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.

Iron Nutrition, Erythrocytes, and Erythropoietin in the NICU: Erythropoietic and Neuroprotective Effects.

Prematurity, maternal diabetes, maternal smoking, being medically underserved, and small size for gestational age are common characteristics of neonates in the NICU and can predispose them to develop congenital iron deficiency. Iron is critical for organ development. In the fetus and newborn, iron is prioritized for red blood cell production, sometimes at the expense of other tissues, including the brain. It is critical to optimize iron levels in newborns to support erythropoiesis, growth, and brain development. Available studies support improved neurodevelopmental outcomes with either iron supplementation or delayed umbilical cord clamping at birth. Erythropoietic doses of erythropoietin/erythrocyte-stimulating agents may also improve neurocognitive outcomes. However, the literature on the effect of liberal red blood cell transfusions on long-term neurodevelopment is mixed. Understanding age-specific normal values and monitoring of iron indices can help individualize and optimize the iron status of patients in the NICU.

Enteral erythropoietin and iron stimulate erythropoiesis in suckling rats.

OBJECTIVES: A primary objective was to evaluate whether addition of enteral iron supplementation will facilitate a systemic erythropoietic effect when feeding erythropoietin (Epo) to suckling rats. A secondary objective was to confirm that iron does not alter the previous finding that enteral Epo exerts local trophic effects on the small intestine. METHODS: Four-day-old Sprague-Dawley rats underwent gastrostomy and were fed a cow's milk-based rat milk substitute for 8 days. We studied rats fed rat milk substitute alone (control), enteral Epo 425 U x kg(-1) x day(-1), and enteral Epo 1700 U x kg(-1) x day(-1), and the effects of oral iron sulfate (Fe) therapy (6 mg x kg(-1) x day(-1)). Blood was collected to measure hemoglobin (Hb), reticulocytes, red cell indices, and zinc protoporphyrin/heme. To confirm previous work describing trophic effects of enteral Epo on the intestine, duodenal villous height was measured. RESULTS: Hb levels in control (84 +/- 1 g/L) were similar to Epo 425 (87 +/- 1 g/L). Hb levels in control+Fe (97 +/- 1 g/L), Epo 425+Fe (97 +/- 1 g/L), and Epo 1700 (94 +/- 1 g/L) were higher than control, P < 0.001, but mean Hb level in Epo 1700+Fe was higher (105 +/- 1 g/L) than the other groups, P < 0.003. Mean cell volume was higher in rats receiving iron supplementation, compared with those without iron, P < 0.005. Duodenal villous height was taller in Epo 1700+Fe compared with control + Fe, P < 0.01. CONCLUSIONS: If combined with sufficient iron supplementation, high-dose Epo artificially fed to suckling rats exerted a systemic erythropoietic effect in addition to the previously reported local trophic effects.

Insulin-like growth factor-I stimulates erythropoiesis when administered enterally.

BACKGROUND: Insulin-like growth factors I and II (IGF-I and IGF-II) are potent growth factors involved in development. IGF-I stimulates proliferation of erythropoietic progenitors and parenteral IGF-I administration stimulates in vivo erythropoiesis in animals. IGF-I and IGF-II are both present in mammalian milks and when milk-borne, are resistant to neonatal gastrointestinal degradation. Whether milk-borne IGF-I or IGF-II regulates neonatal erythropoiesis in not known. We hypothesized that physiological doses of enteral IGFs stimulate erythropoiesis in suckling rats. METHODS: Eight day-old Sprague Dawley rats were artificially fed for 4 days with rat milk substitute (RMS) or RMS supplemented with physiological levels of IGF-I or IGF-II. Rats fed IGF-I and IGF-II were compared to control RMS. Blood and marrow were collected; measures of red cell mass, measures of erythropoietic stimulus, and indices of iron status were measured. RESULTS: Rats fed IGF-I had higher hemoglobin (Hb) levels (100 +/- 10 g/l), compared to those fed RMS (94 +/- 9) or IGF-II (91 +/- 6), p < 0.001. After IGF-I supplementation, red blood cell counts (RBC) (p < 0.04) and hematocrits (p < 0.002) were also higher. Plasma erythropoietin (Epo) levels, reticulocytes, plasma iron and erythrocyte iron incorporation were similar. CONCLUSION: Intact enteral IGF-I reaches distal erythropoietic tissue resulting in greater red cell mass, but not by increasing plasma Epo levels or by altering cellular iron transport.

