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Biomedical subjects

Michael K Georgieff

Publications and source records attributed to Michael K Georgieff.

At least 19 recordsLinked to original sources
PubMed2006

Iron in fetal and neonatal nutrition.

Both iron deficiency and iron excess during the fetal and neonatal period bode poorly for developing organ systems. Maternal conditions such as iron deficiency, diabetes mellitus, hypertension and smoking, and preterm birth are the common causes of perinatal iron deficiency. Long-term neurodevelopmental impairments and predisposition to future iron deficiency that are prevalent in infants with perinatal iron deficiency require early diagnosis, optimal treatment and adequate follow-up of infants at risk for the condition. However, due to the potential for oxidant-mediated tissue injury, iron overload should be avoided in the perinatal period, especially in preterm infants.

Anemia, Iron-Deficiency↗
PubMed2006

Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia-ischemia.

The hippocampus is injured in both hypoxia-ischemia (HI) and perinatal iron deficiency that are co-morbidities in infants of diabetic mothers and intrauterine growth restricted infants. We hypothesized that preexisting perinatal iron deficiency predisposes the hippocampus to greater injury when exposed to a relatively mild HI injury. Iron-sufficient and iron-deficient rats (hematocrit 40% lower and brain iron concentration 55% lower) were subjected to unilateral HI injury of 15, 30, or 45 mins (n=12 to 13/HI duration) on postnatal day 14. Sixteen metabolite concentrations were measured from an 11 microL volume on the ipsilateral (HI) and contralateral (control) hippocampi 1 week later using in vivo 1H NMR spectroscopy. The concentrations of creatine, glutamate, myo-inositol, and N-acetylaspartate were lower on the control side in the iron-deficient group (P<0.02, each). Magnetic resonance imaging showed hippocampal injury in the majority of the iron-deficient rats (58% versus 11%, P<0.0001) with worsening severity with increasing durations of HI (P=0.0001). Glucose, glutamate, N-acetylaspartate, and taurine concentrations were decreased and glutamine, lactate and myo-inositol concentrations, and glutamine/glutamate ratio were increased on the HI side in the iron-deficient group (P<0.01, each), mainly in the 30 and 45 mins HI subgroups (P<0.02, each). These neurochemical changes likely reflect the histochemically detected neuronal injury and reactive astrocytosis in the iron-deficient group and suggest that perinatal iron deficiency predisposes the hippocampus to greater injury from exposure to a relatively mild HI insult.

Animals↗
PubMed2006

Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats.

BACKGROUND: Iron deficiency anemia (IDA) has been associated with altered cognitive, motor, and social-emotional outcomes in human infants. We recently reported that rats with chronic perinatal IDA, had altered regional brain iron, monoamines, and sensorimotor skill emergence during early development. OBJECTIVE: To examine the long-term consequences of chronic perinatal IDA on behavior, brain iron and monoamine systems after dietary iron treatment in rats. METHODS: Sixty dams were randomly assigned to iron-sufficient (CN) or low-iron (EID) diets during gestation and lactation. Thereafter, all offspring were fed the iron-sufficient diet, assessed for hematology and behavior after weaning and into adulthood and for brain measures as adults (regional brain iron, monoamines, dopamine and serotonin transporters, and dopamine receptor). Behavioral assessments included sensorimotor function, general activity, response to novelty, spatial alternation, and spatial water maze performance. RESULTS: Hematology and growth were similar for EID and CN rats by postnatal day 35. In adulthood, EID thalamic iron content was lower. Monoamines, dopamine transporter, and dopamine receptor concentrations did not differ from CN. EID serotonin transporter concentration was reduced in striatum and related regions. EID rats had persisting sensorimotor deficits (delayed vibrissae-evoked forelimb placing, longer sticker removal time, and more imperfect grooming chains), were more hesitant in novel settings, and had poorer spatial water maze performance than CN. General activity and spatial alternation were similar for EID and CN. CONCLUSION: Rats that had chronic perinatal IDA showed behavioral impairments that suggest persistent striatal dopamine and hippocampal dysfunction despite normalization of hematology, growth and most brain measures.

Anemia, Iron-Deficiency↗
PubMed2006

Moderate iron deficiency in infancy: biology and behavior in young rats.

