProportion and distribution of cell typesBlood supplyHormone receptor populations
Principles
5. The placenta plays a key roll
6. Compensation carries a price
Principles7. Postnatal attempts to
reverse consequences or an unexpected postnatal environment may bedetrimental
8. Fetal and adult cellular mechanisms differ
Principles9. The effects may cross
generations
10. Differing effects on males and females
Pima Indians50% AO diabetesGenetic???Risk of DM greater if grandmother rather than Grandfather diabeticEpidemic rise in incidenceFABP2 studies
The Island of NauruLimited food /resources
Discovered Fertilizer
Affluent with plenty of food
Incidence of NIDDM to 30%
Men with NIDDM had lowest birthweight
Falling incidence of NIDDM
Gestational Diabetes
Streptozocin Saline
Normal Pregnancy
Ouch!Ouch!
Animal Evidence
Insulin regulation in ratsFetus of DM ratsIslet cell burn outMacrosomiaUpregulation of Insulin receptorsGlucose dysregulation at birth
Life-long Effects of GDM
5
10
Day 0 Day 30 Day 90
Mouse Babies Mouse Babies
Glucose
Life-long Effects of GDM
175
350
Day 0 Day 30 Day 90
Mouse Babies Mouse Babies
InsulinLevel
Long-term Effects
Prenatal exposure to excess glucose causes increased insulin in fetus
Fetal macrosomia and alterations in insulin receptor sensitivity
Continued obesity andincreased susceptibility to Type II diabetes later in life
Transgenerational Effects
Mouse Babies Mouse Babies
Gestational Diabetes Normal Pregnancy
Mouse Babies Mouse Babies
Etc. Etc.
Insulin and GlucoseInadequate insulin actionHyperglycemiaAbnormal plasma amino acidsCell catabolismFetal exposurehyperglycemiaabnormal mix of amino acids
Nutrition Deprivation
Just before Birthshorter lifespan
Just after birthincreased lifespan
Catch up feedingSHORTER LIFESPAN
Low Protein DietJoseph Hoet et al
1/2 protein ®¯ Islet cell formation¯ blood vessel formation
Nicholas Hales¯ Protein ®
Altered liver cell type distribLiver glucose export > import¯ Islet Cell glucose sensitivity
The Thrifty GenotypeDeficient Maternal nutrition or
poor placental function
Fetus develops thrifty metabolism:1. Fetus conserves for important tissues2. Fetus prepares for harsh extrauterine life
Hyperactive AdrenalInsulin resistance
Decreases Glucose use by muscleSaves glucose for brain/heart
Fetal vs neonatal growth
Fowden et al
Room in the Womb
62% of Birth weight variationis environmental
John Hammond1930’s
Clydsdale Mare Clydsdale Stallion
Little Foal
Shetland MareShetland Stallion
Big Foal
Perinatal MortalityCochabamba > La Paz > Santa Cruz
Stress Response
Stressor
HypothalamusCRH
Ant Pituitary
Glucocorticoids
Stress Response
ACTH
Cortisol
Stress HormoneInactivated by placentaCO, vascular sensitivityMoodImmune SystemSleep/Wake cycles
Stress Stimuli vs ResponseEvolutionary ProvisionRun!! NOTMobilize GlucoseMobilize FatCV efficiency
stress response¯ Cortisol receptors
cortisol
Nl stress response
Nl stress response
Young Adult OffspringAdult Pregnant Rats
Newborn Rats withstressed mothers
Nl stress response
Adult
Reversing the Damage
It’s all my mother’s fault!
Patient Selection Inclusion Criteria
Live births between 1993 - 1998Birth weight < 1500 gramsNo fetal anomaliesUtah residents
Study GroupsGroup 1 - No steroidsGroup 2 - Single course1 set of 2 injections
Group 3 - Multiple course > 2 sets of injections more than one
week apart
Bayley Scales of Infant DevelopmentMental - MDI Psychomotor - PDI
Auditory/visual skills
Language
Problem solving
Social skills
Number concepts
Extremity movements
Basic motor skills
Hand control
Complex motor skills
Logistic Regression Multiple courses
MDI < 86
OR 95% CL
1.47 0.80 - 2.8
MDI < 70 2.35 1.1 - 5.2
Logistic Regression Multiple courses
OR 95% CL
PDI < 86 3.0 1.6 - 5.7
PDI < 70 2.5 1.3 - 4.9
ConclusionMultiple courses of
antenatal steroids are associated with adverse mental and psychomotor
development
CancerNurses Health Study
n = 2000Controlled for usual factors2 Kg vs 4 Kg birthweight0.5 is OR of developing Br CA? Estrogen effect
Prostate Ca linked to BW
Depressed Monkeys3 Groups of Pregnant Monkeys
1. Plenty of food2. Scarce food3. Variable food
Stressed group 3antisocial offspringhigh cortisol mothersoffspring
Long-term Follow-upThe Utah Study
Utah population databaseIdentified men born between 1947 and 1957
Preeclampsia N=104Normal controls N=97
Questionnaire, limited exam and blood samples
Chronic Disease
0
2
4
6
8
10
Diabetes Hrt Dz Clot MI
Case ControlP = 0.33
P = 0.24
P = 0.71P = 0.94
Chronic Disease
0
50
100
150
Chronic Dz ScoreAny Chronic Dz
Case Control
P = 0.003
63
26
P = 0.0003
77
130
Hypertension
0
20
40
60
80
Reported HTNMeasured HTN
CaseControl
P = 0.018
P = 0.032
ETOH and Tobacco
0
10
20
30
TobaccoETOH
CaseControl
P = 0.29
P = 0.12
Sibling History
0
5
10
15
20
25
30
Sib with HTN Sib with DM Sib with Depression
Case ControlP = 0.048
P = 0.97P = 0.24
Birth weight
0
10
20
30
40
50
60
70
BirthweightPercentile
Case Control
P = 0.0005
3044 3453
P = 0.024
34
49
When case or control status is included neither birthweight nor birthweight percentile are significant predictors of hypertension or chronic disease.
Regression Analysis
1. It’s not all genetic2. The uterine environment has a profound effect
3. What we do makes a difference
“The child is the father of the man”
