Biomarkers of Brain Dysfunction in Perinatal Iron Deficiency.

Iron deficiency in the fetal and neonatal period (perinatal iron deficiency) bodes poorly for neurodevelopment. Given its common occurrence and the negative impact on brain development, a screening and treatment strategy that is focused on optimizing brain development in perinatal iron deficiency is necessary. Pediatric societies currently recommend a universal iron supplementation strategy for full-term and preterm infants that does not consider individual variation in body iron status and thus could lead to undertreatment or overtreatment. Moreover, the focus is on hematological normalcy and not optimal brain development. Several serum iron indices and hematological parameters in the perinatal period are associated with a risk of abnormal neurodevelopment, suggesting their potential use as biomarkers for screening and monitoring treatment in infants at risk for perinatal iron deficiency. A biomarker-based screening and treatment strategy that is focused on optimizing brain development will likely improve outcomes in perinatal iron deficiency.

Prognostic Performance of Hematological and Serum Iron and Metabolite Indices for Detection of Early Iron Deficiency Induced Metabolic Brain Dysfunction in Infant Rhesus Monkeys.

BACKGROUND: The current pediatric practice of monitoring for infantile iron deficiency (ID) via hemoglobin (Hgb) screening at one y of age does not identify preanemic ID nor protect against later neurocognitive deficits. OBJECTIVES: To identify biomarkers of iron-related metabolic alterations in the serum and brain and determine the sensitivity of conventional iron and heme indices for predicting risk of brain metabolic dysfunction using a nonhuman primate model of infantile ID. METHODS: Simultaneous serum iron and RBC indices, and serum and cerebrospinal fluid (CSF) metabolomic profiles were determined in 20 rhesus infants, comparing iron sufficient (IS; N = 10) and ID (N = 10) infants at 2 and 4 mo of age. RESULTS: Reticulocyte hemoglobin (RET-He) was lower at 2 wk in the ID group. Significant IS compared with ID differences in serum iron indices were present at 2 mo, but Hgb and RBC indices differed only at 4 mo (P < 0.05). Serum and CSF metabolomic profiles of the ID and IS groups differed at 2 and 4 mo (P < 0.05). Key metabolites, including homostachydrine and stachydrine (4-5-fold lower at 4 mo in ID group, P < 0.05), were altered in both serum and CSF. Iron indices and RET-He at 2 mo, but not Hgb or other RBC indices, were correlated with altered CSF metabolic profile at 4 mo and had comparable predictive accuracy (area under the receiver operating characteristic curve scores, 0.75-0.80). CONCLUSIONS: Preanemic ID at 2 mo was associated with metabolic alterations in serum and CSF in infant monkeys. Among the RBC indices, only RET-He predicted the future risk of abnormal CSF metabolic profile with a predictive accuracy comparable to serum iron indices. The concordance of homostachydrine and stachydrine changes in serum and CSF indicates their potential use as early biomarkers of brain metabolic dysfunction in infantile ID.

Intranasal insulin treatment partially corrects the altered gene expression profile in the hippocampus of developing rats with perinatal iron deficiency.

Perinatal iron deficiency (FeD) targets the hippocampus and leads to long-term cognitive deficits. Intranasal insulin administration improves cognitive deficits in adult humans with Alzheimer's disease and type 2 diabetes and could provide benefits in FeD-induced hippocampal dysfunction. To objective was to assess the effects of intranasal insulin administration intranasal insulin administration on the hippocampal transcriptome in a developing rat model of perinatal FeD. Perinatal FeD was induced using low-iron diet from gestational day 3 until postnatal day (P) 7, followed by an iron sufficient (FeS) diet through P21. Intranasal insulin was administered at a dose of 0.3 IU twice daily from P8 to P21. Hippocampi were removed on P21 from FeS control, FeD control, FeS insulin, and FeD insulin groups. Total RNA was isolated and profiled using next-generation sequencing. Gene expression profiles were characterized using custom workflows and expression patterns examined using ingenuity pathways analysis (n = 7-9 per group). Select RNAseq results were confirmed via qPCR. Transcriptomic profiling revealed that mitochondrial biogenesis and flux, oxidative phosphorylation, quantity of neurons, CREB signaling in neurons, and RICTOR-based mTOR signaling were disrupted with FeD and positively affected by intranasal insulin treatment with the most benefit observed in the FeD insulin group. Both perinatal FeD and intranasal insulin administration altered gene expression profile in the developing hippocampus. Intranasal insulin treatment reversed the adverse effects of FeD on many molecular pathways and could be explored as an adjunct therapy in perinatal FeD.

