Developmental Origins of Health and Disease (DOHaD) and the Barker Hypothesis

Introduction to Developmental Origins of Health and Disease (DOHaD)

  • Definition: Developmental Origins of Health and Disease (DOHaD) is a field of research focused on the powerful influence that the early life environment—specifically the environment in utero—has on the development of health and the risk of disease later in life.

  • Primary Objective: To unpack the association between early life conditions and adult disease in order to identify opportunities for the prevention of chronic health conditions.

  • Key Indicator: Birth weight is a primary indicator used to measure the quality of the early life environment during pregnancy. An inadequate or poor environment during pregnancy typically results in a baby being born with a low birth weight.

Disease Associations with Birth Weight

  • Conditions Linked to Low Birth Weight: Research has established a strong awareness that low birth weight is associated with an increased risk for several adult diseases, including:

    • Hypertension (high blood pressure).

    • Type 2 diabetes.

    • Metabolic syndrome (including various related physiological markers).

    • Altered immune responses.

    • Respiratory disease.

    • Mental health outcomes, specifically depression and anxiety.

  • The U-Shaped Risk Curve: While low birth weight increases risk, the relationship is often U-shaped rather than linear.

    • High Birth Weight Risks: Babies born with very high birth weights (often occurring in pregnancies complicated by maternal hyperglycemia or gestational diabetes) also face increased health risks later in life.

    • Insulin as a Growth Factor: In cases of maternal hyperglycemia, high glucose levels in mothers promote insulin secretion in the fetus. Because insulin is a powerful growth factor, this leads to increased fetal weight and changes in the development of glucose and insulin-related pathways, predisposing the offspring to diabetes.

The Barker Hypothesis

  • Origins: The concept was proposed by David Barker, who first identified the link between early life environment quality and adult health outcomes.

  • The Barker Hypothesis Definition: This hypothesis states that early life environmental manipulation impacts later physiological changes and disease risks.

  • Barker’s Vision: Barker argued that diseases such as heart disease or osteoporosis are not "mandated by the human genome" and barely existed 100 years ago. He characterized them as "unnecessary diseases" that could be prevented if society had the will to address their early origins.

  • Geographic Patterns of Disease:

    • Barker utilized records from a midwife in Southampton to track health associations.

    • Mapping the United Kingdom revealed that counties with high infant death rates in the 1900s corresponded closely to areas with high rates of heart disease deaths in the 1960s and 1970s.

    • Interpretation: High infant death rates indicated complicated pregnancies and poor utero environments. Those who survived these environments were more likely to develop heart disease as adults.

Statistical Data on Birth Weight and Disease

  • Type 2 Diabetes and Glucose Intolerance: Historical data demonstrates a "step-down relationship" where the lower a man's birth weight, the higher the odds ratio for developing glucose intolerance or type 2 diabetes.

  • Metabolic Syndrome: Similar to diabetes, the odds ratio for developing metabolic syndrome decreases as birth weight increases (until it reaches the high-weight threshold).

  • Hypertension: Data tracking the incidence of hypertension shows that individuals with a lower birth weight (measured in kilograms) exhibit a higher incidence of high blood pressure as adults.

Postnatal Environment and Growth Trajectories

  • The Role of Early Childhood Growth: Adult health is not solely determined by birth weight; the postnatal growth trajectory is also critical.

  • Catch-Up Growth Phenomenon: Research tracking individuals who developed hypertension shows a specific growth pattern:

    • The individuals are born small relative to the population mean (Z \text{-score} < 0).

    • Their weight remains low compared to the general population until approximately age seven.

    • At around age seven and a half, these individuals experience "catch-up growth," where they not only reach the population mean but quickly overshoot it.

  • Consequences: This rapid catch-up growth, following a period of being small in utero and early childhood, is a significant factor in programming adult health issues.

Evolutionary Theory: Predictive Adaptive Response (PAR)

  • Core Theory: The Predictive Adaptive Response (PAR) theory suggests that a fetus adapts its physiology based on signals received from the maternal environment to prepare for the environment it expects to encounter after birth.

  • Thrifty Adaptation:

    • If a fetus is exposed to nutrient restriction, it slows its growth and undergoes "thrifty adaptation."

    • This programming allows the body to be highly efficient at fat storage and nutrient sequestration.

  • Survival Advantage vs. Mismatch:

    • Match: If the child is born into a nutrient-poor environment, the "thrifty" physiology is a survival advantage.

    • Mismatch: If the child is born into a nutrient-rich environment (the "modern world"), the thrifty programming leads to obesity, metabolic syndrome, and diabetes.

  • Case Studies in Famine:

    • Dutch Hunger Winter (WWII): A short-term famine (3–4 months). Offspring were programmed for thrift but born into a nutrient-rich environment after the famine ended, leading to high rates of hypertension and obesity (a mismatch).

    • Siege of Leningrad: A long-term famine (over 12–18 months). Offspring were programmed for thrift and remained in a nutrient-poor environment for a long duration, which resulted in fewer adverse health outcomes compared to the Dutch cohort (a match).

Worldwide Epidemiological Evidence and Events

  • The Holocaust: Research into children born to women in concentration camps to observe long-term developmental impacts.

  • 9/11 Terrorist Attacks: Tracking offspring of women pregnant during the attacks (specifically those at the World Trade Center or who lost partners).

    • Finding: Third-trimester exposure led to altered HPA axis (Hypothalamic-Pituitary-Adrenal axis) development and altered behavioral stress responses in children.

  • Quebec Ice Storm: A period of 80 hours of freezing rain, leading to severe acute stress (no electricity/water, trapped indoors). Offspring showed behavioral differences later in life.

  • Great Chinese Famine: Occurred due to changes in private farm ownership; offspring exposed in utero developed altered health trajectories.

  • Indigenous Populations and Colonialism: An under-researched area. While colonialism and systemic inequity clearly impact health, data is limited by a lack of historical records and current health inequities.

DOHaD in the Modern Context

  • Modern Environmental Stressors: The current environment presents several factors that alter fetal development trajectories:

    • Increased density of living and less access to green space.

    • High-calorie, nutritionally poor, and cheap food ("Life of Plenty").

    • Sedentary behaviors and low physical activity.

    • Substance use (alcohol and smoking).

    • Decreased community connection and loss of the "village" support system for raising children.

    • The emerging effects of climate change.

  • Individual Variation: While population-based epidemiological studies are essential, they must be balanced with an understanding of individual genetics, biology, and specific experiences.

  • Research Methodology: Because epidemiological studies are suggestive but not unequivocal, researchers use animal models to examine specific biological mechanisms and eliminate the confounding factors found in human populations.