Iron Deficiency in Infancy is Associated with Altered Neural Correlates of Recognition Memory at 10 Years

doi:10.1016/j.jpeds.2011.12.011

The Journal of Pediatrics

Volume 160, Issue 6, June 2012, Pages 1027-1033

https://doi.org/10.1016/j.jpeds.2011.12.011 Get rights and content

Objective

To determine the long-term effects of iron deficiency on the neural correlates of recognition memory.

Study design

Non-anemic control participants (n = 93) and 116 otherwise healthy formerly iron-deficient anemic Chilean children were selected from a larger longitudinal study. Participants were identified at 6, 12, or 18 months as iron-deficient anemic or non-anemic and subsequently received oral iron treatment. This follow-up was conducted when participants were 10 years old. Behavioral measures and event-related potentials from 28 scalp electrodes were measured during an new/old word recognition memory task.

Results

The new/old effect of the FN400 amplitude, in which new words are associated with greater amplitude than old words, was present within the control group only. The control group also showed faster FN400 latency than the formerly iron-deficient anemic group and larger mean amplitude for the P300 component.

Conclusions

Although overall behavioral accuracy is comparable in groups, the results show that group differences in cognitive function have not been resolved 10 years after iron treatment. Long-lasting changes in myelination and energy metabolism, perhaps especially in the hippocampus, may account for these long-term effects on an important aspect of human cognitive development.

Section snippets

Methods

The children in this study were involved in earlier research in Chile on the behavioral, developmental, and neurofunctional effects of IDA. All participants were healthy, full-term infants (≥3 kg) with no prenatal complications or acute or chronic illnesses. Anemia was defined as venous hemoglobin level ≤100 g/L at 6 months and <110 g/L at 12 and 18 months. Iron deficiency was defined as two of 3 iron measures in the iron-deficient range (mean corpuscularcell volume <70 flfL, erythrocyte

Results

The Table shows background characteristics of the participants, including iron status in infancy and at 10 years. The mean age at test was 10.2 years for both the FIDA and control groups (range, 9.7-11.0 years). All participants had normal or corrected-to-normal vision; two participants (both in the control group) were left-handed. Only one child had IDA at 10 years, defined with age-appropriate National Health and Nutrition Survey II and III cutoffs24, 25 as hemoglobin level <112 g/L and two

Discussion

Both the FIDA and control groups performed the recognition memory task with equal accuracy throughout the study, which means that the children in the FIDA group were not behaviorally impaired in their ability to make a new/old distinction. This finding suggests that the memory processes necessary for the task were largely intact in both groups. However, despite comparable accuracy throughout the study, it is important to note that the control group’s response times were significantly faster