Nonhematopoietic Umbilical Cord Blood Stem Cell Administration Improves Long-term Neurodevelopment After Periventricular-Intraventricular Hemorrhage in Neonatal Rats.

Periventricular-intraventricular hemorrhage (PIVH) is common in extremely low gestational age neonates (ELGAN) and leads to motor and behavioral impairments. Currently there is no effective treatment for PIVH. Whether human nonhematopoietic umbilical cord blood-derived stem cell (nh-UCBSC) administration reduces the severity of brain injury and improves long-term motor and behavioral function was tested in an ELGAN-equivalent neonatal rat model of PIVH. In a collagenase-induced unilateral PIVH on postnatal day (P) 2 model, rat pups received a single dose of nh-UCBSCs at a dose of 1 × 106 cells i.p. on P6 (PIVH + UCBSC group) or were left untreated (Untreated PIVH group). Motor deficit was determined using forelimb placement, edge-push, and elevated body swing tests at 2 months (N = 5-8). Behavior was evaluated using open field exploration and rearing tests at 4 months (N =10-12). Cavity volume and hemispheric volume loss on the PIVH side were determined at 7 months (N = 6-7). Outcomes were compared between the Untreated PIVH and PIVH + UCBSC groups and a Control group. Unilateral motor deficits were present in 60%-100% of rats in the Untreated PIVH group and 12.5% rats in the PIVH + UCBSC group (P = 0.02). Untreated PIVH group exhibited a higher number of quadrant crossings in open field exploration, indicating low emotionality and poor habituation, and had a cavitary lesion and hemispheric volume loss on the PIVH side. Performance in open field exploration correlated with cavity volume (r2 = 0.25; P < 0.05). Compared with the Untreated PIVH group, performance in open field exploration was better (P = 0.0025) and hemispheric volume loss was lower (19.9 ± 4.4% vs 6.1 ± 2.6%, P = 0.018) in the PIVH + UCBSC group. These results suggest that a single dose of nh-UCBSCs administered in the subacute period after PIVH reduces the severity of injury and improves neurodevelopment in neonatal rats.

Bayesian predictive modeling of multi-source multi-way data.

A Bayesian approach to predict a continuous or binary outcome from data that are collected from multiple sources with a multi-way (i.e., multidimensional tensor) structure is described. As a motivating example, molecular data from multiple 'omics sources, each measured over multiple developmental time points, as predictors of early-life iron deficiency (ID) in a rhesus monkey model are considered. The method uses a linear model with a low-rank structure on the coefficients to capture multi-way dependence and model the variance of the coefficients separately across each source to infer their relative contributions. Conjugate priors facilitate an efficient Gibbs sampling algorithm for posterior inference, assuming a continuous outcome with normal errors or a binary outcome with a probit link. Simulations demonstrate that the model performs as expected in terms of misclassification rates and correlation of estimated coefficients with true coefficients, with large gains in performance by incorporating multi-way structure and modest gains when accounting for differing signal sizes across the different sources. Moreover, it provides robust classification of ID monkeys for the motivating application.

Neonatal hyperbilirubinemia differentially alters the neurochemical profiles of the developing cerebellum and hippocampus in a preterm Gunn rat model.