Iron deficiency anemia in early childhood is associated with developmental delays and perhaps, irreversible alterations in neurological functioning. The goals were to determine if dietary induced gestational and lactational iron deficiency alters brain monoamine metabolism and behaviors dependent on that neurotransmitter system. Young pregnant rats were provided iron deficient or control diets from early in gestation through to weaning of pups and brain iron concentration, regional monoamine variables and achievement of specific developmental milestones were determined throughout lactation. Despite anemia during lactation, most brain iron concentrations did not fall significantly until P25, and well after significant changes in monoamine levels, transporter levels, and D2R density changed in terminal fields. The changes in D2R density were far smaller than previously observed models that utilized severe dietary restriction during lactation or after weaning. Iron deficient pups had normal birth weight, but were delayed in the attainment of a number of milestones (bar holding, vibrissae-evoked forelimb placing). This approach of iron deficiency in utero and during lactation sufficient to cause moderate anemia but not stunt growth demonstrates that monaminergic metabolism changes occur prior to profound declines in brain iron concentration and is associated with developmental delays. Similar developmental delays in iron deficient human infants suggest to us that alterations in iron status during this developmental period likely affects developing brain monaminergic systems in these infants.

Age Factors↗
PubMed2006

Iron deficiency and brain development.

Iron deficiency (ID) is common in pregnant women and infants worldwide. Rodent models show that ID during gestation/lactation alters neurometabolism, neurotransmitters, myelination, and gene/protein profiles before and after iron repletion at weaning. Human infants with iron deficiency anemia test lower in cognitive, motor, social-emotional, and neurophysiologic development than comparison group infants. Iron therapy does not consistently improve developmental outcome, with long-term differences observed. Poorer outcome has also been shown in human and monkey infants with fetal/neonatal ID. Recent randomized trials of infant iron supplementation show benefits, indicating that adverse effects can be prevented and/or reversed with iron earlier in development or before ID becomes severe or chronic. This body of research emphasizes the importance of protecting the developing brain from ID.

Animals↗
PubMed2006

Diet-induced iron deficiency anemia and pregnancy outcome in rhesus monkeys.

BACKGROUND: Iron deficiency anemia (IDA) is relatively common in the third trimester of pregnancy, but causal associations with low birth weight and compromised neonatal iron status are difficult to establish in human populations. OBJECTIVE: The objective was to determine the effects of diet-induced IDA on intrauterine growth and neonatal iron status in an appropriate animal model for third-trimester IDA in women. DESIGN: Hematologic and iron-status measures, pregnancy outcomes, and fetal and neonatal evaluations were compared between pregnant rhesus monkeys (n = 14) fed a diet containing 10 microg Fe/g diet from the time of pregnancy detection (gestation days 28-30) and controls (n = 24) fed 100 microg Fe/g diet. RESULTS: By the third trimester, 79% of the iron-deprived dams and 29% of the control monkeys had a hemoglobin concentration <11 g/dL. There were also significant group differences in hematocrit, mean corpuscular volume, transferrin saturation, serum ferritin, and serum iron. At birth, the newborns of monkeys iron-deprived during pregnancy had significantly lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin values and a lower ratio of erythroid to total colony-forming units in bone marrow than did the control newborns. Pregnancy weight gain did not differ significantly between the iron-deprived and control dams, and the fetuses and newborns of the iron-deprived dams were not growth retarded relative to the controls. Gestation length, the number of stillbirths, and neonatal neurobehavioral test scores did not differ significantly by diet group. CONCLUSION: These data indicate that an inadequate intake of iron from the diet during pregnancy in rhesus monkeys can lead to compromised hematologic status of the neonate without indications of growth retardation or impaired neurologic function at birth.

Anemia, Iron-Deficiency↗
PubMed2006

The role of chronic hypoxia in the development of neurocognitive abnormalities in preterm infants with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is the most common pulmonary morbidity in preterm infants and is associated with chronic hypoxia. Animal studies have demonstrated structural, neurochemical and functional alterations due to chronic hypoxia in the developing brain. Long-term impairments in visual-motor, gross and fine motor, articulation, reading, mathematics, spatial memory and attention skills are prevalent in survivors of bronchopulmonary dysplasia, and impairments appear to correlate with the severity of hypoxia. However, due to the simultaneous occurrence of multiple neurodevelopmental risk factors, a primary or potentiating role for chronic hypoxia in these impairments has yet to be conclusively established.

Animals↗
PubMed2006

The effect of maternal diabetes during pregnancy on the neurodevelopment of offspring.

