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

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

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

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. http://thebumpoc.com/?p=320

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

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

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

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

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

Fetal Programming Stimulus Adaptation

Fetal Programming Maternal Malnutrition ?

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

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

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

Hertfordshire Studies: Insulin Resistance Published in early 1990s (Hales, Barker et al.) 468 men born in Hertfordshire 1920-1930 and still living there Birthweights recorded Tests for insulin resistance performed: fasting glucose and insulin before and after glucose drink

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; 303:1019-22

Sheffield Study: Cardiovascular Mortality 5585 men and 10,141 women born in Sheffield, UK 1911-1930. 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

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

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

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

Epigenetics: Methylation “Silences” Genes

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

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

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

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

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