Neonatal hyperbilirubinemia (NHB) can lead to brain injury in newborn infants by affecting specific regions including the cerebellum and hippocampus. Extremely preterm infants are more vulnerable to bilirubin neurotoxicity, but the mechanism and extent of injury is not well understood. A preterm version of the Gunn rat model was utilized to investigate severe preterm NHB. Homozygous/jaundiced Gunn rat pups were injected (i.p.) on postnatal day (P) 5 with sulfadimethoxine, which increases serum free bilirubin capable of crossing the blood-brain barrier and causing brain injury. The neurochemical profiles of the cerebellum and hippocampus were determined using in vivo 1 H MRS at 9.4 T on P30 and compared with those of heterozygous/non-jaundiced control rats. Transcript expression of related genes was determined by real-time quantitative PCR. MRI revealed significant morphological changes in the cerebellum of jaundiced rats. The concentrations of myo-inositol (+54%), glucose (+51%), N-acetylaspartylglutamate (+21%), and the sum of glycerophosphocholine and phosphocholine (+17%) were significantly higher in the cerebellum of the jaundiced group compared with the control group. Despite the lack of morphologic changes in the hippocampus, the concentration of myo-inositol (+9%) was higher and the concentrations of creatine (-8%) and of total creatine (-3%) were lower in the jaundiced group. In the hippocampus, expression of calcium/calmodulin dependent protein kinase II alpha (Camk2a), glucose transporter 1 (Glut1), and Glut3 transcripts were downregulated in the jaundiced group. In the cerebellum, glial fibrillary acidic protein (Gfap), myelin basic protein (Mbp), and Glut1 transcript expression was upregulated in the jaundiced group. These results indicate osmotic imbalance, gliosis, and changes in energy utilization and myelination, and demonstrate that preterm NHB critically affects brain development in a region-specific manner, with the cerebellum more severely impacted than the hippocampus.

Reticulocyte Hemoglobin Equivalent has Comparable Predictive Accuracy as Conventional Serum Iron Indices for Predicting Iron Deficiency and Anemia in a Nonhuman Primate model of Infantile Iron Deficiency.

BACKGROUND: Infantile iron deficiency (ID) causes anemia and compromises neurodevelopment. Current screening relies on hemoglobin (Hgb) determination at 1 year of age, which lacks sensitivity and specificity for timely detection of infantile ID. Low reticulocyte Hgb equivalent (RET-He) indicates ID, but its predictive accuracy relative to conventional serum iron indices is unknown. OBJECTIVES: The objective was to compare diagnostic accuracies of iron indices, red blood cell (RBC) indices, and RET-He for predicting the risk of ID and IDA in a nonhuman primate model of infantile ID. METHODS: Serum iron, total iron binding capacity, unsaturated iron binding capacity, transferrin saturation (TSAT), Hgb, RET-He, and other RBC indices were determined at 2 wk and 2, 4, and 6 mo in breastfed male and female rhesus infants (N = 54). The diagnostic accuracies of RET-He, iron, and RBC indices for predicting the development of ID (TSAT < 20%) and IDA (Hgb < 10 g/dL + TSAT < 20%) were determined using t tests, area under the receiver operating characteristic curve (AUC) analysis, and multiple regression models. RESULTS: Twenty-three (42.6%) infants developed ID and 16 (29.6%) progressed to IDA. All 4 iron indices and RET-He, but not Hgb or RBC indices, predicted future risk of ID and IDA (P < 0.001). The predictive accuracy of RET-He (AUC = 0.78, SE = 0.07; P = 0.003) for IDA was comparable to that of the iron indices (AUC = 0.77-0.83, SE = 0.07; P ≤ 0.002). A RET-He threshold of 25.5 pg strongly correlated with TSAT < 20% and correctly predicted IDA in 10 of 16 infants (sensitivity: 62.5%) and falsely predicted possibility of IDA in only 4 of 38 unaffected infants (specificity: 89.5%). CONCLUSIONS: RET-He is a biomarker of impending ID/IDA in rhesus infants and can be used as a hematological parameter to screen for infantile ID.

