188. Fetal Origins of Disease

Question 1

Developmental Origins of Heath and Disease Hypothesis

• what is it
• what is the Barker Hypothesis
• what is epigenetics, types
• how does maternal fetal programming play a role in over and undernutrition

Answer 1

How prenatal and childhood factors influent adult health risk factors + outcomes
Barker Hypothesis: low birth weight causes INCREASED risk of CAD, HTN, T2DM (early life events determine in part later disease development and mortality)
Epigenetics: study of changes in gene fx w/o changes in DNA sequence (DNA methylation, histone modification)

Undernutrition:
Undernourished mother - undernourished fetus - low birth weight - insulin resistance - postnatal undernutrition or overnutrition [NUTRIENT-MEDIATED TERATOGENESIS]

Overnutrition:
pregestational/gestational hyperglycemia - altered fuels - fetal adiposity + islet dysfx = macrosomia = obesity + hyperglycemia = post natal overnutrition [FUEL-MEDIATED TERATOGENESIS]

Question 2

Developmental Disruption vs. Developmental Plasticity

Answer 2

Both occur during critical periods of development
Disruption = Teratogenesis
- causes HARM - no advantage to fetus
- ex: FETAL ALCOHOL SYNDROME (timing of exposure: 1st trimester - birth defects + malformations; 3rd trimester - CNS abnormalities, lack of gyri folds)

Plasticity = developmental adaptation

• change in biologic programming that may induce a survival advantage
• ex: low birth weight - adaptation: catch-up growth - increased metabolic load - increased storage of extra fat - higher risk of metabolic disease

Question 3

Pathophysiology of Intrauterine Growth Restriction (IUGR)

What is the Thrifty Phenotype Hypothesis?

Answer 3

IUGR: due to utero-placenta insufficiency - placenta blood flow is only source of fetal nutrition - disrupted due to placental defects and maternal causes
- leads to glu and ins metabolism adaptations to adverse uterine enviro (higher risk for adult DM, CVD, Obesity!)

Thrifty Phenotype Hypothesis: explains how fetal malnutrition leads to Metabolic Syndrome

1. T2 DM: fetal malnutrition = ins resistance, low b-cell mass or islet fx = infant malnutrition = decreased adult b-cell fx = T2 DM
2. Dyslipidemia: fetal malnutrition = other organ malfx (liver)
3. HTN: fetal malnutrition = HTN

Timing of fetal/maternal exposure to malnutrition is important (famine studies)

Question 4

Gestational DM

• what is it
• pathophys

What are the maternal ins requirements in pregnancy?

What is the effect of poorly controlled maternal DM?

Answer 4

GDM: developmental overnutrition and fuel-mediated teratogenesis
Maternal: low insulin (DM) = more BG, AA, lipids delivered to placenta
Fetal: high mixed nutrient delivery = stim fetal ins production = macrosomia, hypoglycemia (transient, bad for brain), high risk of childhood obesity, impaired glu tolerance = DM in childhood

1st trimester = ins sensitive (low ins requirements)
3rd trimester = high ins requirement (mom needs lots of insulin as baby grows rapidly during birth)

Poor control = worse outcomes
Pregnant mom: preeclampsia/HTN, preterm labor, C-section, future T2DM risk
Fetus: macrosomia, hypoglycemia, jaundice, resp distress, obesity, ins resist

Question 5

What are RFs for Gestational DM?
How does GDM increase risk of stillbirth, jaundice, resp distress in fetus?

What is the trend in youth onset T2DM? How is the disease different than adult onset T2DM?

Answer 5

Maternal age > 35, overweight/obese maternal BMI, +FamHx DM, parity >2

Stillbirth: fetal hyperinsulinemia = high fetal substrate uptake = high tissue O2 consumption (more demand, less supply) = hypoxia = stillbirth
Jaundice: high fetal substrate uptake = macrosomia = myocardiopathy = altered O2 delivery = hypoxia = high erythropoietin = polycythemia = high RBC breakdown = hyperbilirubinemia = jaundice
Resp Distress: myocardiopathy (macrosomia) and decreased lung surfactant synthesis due to increased insulin

Youth trends RISING IN PREVALENCE
Children: more severe + rapid B-cell deterioration: less ins sensitive (even post-puberty), earlier disease complications, poor tx options

Question 6

What are three other systems impacted by the DOHaD (developmental origins of health and disease) hypothesis?

Answer 6

1. Asthma/Allergy/Atopy: enviro exposure influence resp/immune system development = asthma risk
2. Endocrine-disrupting chemicals: increased evidence linking to metabolic syndrome if disturbed b/w conception and birth (time of high cell differentiation and replication) - BPA, phthalates, PCBs, organochlorine, pesticides
3. Fetal Neurodevelopment: maternal anxiety/depression/stress influences fetus (maternal stress in early pregnancy causes inattentiveness/hyperactivity in boys, autism-like traits)