Intestinal transport of insulin-like growth factor-I (igf-I) in the suckling rat.

OBJECTIVES: Insulin-Like Growth Factor-1 is a potent growth-promoting peptide that is present in mammalian milk. Previous studies have suggested that milk-borne IGF-1 may be absorbed intact from the gastrointestinal tract of the suckling but the mechanism responsible for such transport is not well documented. The present study was designed to investigate in an in vivo suckling rat model whether or not intestinal absorption of IGF-1 is a saturable phenomenon. METHODS: Suckling rats (10-12 days postnatal age) were studied under anesthesia. A jejunal loop from each rat pup was isolated and injected intraluminally with 1-2 x 10 cpm of rh I-IGF-I. Injections were performed in paired littermates either with or without a preceding injection of unlabeled IGF-I of 20, 500, or 1000 ng/ml concentration. After flushing, the loops and livers were homogenized and counted in a gamma counter. In addition, homogenates of jejunum and liver were precipitated with trichloroacetic acid (TCA) and the precipitates also counted. In selected instances (jejunum), acid gel chromatography of homogenates was also performed. RESULTS: Retention of radioactivity was observed in all jejunal specimens, but the pre-incubation of jejunal loops with unlabeled IGF-1 was associated with a biphasic response, i.e. at low dose (20 ng/ml) pre-incubation limited retention of radioactivity, but at a high dose (1000 ng/ml), retention was enhanced (P < 0.05). Linear regression analysis confirmed this inverse relationship. Liver radioactivity followed a similar pattern. Between 40 and 49% of the radioactivity in jejunal and liver homogenates was TCA precipitable. Chromatography of jejunal homogenates showed that approximately 40% of cpm migrated in a position identical with that of intact IGF-1. CONCLUSIONS: The intestinal uptake of IGF-1 in the suckling is nonsaturable, confirming previous in vitro studies and suggesting that a nonreceptor-dependent method of transepithelial transport is important in this process.

Iron status and the treatment of the anemia of prematurity.

Many unanswered issues regarding rhEPO therapy in prematurity remain, including which premature infants best respond to rhEPO, what the long-term effect of decreased erythrocyte transfusions is, how nutritional supplementation optimizes the effect of rhEPO, whether or not rhEpo therapy causes iron deficiency later in life, and whether or not it is safe to supplement with parenteral iron. Further study of rhEPO therapy and iron status in prematurity is necessary.

Iron-deficient erythropoiesis in neonatal rats.

Anemia in premature infants is extremely common. Precise quantitation of iron status and determination of iron incorporation into erythrocytes are important in monitoring therapy for anemia in premature infants, especially when treating with recombinant human erythropoietin (rhEPO). However, the traditional indices of the iron status have limited usefulness in this population. The goal of the current work is to develop an experimental animal model system that addresses the clinical issue relating to quantitation of iron delivery to erythrocytes. We first determined normal hematological values for nontreated, dam-suckled Sprague-Dawley rats by measuring markers of erythropoiesis and iron status during the first 12 postnatal days (PND). The experimental group of rats were administered parenteral rhEpo (430 IU.kg(-1). day(-1)) for 8 days (from PND 4 until PND 12) in the absence (rhEpo(-Fe)) or presence (rhEpo(+Fe)) of oral iron supplementation (6 mg.kg(-1).day(-1)). Rat pups receiving oral iron only (control(+Fe)) and pups that were sham fed with the orogastric tube (control(-Fe)) were included as controls. Hematological parameters were measured in blood and bone marrow. In a pattern similar to that seen in premature infants during the first 2 months of life, the levels of these hematopoietic markers were dynamic and changed during the first 12 PND. After challenging experimental animals with subcutaneous rhEpo, evidence of iron-deficient erythropoiesis was seen in the rhEpo(-Fe) group. Red blood cell levels and absolute reticulocyte counts were higher in both groups receiving rhEpo as compared with the controls. However, the rhEpo(-Fe) group experienced a lower hemoglobin level, a lower mean red cell volume, a greater red cell distribution width, and a higher zinc protoporphyrin/heme (ratio than the rhEpo(+Fe) group. The neonatal rat is an excellent model of iron-deficient erythropoiesis and will be useful in designing future mechanistic studies examining the interplay between iron and erythropoiesis in the anemic, iron-challenged premature neonate.