Tandem mass tag proteomic and untargeted metabolomic profiling reveals altered serum and CSF biochemical datasets in iron deficient monkeys.

The effects of early-life iron deficiency anemia (IDA) extend past the blood and include both short- and long-term adverse effects on many tissues including the brain. Prior to IDA, iron deficiency (ID) can cause similar tissue effects, but a sensitive biomarker of iron-dependent brain health is lacking. To determine serum and CSF biomarkers of ID-induced metabolic dysfunction we performed proteomic and metabolomic analysis of serum and CSF at 4- and 6- months from a nonhuman primate model of infantile IDA. LC/MS/MS analyses identified a total of 227 metabolites and 205 proteins in serum. In CSF, we measured 210 metabolites and 1,560 proteins. Data were either processed from a Q-Exactive (Thermo Scientific, Waltham, MA) through Progenesis QI with accurate mass and retention time comparisons to a proprietary small molecule database and Metlin or with raw files imported directly from a Fusion Orbitrap (Thermo Scientific, Waltham, MA) through Sequest in Proteome Discoverer 2.4.0.305 (Thermo Scientific, Waltham, MA) with peptide matches through the latest Rhesus Macaque HMDB database. Metabolite and protein identifiers, p-values, and q-values were utilized for molecular pathway analysis with Ingenuity Pathways Analysis (IPA). We applied multiway distance weighted discrimination (DWD) to identify a weighted sum of the features (proteins or metabolites) that distinguish ID from IS at 4-months (pre-anemic period) and 6-months of age (anemic).

Intranasal Insulin Attenuates the Long-Term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats.

Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis, and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain, and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer's disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group), or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut4, and Glut8), and poly(ADP-ribose) polymerase-1 (Parp1, a marker of oxidative stress) were determined on P7 using in vivo 1H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis, and synaptogenesis were determined at adulthood using 1H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ + INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus.

Cerebral Effects of Neonatal Dysglycemia.

This article summarizes the available evidence reporting the relationship between perinatal dysglycemia and long-term neurodevelopment. We review the physiology of perinatal glucose metabolism and discuss the controversies surrounding definitions of perinatal dysglycemia. We briefly review the epidemiology of hypoglycemia and hyperglycemia in fetal, preterm, and term infants. We discuss potential pathophysiologic mechanisms contributing to dysglycemia and its effect on neurodevelopment. We highlight current strategies to prevent and treat dysglycemia in the context of neurodevelopmental outcomes. Finally, we discuss areas of future research and the potential role of continuous glucose monitoring.

Multiomic profiling of iron-deficient infant monkeys reveals alterations in neurologically important biochemicals in serum and cerebrospinal fluid before the onset of anemia.

The effects of iron deficiency (ID) during infancy extend beyond the hematologic compartment and include short- and long-term adverse effects on many tissues including the brain. However, sensitive biomarkers of iron-dependent brain health are lacking in humans. To determine whether serum and cerebrospinal fluid (CSF) biomarkers of ID-induced metabolic dysfunction are concordant in the pre/early anemic stage of ID before anemia in a nonhuman primate model of infantile iron deficiency anemia (IDA). ID (n = 7), rhesus infants at 4 mo (pre-anemic period) and 6 mo of age (anemic) were examined. Hematological, metabolomic, and proteomic profiles were generated via HPLC/MS at both time points to discriminate serum biomarkers of ID-induced brain metabolic dysfunction. We identified 227 metabolites and 205 proteins in serum. Abnormalities indicating altered liver function, lipid dysregulation, and increased acute phase reactants were present in ID. In CSF, we measured 210 metabolites and 1,560 proteins with changes in ID infants indicative of metabolomic and proteomic differences indexing disrupted synaptogenesis. Systemic and CSF proteomic and metabolomic changes were present and concurrent in the pre-anemic and anemic periods. Multiomic serum and CSF profiling uncovered pathways disrupted by ID in both the pre-anemic and anemic stages of infantile IDA, including evidence for hepatic dysfunction and activation of acute phase response. Parallel changes observed in serum and CSF potentially provide measurable serum biomarkers of ID that reflect at-risk brain processes prior to progression to clinical anemia.