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Neonatal outcomes from a randomized controlled trial of maternal treatment of iron deficiency anemia with intravenous ferumoxytol vs oral ferrous sulfate
2023, American Journal of Obstetrics and Gynecology MFM
Anemia in pregnancy is common worldwide and has known maternal risks. The relationship between the types of treatment offered for maternal anemia and the effects on the fetus and newborn are largely uninvestigated.
This study aimed to investigate whether maternal treatment with intravenous ferumoxytol compared to oral ferrous sulfate results in an increase in neonatal hematologic and iron indices. These analyses were planned secondary outcomes and post hoc analysis from the trial with a primary outcome of change in maternal hemoglobin.
A randomized controlled trial including 124 participants with anemia by World Health Organization criteria was performed in which participants were allocated in a 1:1 ratio to either 2 infusions of 510 mg of intravenous ferumoxytol or 325 mg oral ferrous sulfate twice daily. Fetal monitoring was performed during each intravenous iron infusion. Standard univariable statistical techniques were used to compare groups and to investigate associations between maternal and neonatal hemoglobin and iron indices.
Cord blood hematological parameters were equivalent between groups. Hemoglobin was 15.7 g/dL vs 15.4 g/dL (P=.6) and hematocrit was 50.5% and 49.2% (P=.4) in those randomized to intravenous ferumoxytol and oral ferrous sulfate, respectively. Iron studies revealed higher cord blood ferritin concentrations in infants of participants treated with intravenous ferumoxytol (294 vs 186, P=.005). There were equivalent iron (158 vs 146, P=.4), transferrin (186 vs 196, P=.4) and total iron binding capacity (246 vs 244, P=1) in neonates of participants receiving intravenous vs oral treatment. There were no effects of the infusions observed on cardiotocography. Gestational age at birth was equivalent between groups. We noted a larger birthweight in neonates of participants treated with intravenous ferumoxytol (3215 g vs 3033 g, P=.09), which was not statistically significant. Post hoc analyses revealed a statistically significant correlation between neonatal ferritin and maternal hemoglobin (P=.006) and neonatal ferritin and maternal ferritin (P=.017) at admission for delivery.
Neonates of participants who received intravenous ferumoxytol were born with higher ferritin concentrations in cord blood, at the same gestation with the same birthweight. Participants with higher hemoglobin and ferritin indices delivered infants with higher ferritin concentrations in cord blood.
Umbilical cord management - the first opportunity to improve healthcare disparities
2023, Seminars in Perinatology
Parenteral Nutrition in Neonates
2023, Principles of Neonatology
Parenteral nutrition is a necessary component of the nutritional and medical management of the premature infant. The fluid, macronutrient, and micronutrient requirements are unique to the premature infant due to their transition from the intrauterine to extrauterine environment, critically ill status, and lack of nutrient stores. Understanding how to properly calculate a premature infant’s parenteral nutrition requirements is critical to ensure adequacy of the administered solution. The increased risk of deficiency and toxicity in this population makes the accuracy of these calculations paramount. It is necessary to consider product compatibilities, contamination, and availability when ordering parenteral nutrition. Utilization of a multidisciplinary team is recommended for management of parenteral nutrition and its associated complications.
Effects of iron supplementation on neural indices of habituation in Bangladeshi children
2023, American Journal of Clinical Nutrition
Iron deficiency and anemia have been associated with poor cognition in children, yet the effects of iron supplementation on neurocognition remain unclear.
We aimed to examine the effects of supplementation with iron on neural indices of habituation using auditory event-related brain potentials (ERPs).
This substudy was nested within a 3-arm, double-blind, double-dummy, individual randomized trial in Bangladesh, in which 3300 8-mo-old children were randomly selected to receive 3 mo of daily iron syrup (12.5 mg iron), multiple micronutrient powders (MNPs) (including 12.5 mg iron), or placebo. Children were assessed after 3 mo of intervention (mo 3) and 9 mo thereafter (mo 12). The neurocognitive substudy comprised a randomly selected subset of children from the main trial. Brain activity elicited during an auditory roving oddball task was recorded using electroencephalography to provide an index of habituation. The differential response to a novel (deviant) compared with a repeated (standard) sound was examined. The primary outcome was the amplitude of the mismatch response (deviant minusstandard tone waveforms) at mo 3. Secondary outcomes included the deviant and standard tone-evoked amplitudes, N2 amplitude differences, and differences in mean amplitudes evoked by deviant tones presented in the second compared with first half of the oddball sequence at mo 3 and 12.
Data were analyzed from 329 children at month 3 and 363 at mo 12. Analyses indicated no treatment effects of iron interventions compared with placebo on the amplitude of the mismatch response (iron syrup compared with placebo: mean difference (MD) = 0.07μV [95% CI: −1.22, 1.37]; MNPs compared with placebo: MD = 0.58μV [95% CI: −0.74, 1.90]) nor any secondary ERP outcomes at mo 3 or 12, despite improvements in hemoglobin and ferritin concentrations from iron syrup and MNPs in this nested substudy.
In Bangladeshi children with >40% anemia prevalence, iron or MNP interventions alone are insufficient to improve neural indices of habituation.
This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12617000660381.
Protocol for a multicenter, double-blinded placebo-controlled randomized controlled trial comparing intravenous ferric derisomaltose to oral ferrous sulfate for the treatment of iron deficiency anemia in pregnancy: The IVIDA2 trial
2022, Contemporary Clinical Trials
Citation Excerpt :
Moreover, iron-deficient mothers are at risk of delivering iron-deficient neonates who, despite iron repletion, remain at risk for delayed growth and development [7]. Fetal‑neonatal iron deficiency has been linked to neurological impairments in infants [8] that may persist into adulthood [7]. Animal studies have demonstrated a clear role for iron in normal brain development, including myelination, dendritic growth, and synapse formation [9–11].
Iron deficiency anemia (IDA) is common during pregnancy and associated with adverse maternal and neonatal outcomes. Treatment with iron supplementation is recommended during pregnancy, but the optimal delivery route is unclear. Oral iron risks has high risk of gastrointestinal side effects and low absorption. Intravenous iron is infused directly but is expensive. The American College of Obstetricians and Gynecologists currently recommends oral iron to treat IDA in pregnancy with intravenous iron reserved as second-line therapy, if needed. This approach is associated with persistent anemia, increasing the risk of peripartum blood transfusion. We aim to provide data on optimal route of iron repletion for IDA in pregnancy.
In IVIDA2, a double-blind, placebo controlled, multicenter randomized trial in the United States, 746 pregnant people with moderate-to-severe IDA (hemoglobin <10 g/dL and ferritin <30 ng/mL) at 24–28 weeks' gestation will be randomized 1:1 to either a single 1000 mg dose of intravenous ferric derisomaltose and oral placebo (1–3 times daily) or a single placebo infusion with 1–3 times daily 325 mg ferrous sulfate (65 mg elemental iron) tablet. The primary outcome is peripartum blood transfusion (blood transfusion from delivery to 7 days postpartum). Secondary outcomes include adverse medication reactions, maternal and neonatal hematologic indices, and offspring neurodevelopment.
A central ethical review board—Advarra—granted ethical approval (Pro00060930). Participating centers—Women & Infants Hospital of Rhode Island, University of Michigan Medical Center, Washington University School of Ethics and dissemination: A central ethical review board—Advarra—granted ethical approval (Pro00060930). Participating centers—Women & Infants Hospital of Rhode Island, University of Michigan Medical Center, Washington University School of.
Iron status and inflammation in women of reproductive age: A population-based biomarker survey and clinical study
2022, Clinical Nutrition ESPEN
Women of reproductive age (WRA) are at increased risk for anemia and iron deficiency. However, there is limited population-level data in India, which could help inform evidence-based recommendations and policy.
To conduct a population-based biomarker survey of anemia, iron deficiency, and inflammation in WRA in Southern India.
Participants were WRA (15-40 y) who were not pregnant or lactating. Blood samples (n = 979) were collected and analyzed for hemoglobin (Hb), serum ferritin (SF), soluble transferrin receptor (sTfR), C-reactive protein (CRP), and alpha-1 acid glycoprotein (AGP). Anemia and severe anemia were defined as Hb < 12.0 and < 8.0 g/dL. Serum ferritin was adjusted for inflammation using BRINDA methods. Iron deficiency was defined as SF <15.0 μg/L, iron insufficiency was defined as SF < 20.0 and < 25.0 μg/L, and iron deficiency anemia was defined as Hb < 12.0 g/dL and SF < 15.0 μg/L. Inflammation was defined as CRP > 5.0 mg/L or AGP > 1.0 g/L. