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”