As many as 10% of pregnancies are complicated by maternal glucose intolerance. With the risk of diabetes and gestational diabetes rising because of the obesity epidemic, that figure is likely to rise. Many obese individuals suffer from the metabolic syndrome, which makes them more prone to glucose intolerance when they are pregnant. Among the potential risks posed by poor maternal glucose control are those to the developing fetal brain. The goal of this article is to acquaint physicians with the results and clinical implications of studies conducted at the University of Minnesota on outcomes of infants of diabetic mothers and, in particular, on the role of iron deficiency in differential brain processing.

Anemia, Iron-Deficiency↗
PubMed2005

In vivo effect of chronic hypoxia on the neurochemical profile of the developing rat hippocampus.

The cognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of the developing hippocampus. Chronic postnatal hypoxia present during infancy in these children may play a role in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronic hypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in the hippocampus was evaluated in a rat model of chronic postnatal hypoxia using in vivo 1H NMR spectroscopy at 9.4 T. Chronic hypoxia was induced by continuously exposing rats (n = 23) to 10% O2 from postnatal day (P) 3 to P28. Fifteen metabolites were quantified from a volume of 9-11 microl centered on the left hippocampus on P14, P21, and P28 and were compared with normoxic controls (n = 14). The developmental trajectory of neurochemicals in chronic hypoxia was similar to that seen in normoxia. However, chronic hypoxia had an effect on the concentrations of the following neurochemicals: aspartate, creatine, phosphocreatine, GABA, glutamate, glutamine, glutathione, myoinositol, N-acetylaspartate (NAA), phosphorylethanolamine, and phosphocreatine/creatine (PCr/Cr) and glutamate/glutamine (Glu/Gln) ratios (P < 0.001 each, except glutamate, P = 0.04). The increased PCr/Cr ratio is consistent with decreased brain energy consumption. Given the well-established link between excitatory neurotransmission and brain energy metabolism, we postulate that elevated glutamate, Glu/Gln ratio, and GABA indicate suppressed excitatory neurotransmission in an energy-limited environment. Decreased NAA and phosphorylethanolamine suggest reduced neuronal integrity and phospholipid metabolism. The altered hippocampal neurochemistry during its development may underlie some of the cognitive deficits present in human infants at risk of chronic hypoxia.

Age Factors↗
PubMed2005

Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus.

Late fetal and early postnatal iron deficiency (ID) is a common condition that causes learning and memory impairments in humans while they are iron deficient and following iron repletion. Rodent models of fetal ID demonstrate significant short- and long-term hippocampal structural and biochemical abnormalities that may predispose hippocampal area CA1 to abnormal electrophysiology. Rat pups made iron deficient during the fetal and early postnatal period were assessed for basal synaptic transmission, paired-pulse facilitation (PPF), and long-term potentiation (LTP) in CA1 at postnatal days (P)15 and P30 while iron deficient and at P65 following iron repletion. Our results showed no differences in basal synaptic transmission between iron sufficient and iron deficient pups at P15 or P30, but the ID group did fail to demonstrate the expected developmental increase in synaptic strength by P65 (P < 0.05). Similarly, PPF ratios from iron deficient slices also failed to demonstrate the characteristic developmental changes seen in the iron sufficient group (P < 0.001). Iron deficient slices retained a developmentally immature P15 pattern of LTP expression at P30 and after iron repletion, and LTP expression was lower (P < 0.05) in the iron deficient group at P65. Thus, ID in the fetal and early postnatal period delays or abolishes the developmental maturation of electrophysiological components of synaptic efficacy and plasticity, resulting in abnormalities beyond the period of deficiency. These findings provide a functional corroboration to previous structural and biochemical abnormalities found in the iron deficient rat hippocampus and provide a potential model for learning and memory deficits seen in humans exposed to fetal and early postnatal ID.

Animals↗
PubMed2005

Childhood cancer following neonatal oxygen supplementation.