Perinatal iron deficiency as an early risk factor for schizophrenia.

Growing evidence indicates that a suboptimal intrauterine environment confers risk for schizophrenia. The developmental model of schizophrenia posits that aberrant brain growth during early brain development and adolescence may interact to contribute to this psychiatric disease in adulthood. Although a variety of factors may perturb the environment of the developing fetus and predispose for schizophrenia later, a common mechanism has yet to be elucidated. Micronutrient deficiencies during the perinatal period are known to induce potent effects on brain development by altering neurodevelopmental processes. Iron is an important candidate nutrient to consider because of its role in energy metabolism, monoamine synthesis, synaptogenesis, myelination, and the high prevalence of iron deficiency (ID) in the mother-infant dyad. Understanding the current state of science regarding perinatal ID as an early risk factor for schizophrenia is imperative to inform empirical work investigating the etiology of schizophrenia and develop prevention and intervention programs. In this narrative review, we focus on perinatal ID as a common mechanism underlying the fetal programming of schizophrenia. First, we review the neural aberrations associated with perinatal ID that indicate risk for schizophrenia in adulthood, including disruptions in dopaminergic neurotransmission, hippocampal-dependent learning and memory, and sensorimotor gating. Second, we review the pathophysiology of perinatal ID as a function of maternal ID during pregnancy and use epidemiological and cohort studies to link perinatal ID with risk of schizophrenia. Finally, we review potential confounding phenotypes, including nonanemic causes of perinatal brain ID and future risk of schizophrenia.

Excess sucrose intake during pregnancy programs fetal brain glucocorticoid receptor expression in female but not male C57Bl/6J mice.

BACKGROUND: Sex-specific mechanisms explaining the association between mothers with obesity and the development of obesity in children are poorly characterized. Permanent changes in fetal brain glucocorticoid receptor (GR) expression caused by exposure to overnutrition in utero may program aberrant energy homeostasis, thereby predisposing the offspring to obesity. This study explores sex differences in brain GR expression using an established mouse model of overnutrition during pregnancy. METHODS: Female C57Bl/6J mice were fed control (CON) or high-fat-high-sucrose (HFHS) diets. Dam cholesterol, insulin, and triglycerides were measured by colorimetric assays. Fetal corticosterone exposure was measured by placental Abca1, Hsd11ß1, Hsd11ß2, and brain Nr3c1 (GR); Pomc expression measured by RT-qPCR. RESULTS: Female, but not male, HFHS fetuses had 46% decreased brain GR and twofold increased Pomc expression. There was decreased Abca1 and Hsd11ß1 but not Hsd11ß2 expression in HFHS placentas. Caloric and sucrose intake, but not fat intake, in dams inversely correlated with fetal GR expression in both sexes. Excess sucrose consumption by dams inversely correlated with female fetal GR and directly correlated with female fetal Pomc expression. CONCLUSIONS: Excess sucrose consumption in pregnant dams caused lower GR and higher Pomc expression in the female fetal brain. Clinical investigation of excess sucrose intake during pregnancy and its subsequent effect on hypothalamic-pituitary-adrenal axis activity and appetite in offspring may lead to novel, sex-specific obesity prevention strategies in the development of obesity in children.

Long-Term Outcomes after Early Neonatal Hyperglycemia in VLBW Infants: A Systematic Review.

