1. Maternal and fetal nutrition
Petrenko N.V., MD, PhD

2. Outline Maternal Undernutrition and Low Birthweight (LBW)
Overnutrition and Metabolic Syndrome
LBW and Metabolic Syndrome: Is There a Relationship?
Fetal Programming, “thrifty phenotype”, and epigenetics
Future Directions

3. Healthy Birthweight = Healthy Life
“Birthweight is a strong indicator not only of a birth mother's health and nutritional status but also a newborn's chances for survival, growth, long-term health and psychosocial development.” UNICEF

4. Low Birthweight (LBW) Definition: birthweight <2500 g (5.5 lbs)
Low birthweight babies are more than 20 times likely to die during infancy than heavier babies.

5. Over 20 Million Low Birthweight Infants Are Born Yearly In The Developing World
UNICEF/WHO 2004

6. Maternal Undernutrition and Low Birthweight
Maternal malnutrition is the leading cause of low birth weight in developing countries
Has varied roots:
Poor nutritional status prior to pregnancy
Short stature
Poor nutrition during pregnancy

7. Low Birthweight and Adult Health
Numerous disorders occur more commonly in adult former LBW babies.
COPD, breast CA, osteoporosis, schizophrenia, metabolic syndrome
LBW babies are more likely than average birthweight babies to develop type 2 diabetes and hypertension in adulthood Barker et al. Rev Reprod 1997

8. Low Birthweight: Studies in Rats
Rats exposed to 50% maternal undernutrition in the last half of pregnancy had poor remodeling of vasculature, a contributing factor to subsequent hypertension.
Khorram O. et al. Repreod Sci 2007
In adulthood, LBW rats developed obesity and had increased expression of lipogenic “obesity” genes Magee et al., Am J Obstet Gynecol 2008

9. Metabolic Syndrome Abdominal obesity High serum triglycerides
Low HDL (high-density lipoprotein)
Insulin resistance
Hypertension
INCREASED RISK OF CARDIOVASCULAR
DISEASE AND TYPE II DIABETES

10. Fetal Programming
Stimulus
Adaptation

11. Fetal Programming
Maternal Malnutrition ?

12. Barker or “Thrifty Phenotype” Hypothesis
Poor fetal and infant growth increase susceptibility to metabolic syndrome later in life

13. Barker or “Thrifty Phenotype” Hypothesis
Maternal Malnutrition
fetal malnutrition
beta-cell mass or islet dysfunction
adult beta-cell function
obesity
age
insulin resistance
hypertension
Metabolic Syndrome

14. Predictive Adaptive Response
FETAL
ENVIRONMENT
POSTNATAL
ENVIRONMENT
ADULT
HEALTH
Adequate Nutrition
Adequate Nutrition
HEALTHY
Poor Nutrition
MALNOURISHED
METABOLIC
SYNDROME
Adequate Nutrition
Poor Nutrition
Poor Nutrition
MALNOURISHED

15. Hertfordshire Studies: Insulin Resistance
Published in early 1990s (Hales, Barker et al.)
468 men born in Hertfordshire and still living there
Birthweights recorded
Tests for insulin resistance performed:
fasting glucose and insulin before and after glucose drink

16. Hertfordshire Studies: Insulin Resistance
Low Birthweight Increases Risk of Insulin Resistance in Adulthood
Odds Ratio Insulin Resistance
Birth Weight (lbs)
Hales CN et al. BMJ 1991; 303:

17. Sheffield Study: Cardiovascular Mortality
5585 men and 10,141 women born in Sheffield, UK
Low birthweight infants had higher risk of coronary artery disease in adulthood
Similar trends in risk for hypertension and type 2 diabetes
Osmond et al. BMJ 1993

18. Sheffield Study: Cardiovascular Mortality
Standardized Mortality Ratio
Birthweight
Osmond et al. BMJ 1993

19. Dutch Winter Hunger Study
Effects of strict food rationing at end of WWII in Holland: Nov 1944 – May 1945
Men and women exposed to famine while in utero had increased risk of insulin resistance and metabolic syndrome as adults
More obesity and coronary artery disease in those exposed to famine during early gestation
Those with low birthweight who became obese during adulthood had more insulin resistance Ravelli et al. Lancet 2998

20. Epigenetics: Clues to Mechanisms of Fetal Programming?
Epigenetics: “The study of heritable changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence.”
Wikipedia

21. Epigenetics: Methylation “Silences” Genes

22. Epigenetics and Obesity: Waterland Mouse Studies
Studies in Avy/a mice:
Mice vary in expression of agouti gene expression
Genetically identical but methylation of agouti gene varies considerably
Tend to overeat and become obese if allowed to eat ad libitum
Good model for human obesity

23. Epigenetics and Obesity: Waterland Mouse Studies
Studies in Avy/a mice:
Allowed mice to eat ad lib and become obese
Bred for three successive generations
Some mice given methyl donor supplement, others not given methyl donor supplement.
food + methyl donor
food only
GROUP 1
GROUP 2

24. Epigenetics and Obesity: Waterland Mouse Studies
Obese mouse dams produce obese offspring,
but methyl donor supplementation prevents this effect
food + methyl donor
food only
maternal weight
3rd generation offspring
weight
Waterland RA et al. Int J Obes 2008

25. Maternal Over-/Undernutrition Increases Risk: Implications for Future Generations
“U” – Shaped Curve
METABOLIC SYNDROME RISK
BIRTH WEIGHT

26. Future Directions: Prevent the “Vicious Cycle” of Obesity and Metabolic Syndrome
Continue to treat maternal undernutrition via programs in resource-poor areas as IMHO currently does.
Address overnutrition/obesity in all areas:
Education
Promote availability of healthy, affordable unprocessed foods