OBJECTIVE: To evaluate the relationship between neonatal oxygen supplementation (O2) and childhood cancer in the Collaborative Perinatal Project (CPP). STUDY DESIGN: The CPP consisted of 54,795 children born between 1959 and 1966 and followed to age 8 years. We used Cox proportional hazards modeling to examine the association between history of neonatal O2 and cancer (n = 48). RESULTS: The hazard ratio (HR) for any O2 was 1.77 (95% confidence interval [CI] = 0.94 to 3.35). The HR for continuous duration of O2 was near 1 and not significant. However, the HRs were 0.69 (95% CI = 0.17 to 2.88) and 2.87 (95% CI = 1.46 to 5.66) when comparing 0 to 2 and 3 or more minutes of O2, respectively, to no O2. The latter association was weaker (HR = 2.00; 95% CI = 0.88 to 4.54) and not significant ( P = .10) when analysis was restricted to cancers diagnosed after age 1 year (n = 41). CONCLUSIONS: These findings are consistent with an association between O 2 for 3 minutes or longer and cancer in childhood, and should serve as a basis for further study.

Child↗
PubMed2005

Explicit memory performance in infants of diabetic mothers at 1 year of age.

The aim of the present research was to investigate the impact of abnormal fetal environment on explicit memory performance. Based on animal models, it was hypothesized that infants of diabetic mothers (IDMs) experience perturbations in memory performance due to exposure to multiple neurologic risk factors including: chronic hypoxia, hyperglycemia/reactive hypoglycemia, and iron deficiency. Memory performance, as measured by the elicited/deferred imitation paradigm, was compared between 13 IDMs (seven females, six males; mean age 365 days, SD 11) and 16 typically developing children (seven females, nine males; mean age 379 days, SD 9). The IDM group was characterized by shorter gestational age (mean 38w, SD 2), greater standardized birthweight scores (mean 3797g, SD 947), and lower iron stores (mean ferritin concentration 87C microg/L, SD 68) in comparison with the control group (mean gestational age: 40w, SD 1; mean birthweight: 3639g, SD 348; mean newborn ferritin concentration 140 microg/L, SD 46). After statistically controlling for both gestational age and global cognitive abilities, IDMs demonstrated a deficit in the ability to recall multi-step event sequences after a delay was imposed. These findings highlight the importance of the prenatal environment on subsequent mnemonic behavior and suggest a connection between metabolic abnormalities during the prenatal period, development of memory, circuitry, and behavioral mnemonic performance.

Adult↗
PubMed2004

Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta.

Placental iron transport during the last trimester of pregnancy determines the iron endowment of the neonate. Iron transport is a function of the major iron transport proteins: transferrin receptor-1 (TfR-1) and ferroportin-1 (FPN-1). The mRNAs for TfR-1 and, potentially, FPN-1 are posttranscriptionally regulated by iron regulatory protein (IRP)-1 and IRP-2. We assessed the effect of gestational age and fetal iron status on IRP-1- and IRP-2-binding activity and on the localization and protein expression of TfR-1 and FPN-1 protein at 24-40 wk of gestation in 21 placentas obtained from iron-sufficient nonanemic mothers. Gestational age had no effect on cord serum ferritin concentration, IRP-2 RNA-binding activity, transporter protein location, and TfR-1 or FPN-1 protein expression. IRP-1 activity remained constant until full term, when it decreased (P = 0.01). Placental ferritin (r = 0.76, P < 0.001) and FPN-1 (r = 0.44, P < 0.05) expression increased with gestational age. Fetal iron status, as indexed by cord serum ferritin concentration, was inversely related to placental IRP-1 (r = -0.66, P < 0.001) and IRP-2 (r = -0.42, P = 0.05) activities. Placental ferritin protein expression correlated better with IRP-1 (r = -0.45, P = 0.04) than with IRP-2 (r = -0.35, P = 0.10) activity. Placental TfR-1 and FPN-1 protein expression was independent of fetal or placental iron status and IRP activities. Iron status had no effect on transport protein localization. We conclude that, toward the end of the third trimester of iron-sufficient human pregnancy, the placenta accumulates ferritin and potentially increases placental-fetal iron delivery through increased FPN-1 expression. IRP-1 may have a more dominant role than IRP-2 activity in regulating ferritin expression.

Adult↗
PubMed2004

Electrographic imaging of recognition memory in 34-38 week gestation intrauterine growth restricted newborns.