INTRODUCTION: Long-term effects of early hyperglycemia in VLBW infants are poorly characterized. The objective of this study was to systematically review the effect of early hyperglycemia on growth, metabolic health, and neurodevelopment after neonatal intensive care unit discharge in VLBW infants. METHODS: The systematic review was conducted in accordance with the PRISMA guidelines. A study protocol was registered in PROSPERO (CRD42019123335). Data sources included Ovid MEDLINE, Embase, Cochrane Library, CINAHL, and Scopus. Selected studies included infants with a blood glucose concentration >150 mg/dL (8.3 mmol/L) during the first 28 days of life, a gestational age (GA) <32 weeks, and/or a birth weight <1,500 g and longitudinal data on growth, metabolic health, or neurodevelopment outcomes. The GRADE system was used to assess quality of evidence. RESULTS: Eight studies (n = 987 infants) reported long-term outcomes from 4-month corrected GA to 7 years old. Most studies compared long-term outcomes of preterm infants with and without hyperglycemia. Two studies addressed outcomes related to interventions following early hyperglycemia. Some studies found differences in growth, metabolic health, and neurodevelopment outcomes between VLBW preterm infants with hyperglycemia and without hyperglycemia, while other studies found no differences between groups. The overall graded quality of evidence was low. CONCLUSIONS: Well-designed randomized controlled and prospective studies are necessary to determine the effect of early hyperglycemia and its treatment on later metabolic and neurodevelopmental outcomes in VLBW infants. Authors propose a potential study design for standardizing the assessment of long-term metabolic and neurodevelopmental outcomes following early hyperglycemia in preterm infants.

Endogenous erythropoietin concentrations and association with retinopathy of prematurity and brain injury in preterm infants.

BACKGROUND: Endogenous erythropoietin (EPO) concentrations vary widely in preterm infants and may be associated with perinatal risk factors and neurological outcomes. Erythropoietin is elevated in fetal hypoxia but is also a potential neuroprotectant. METHODS: In a prospective study of 27 infants ≤ 30 weeks gestation, serum erythropoietin concentrations were measured during the first month of life, on day 1 and weeks 1, 2, and 4, and related to perinatal risk factors and outcomes including retinopathy of prematurity and cerebral injury evaluated near term-equivalent post menstrual age using magnetic resonance imaging with quantitative scoring. RESULTS: Lower birth weight was associated with higher EPO concentrations throughout the first 2 weeks of life (r = -0.6, p < 0.01). Higher day 1 and week 1 EPO concentrations were associated with lower Apgar score at 1 minute (r = - 0.5) and 5 minutes (r = -0.7), respectively (p < 0.01). Higher day 1 EPO concentrations and 2-week area under the curve were associated with increased risk (p = 0.01) and severity (r = 0.5, p < 0.02) of retinopathy of prematurity. Higher EPO concentrations at 2 weeks were associated with increased total brain injury score (r = 0.5, p < 0.05). CONCLUSION: Elevated endogenous erythropoietin concentrations in the first two weeks of life are associated with lower birth weight and increased risk of adverse outcomes.

Infantile Iron Deficiency Affects Brain Development in Monkeys Even After Treatment of Anemia.

A high percent of oxidative energy metabolism is needed to support brain growth during infancy. Unhealthy diets and limited nutrition, as well as other environmental insults, can compromise these essential developmental processes. In particular, iron deficiency anemia (IDA) has been found to undermine both normal brain growth and neurobehavioral development. Even moderate ID may affect neural maturation because when iron is limited, it is prioritized first to red blood cells over the brain. A primate model was used to investigate the neural effects of a transient ID and if deficits would persist after iron treatment. The large size and postnatal growth of the monkey brain makes the findings relevant to the metabolic and iron needs of human infants, and initiating treatment upon diagnosis of anemia reflects clinical practice. Specifically, this analysis determined whether brain maturation would still be compromised at 1 year of age if an anemic infant was treated promptly once diagnosed. The hematology and iron status of 41 infant rhesus monkeys was screened at 2-month intervals. Fifteen became ID; 12 met clinical criteria for anemia and were administered iron dextran and B vitamins for 1-2 months. MRI scans were acquired at 1 year. The volumetric and diffusion tensor imaging (DTI) measures from the ID infants were compared with monkeys who remained continuously iron sufficient (IS). A prior history of ID was associated with smaller total brain volumes, driven primarily by significantly less total gray matter (GM) and smaller GM volumes in several cortical regions. At the macrostructual level, the effect on white matter volumes (WM) was not as overt. However, DTI analyses of WM microstructure indicated two later-maturating anterior tracts were negatively affected. The findings reaffirm the importance of iron for normal brain development. Given that brain differences were still evident even after iron treatment and following recovery of iron-dependent hematological indices, the results highlight the importance of early detection and preemptive supplementation to limit the neural consequences of ID.

