Low birth weight (LBW) in infants, due to intrauterine growth retardation (IUGR), defined as weight <2500gms at term gestation, remains a critical problem in the developing countries and is a major contributor to the morbidity and mortality. It is estimated that almost 30% of all live births in developing countries are LBW. A strong association has been shown in adulthood between LBW and non-communicable diseases, such as type 2 diabetes, hypertension and coronary heart disease. Indirect evidence from intervention studies of micronutrient or protein/energy supplement suggests that no single nutrient is itself responsible for the IUGR. Studies with humans and experimental animals have shown that perturbation in the methionine and one carbon metabolism in the mother and possibly in the fetus, impacts fetal growth and "programming" of the metabolism of the infant and ultimately causes the observed phenotype. We have reported specific gestational-related changes in methionine metabolism in healthy women and in the human newborn infant. Isocaloric protein restriction in rodents during pregnancy, results in IUGR, metabolic re-programming, and long term morbidity in the off spring. In humans, a significant correlation between maternal B12 and folate status and insulin resistance in their children at age 6 years has been observed. We hypothesize that marginal protein intake and altered micronutrient status, insufficient to cause "classical" deficiency syndrome, will impact one carbon metabolism and methyl transfers in the mother and the fetus and thereby alter fetal growth.
The specific aims are to longitudinally document maternal methionine, homocysteine metabolism, relate it to nutrient (protein) intake, folate, B12, pyridoxine status, and measures of insulin resistance. Methionine metabolism, transmethylation and transsulfuration, will be measured using a novel and innovative stable isotope labeled methionine loading test early and late in gestation. These data will be related to the macro and micronutrient status of the mother estimated by dietary recall, plasma B12, methylmalonic acid, pyridoxine and red blood cell folate levels. The physiological measurements of methionine metabolism will allow us to identify the effect of subclinical changes in nutrient status on the one carbon metabolism of the mother. These physiological data will be related to fetal growth as assessed by birth weight and body composition, and metabolic and hormonal assessments in the cord blood. These studies will identify the mechanism of IUGR and lead to the development of strategic recommendations at the identified critical periods in pregnancy using various methyl donors with the goal of preventing both immediate neonatal and long term "programming" consequences in the baby. There are major public health and economic implications for this study, when one considers the enormous magnitude of the LBW, the associated clinical problems and the economic burden to the society.

Public Health Relevance

Low birth weight (LBW) due to intrauterine growth retardation affects almost 30% of the babies in developing countries and is a major contributor to morbidity and mortality in infants and children. In addition low birth weight is strongly related to non-communicable diseases in adults such as diabetes, obesity, heart disease, hypertension etc. The exact mechanism/s responsible for fetal growth retardation is not known. Methionine, an essential amino acid, along with folic acid, is a key component of one-carbon metabolism and methyl transfers in every cell in the body. Methionine and folate metabolism can be perturbed by nutrient and hormonal mediators and may cause specific changes in many organs in the body of the mother, placenta and the fetus. These data suggest that it may not be a single nutrient deficiency that cause fetal growth retardation and low birth weight but could be the inadequacies of several nutrients in combination, which by themselves singly are insufficient to cause deficiency syndrome. Since all of these affect metabolism, cell growth and gene expression through one carbon metabolism, we propose assessment of the later using sophisticated non- invasive method to identify these changes and relate them to infants'birth weight and metabolism. We hypothesize that changes in one carbon metabolism as a result of nutrient (vitamins and protein) insufficiency cause fetal growth retardation by nutrient gene interaction and cause permanent changes leading to adult disease like diabetes, obesity and hypertension. The proposed studies, if successful, are likely to have a high impact on our understanding of the role of multiple nutrient deficiencies and consequent perturbations in one carbon metabolism and methyl transfers on fetal growth. In addition such studies could provide a scientific rational basis for targeted interventions during pregnancy in order to prevent low birth weight. The health impact of the study is enormous, considering the magnitude of the problem not only for infants but also for these babies in adult life. In addition low birth weight also carries a huge economic burden to the society.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Pregnancy and Neonatology Study Section (PN)
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Raju, Tonse N
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Cleveland Clinic Lerner
Other Basic Sciences
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United States
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