Electrophysiological imaging of recognition memory using event-related potentials (ERPs) in intrauterine growth-restricted (IUGR) newborns allows assessment of recognition memory before the onset of multiple confounding variables. Animal models that reproduce the physiologic components associated with IUGR have demonstrated adverse effects on the hippocampus, a structure that is essential to normal memory processing. Previous electrophysiologic studies have demonstrated shortened auditory-evoked potential (AEP) and visual-evoked potential (VEP) latencies in IUGR infants suggesting accelerated neural maturation in response to the adverse in-utero environment. The hypothesis of the current study was that newborns with IUGR and head-sparing would demonstrate altered auditory recognition memory when compared to controls and that the configuration of the alteration would evidence advanced maturation but still be different from that of typically grown newborns. Twelve IUGR newborns born at 34-38 weeks gestation with head-sparing and 16 age-matched control newborns were tested with both a speech/nonspeech paradigm to assess auditory sensory processing and a novel (stranger's voice) and familiar (mother's voice) paradigm to assess recognition memory. In the recognition memory experiment, a three-way interaction of condition, lead, and group was identified for the lateral leads T4, CM3, and CM4 with the response to the mother being of much greater area in the IUGR cohort than in the controls. This ERP configuration has previously been reported for the midline leads in term newborns. The findings indicate that IUGR newborns with head-sparing have electrophysiologic evidence of accelerated maturation of cognitive processing suggesting an atypical process of maturation that may not support typical cognitive development.

Acoustic Stimulation↗
PubMed2004

Infants of diabetic mothers.

Advances in the management of the mother with diabetes have reduced the rate of morbidity and mortality for her infant. Aggressive control of maternal glycemic status is warranted, because most morbidities are epidemiologically and pathophysiologically closely linked to fetal hyperglycemia and hyperinsulinemia. The burgeoning public health problem of overweight and obesity in children will likely result in an increased incidence of metabolic syndrome X, characterized by insulin resistance and type II diabetes in adulthood. An early manifestation of this may be glucose intolerance during pregnancy in overweight women without diabetes. Clinicians must continue to have a high degree of suspicion for the diagnosis of diabetes during gestation and screen offspring of women with gestational diabetes for neonatal sequelae.

Child Development↗
PubMed2004

Effects of prenatal betamethasone exposure on regulation of stress physiology in healthy premature infants.

The objective of this study was to examine the effects of prenatal exposure to betamethasone, a corticosteroid, on postnatal stress regulation, particularly activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Effects were assessed by measuring salivary cortisol production at baseline and in response to two potentially stressful events, a heel-stick blood draw and a physical exam, in infants born at 33-34 weeks gestation. Subjects included 9 infants with antenatal betamethasone treatment (2 doses of 12 mg of betamethasone administered intramuscularly to the mother twelve hours apart) and 9 infants without such treatment. Testing took place 3-6 days after delivery. Measures of behavioral distress confirmed that both events were stressful to these premature infants. Infants with betamethasone exposure, however, failed to exhibit increases in cortisol to either stressor. In contrast, infants without betamethasone exposure displayed elevated cortisol to the heel-stick blood draw but not the physical exam. These findings suggest that antenatal corticosteroids suppress infants' HPA response to a stressor typically encountered in a neonatal intensive care situation.

Analysis of Variance↗
PubMed2004

Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers.

Infants of diabetic mothers (IDMs) are at risk for perinatal brain iron deficiency that may target the developing hippocampus. The objective of this study was to evaluate hippocampally based recognition memory and infant development in IDMs with suspected brain iron deficiency (BID; cord ferritin </=34 microg/L) compared with IDMs with sufficient brain iron stores (BIS; cord ferritin >34 microg/L) using event-related potentials (ERPs). ERPs assessed neonatal auditory cortical responses to sounds and auditory recognition memory in response to the mother's voice compared with a stranger's voice. Thirty-two newborn IDMs had cord serum ferritin concentrations and provided neonatal ERP data (n = 23) and/or blinded 1 y developmental assessments (n = 28). Auditory cortical responses to speech and nonspeech sounds were similar in the BID and BIS groups. In the maternal voice recognition paradigm, peak latencies were shorter in the BID group than in the BIS group. Infants in the BIS group displayed a significant negative slow wave for the strangers' voices compared with the mothers' voices, whereas the BID group did not. Higher cord ferritin concentrations were correlated with larger negative slow waves at the right temporal (T4) electrode site. At 1 y of age, motor development was slower in the BID group than in the BIS group. IDMs suspected to have BID demonstrated impaired neonatal auditory recognition memory and lower psychomotor developmental scores at 1 y of age than IDMs with BIS. These impairments map onto areas of the developing brain known to be vulnerable to iron deficiency.

Auditory Perception↗