Postnatally acquired iron deficiency causes long-term nonhematologic (heart, brain) organ dysfunction. Up to 125,000 infants of diabetic mothers (IDM) are born each year with reduced iron stores. IDM are prone to abnormal cardiac and neurologic function in the newborn period and to long-term abnormal cognitive development We are evaluating the hypothesis that fetal iron deficiency associated with maternal diabetes mellitus may contribute to this pathophysiology in the newborn period. Tissue studies of infants of diabetic mothers demonstrate liver, brain and myocardial iron depletion at birth. These iron abnormalities are most likely due to sequestration of available fetal iron in an expanded red cell mass. Although placental transferrin receptor protein expression is increased in diabetic pregnancies, the affinity of the receptor is reduced, resulting in no apparent increase in iron transport in spite of increased fetal iron demand and fetal tissue iron deficiency. Our long-term objectives are to: 1) study the regulation of the placental iron transfer mechanism during fetal hypoxia and augmented iron demand in IDM; 2) document postnatal myocardial and neurologic sequelae of fetal iron deficiency. We hypothesize that: 1) placental transferrin receptor (TR) expression and binding affinity for transferrin are regulated by fetal iron demand and insulin; 2) fetal myocardial iron deficiency results in decreased neonatal cardiac ATP generation and reduced myocardial function; 3) fetal brain iron deficiency in IDM contributes to a higher rate of cognitive neurologic sequelae in IDM. Forty pregnant insulin-dependent diabetic women will be recruited at 36 weeks gestation. Their newborns' cord blood will be sampled for serum ferritin concentration and subsequently divided into two groups of 20: those with low ferritins and those with normal ferritins. Twenty additional age-matched infants born to non-diabetic mothers will serve as controls. Placental TR expression (immunohistochemistry), TR mRNA (Northern and dot blot) and 125I-transferrin binding (Scatchard analysis) in IDM with low ferritins will be compared to IDM with normal ferritins and to controls. The relationship of TR, TR mRNA and TR binding to duration of fetal hypoxia, and degrees of fetal hyperinsulinemia, iron demand and placental non-heme iron will be assessed in humans and guinea pigs. Structural alterations of TR in human diabetic pregnancies will be assessed. Neonatal cardiac contractility in iron-deficient IDM will be assessed by echocardiography. Iron-deficient newborn guinea pig hearts (generated by prolonged fetal hypoxia and iron deficiency) will have cytochrome c, ATP, ADP, AMP and creatine phosphate concentrations and myocardial contracti1ity measured and compared to non-hypoxic iron- sufficient controls to assess the effect of fetal iron deficiency on myocardial energy metabolism and contractility. Cognitive function (discriminative memory) of human IDM will be assessed by event-related potential (ERP) recording in the newborn period and by ERP, Bayley Scales of Infant Development, and Piaget A not B test at 18 months and compared to controls.

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University of Minnesota Twin Cities
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Georgieff, Michael K; Tran, Phu V; Carlson, Erik S (2018) Atypical fetal development: Fetal alcohol syndrome, nutritional deprivation, teratogens, and risk for neurodevelopmental disorders and psychopathology. Dev Psychopathol 30:1063-1086
Georgieff, Michael K; Ramel, Sara E; Cusick, Sarah E (2018) Nutritional influences on brain development. Acta Paediatr 107:1310-1321
Cusick, Sarah E; Georgieff, Michael K; Rao, Raghavendra (2018) Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children. Nutrients 10:
Fretham, Stephanie J B; Carlson, Erik S; Georgieff, Michael K (2013) Neuronal-specific iron deficiency dysregulates mammalian target of rapamycin signaling during hippocampal development in nonanemic genetic mouse models. J Nutr 143:260-6
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Riggins, Tracy; Miller, Neely C; Bauer, Patricia J et al. (2009) Electrophysiological indices of memory for temporal order in early childhood: implications for the development of recollection. Dev Sci 12:209-19
Rao, Raghavendra; Georgieff, Michael K (2009) Iron therapy for preterm infants. Clin Perinatol 36:27-42
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