Paula Hertel Thevananther, M.D.April 30, 2011

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

“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

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

UNICEF/WHO 2004

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

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

In adulthood, LBW rats developed obesity and had increased expression of lipogenic “obesity” genes Magee et al., Am J Obstet Gynecol 2008

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

Abdominal obesityHigh serum triglyceridesLow HDL (high-density lipoprotein)

Insulin resistanceHypertensionINCREASED RISK OF CARDIOVASCULARDISEASE AND TYPE II DIABETES

Stimulus

Adaptation

Maternal Malnutrition

?

Poor fetal and infant growth increase susceptibility to

metabolic syndrome later in life

Maternal Malnutrition

Metabolic Syndrome

beta-cell mass or islet dysfunction

adult beta-cell function

insulin resistance

fetal malnutrition

hypertension

obesity age

Adequate Nutrition

Poor Nutrition

FETALENVIRONMENT

POSTNATALENVIRONMENT

ADULTHEALTH

Adequate Nutrition

Poor Nutrition

Adequate Nutrition

Poor Nutrition

METABOLICSYNDROME

HEALTHY

MALNOURISHED

MALNOURISHED

Published in early 1990s (Hales, Barker et al.)

468 men born in Hertfordshire 1920-1930 and still living there

Birthweights recordedTests for insulin resistance performed: fasting glucose and insulin before and after glucose drink

Birth Weight (lbs)Odds

Rat

io I

nsul

in R

esis

tanc

e

Hales CN et al. BMJ 1991; 303:1019-22

Low Birthweight Increases Risk of Insulin Resistance in Adulthood

Osmond et al. BMJ 1993

Standardized Mortality Ratio

Birthweight

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:

“The study of heritable changes in phenotype (appearance) or gene expression caused by

mechanisms other than changes in the underlying DNA

sequence.”Wikipedia

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

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

Waterland RA et al. Int J Obes 2008

food + methyl donorfood only

maternal weight

3rd generation offspringweight

Obese mouse dams produce obese offspring, but methyl donor supplementation prevents this effect

METABOLIC SYNDROME RISK

BIRTH WEIGHT

“U” – Shaped Curve

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