Correcting iron deficiency anemia with iron dextran alters the serum metabolomic profile of the infant Rhesus Monkey.

BACKGROUND: The effects of infantile iron deficiency anemia (IDA) extend beyond hematological indices and include short- and long-term adverse effects on multiple cells and tissues. IDA is associated with an abnormal serum metabolomic profile, characterized by altered hepatic metabolism, lowered NAD flux, increased nucleoside levels, and a reduction in circulating dopamine levels. OBJECTIVES: The objective of this study was to determine whether the serum metabolomic profile is normalized after rapid correction of IDA using iron dextran injections. METHODS: Blood was collected from iron-sufficient (IS; n = 10) and IDA (n = 12) rhesus infants at 6 months of age. IDA infants were then administered iron dextran and vitamin B via intramuscular injections at weekly intervals for 2 to 8 weeks. Their hematological and metabolomic statuses were evaluated following treatment and compared with baseline and a separate group of age-matched IS infants (n = 5). RESULTS: Serum metabolomic profiles assessed at baseline and after treatment via HPLC/MS using isobaric standards identified 654 quantifiable metabolites. At baseline, 53 metabolites differed between IS and IDA infants. Iron treatment restored traditional hematological indices, including hemoglobin and mean corpuscular volume, into the normal range, but the metabolite profile in the IDA group after iron treatment was markedly altered, with 323 metabolites differentially expressed when compared with an infant's own baseline profile. CONCLUSIONS: Rapid correction of IDA with iron dextran resulted in extensive metabolic changes across biochemical pathways indexing the liver function, bile acid release, essential fatty acid production, nucleoside release, and several neurologically important metabolites. The results highlight the importance of a cautious approach when developing a route and regimen of iron repletion to treat infantile IDA.

Predictors of severe intraventricular hemorrhage in preterm infants under 29-weeks gestation.

Purpose: Preterm infants <29 weeks of gestation are at risk for severe intraventricular hemorrhage (IVH). Lower gestational age, birth weight, severe illness, as indexed by higher Score for Neonatal Acute Physiology - Perinatal Extension II (SNAPPE-II) are associated with severe IVH. The role of coagulation abnormalities on the first day after birth in severe IVH remains controversial. The present study investigated factors that predict the risk of severe IVH, including SNAPPE-II at 12 h and coagulation parameters on the first day after birth.Materials and methods: A retrospective chart review of infants < 29 weeks of gestation from January 2008 to December 2013 was performed. Prenatal and postnatal characteristics, SNAPPE-II at 12 h, coagulation parameters [prothrombin time (PT), INR, partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen] on the first day and cranial ultrasound examination records were collected. The association between clinical and laboratory variables and severe IVH was determined. A joint predictive model for the risk of severe IVH (grades 3 and 4) versus no-mild IVH (grades 0, 1, and 2) was developed using multiple regression analysis.Results: Preterm infants of gestational age < 29 weeks were included (n = 101). Fifteen (15%) infants had severe IVH. Lower gestational age (p = .006), birth weight (p = .008), African American race (p = .031) and higher SNAPPE-II at 12 h (p = .001) were associated with severe IVH. Infants with severe IVH had longer PT (p = .004), higher INR (p = .004) and lower platelet count (p = .034) than those with no-mild IVH. Stepwise logistic regression showed that only SNAPPE-II at 12 h was an independent predictor of severe IVH. For each unit increase in SNAPPE-II, the log odds of severe IVH increased by 0.045 (95% CI: [0.017, 0.073]; p = .002). A threshold of 55 on the SNAPPE-II yielded a sensitivity of 60% (9/15), a specificity of 91% (78/86), a positive predictive value (PPV) of 53% (9/17) and a negative predictive value (NPV) of 93% (78/84). All other demographic and clinical variables and coagulation abnormalities had an insignificant coefficient (p > .05) when included in a bivariate logistic model with SNAPPE-II.Conclusion: SNAPPE-II at 12 h after birth is an independent predictor of severe IVH in preterm infants with gestational age < 29 weeks.

Early-Life Iron Deficiency and Its Natural Resolution Are Associated with Altered Serum Metabolomic Profiles in Infant Rhesus Monkeys.

BACKGROUND: Iron deficiency is the most common nutrient deficiency in human infants aged 6 to 24 mo, and negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. There can be persistent influences on long-term metabolic health beyond its acute effects. OBJECTIVES: The objective was to determine how iron deficiency in infancy alters the serum metabolomic profile and to test whether these effects persist after the resolution of iron deficiency in a nonhuman primate model of spontaneous iron deficiency. METHODS: Blood was collected from naturally iron-sufficient (IS; n = 10) and iron-deficient (ID; n = 10) male and female infant rhesus monkeys (Macaca mulatta) at 6 mo of age. Iron deficiency resolved without intervention upon feeding of solid foods, and iron status was re-evaluated at 12 mo of age from the IS and formerly ID monkeys using hematological and other indices; sera were metabolically profiled using HPLC/MS and GC/MS with isobaric standards for identification and quantification at both time points. RESULTS: A total of 413 metabolites were measured, with differences in 40 metabolites identified between IS and ID monkeys at 6 mo (P$\le $ 0.05). At 12 mo, iron-related hematological parameters had returned to normal, but the formerly ID infants remained metabolically distinct from the age-matched IS infants, with 48 metabolites differentially expressed between the groups. Metabolomic profiling indicated altered liver metabolites, differential fatty acid production, increased serum uridine release, and atypical bile acid production in the ID monkeys. CONCLUSIONS: Pathway analyses of serum metabolites provided evidence of a hypometabolic state, altered liver function, differential essential fatty acid production, irregular uracil metabolism, and atypical bile acid production in ID infants. Many metabolites remained altered after the resolution of ID, suggesting long-term effects on metabolic health.

Reticulocyte hemoglobin content as an early predictive biomarker of brain iron deficiency.

BACKGROUND: Fetal and neonatal brain iron content is compromised at the time of anemia, suggesting that screening for iron deficiency by measuring hemoglobin is inadequate to protect the brain. Reticulocyte hemoglobin (Ret-He) reflects iron-deficient (ID) erythropoiesis prior to anemia. METHODS: At postnatal day (P), 10 and 20 iron-sufficient rat pups were fostered to ID dams to produce a postnatal ID (PNID) group, which was compared to 20 iron-sufficient (IS) pups fostered by IS dams. Pups were assessed from P13 to P15 for hemoglobin, hematocrit, reticulocyte count, and Ret-He. Hippocampal iron status was assessed by transferrin receptor-1 (Tfrc-1) and divalent metal transporter-1 (Slc11a2) mRNA expression. RESULTS: At P13, brain iron status was similar between groups; only Ret-He was lower in the PNID group. At P14, the PNID group had lower Ret-He, hematocrit, mean corpuscular volume (MCV), and reticulocyte percentage (RET%). Tfrc-1 expression was increased, consistent with brain iron deficiency. Both Ret-He and MCV correlated with brain iron status at P14 and P15. CONCLUSIONS: Ret-He was the only red cell marker affected prior to the onset of brain ID. The clinical practice of using anemia as the preferred biomarker for diagnosis of iron deficiency may need reconsidering.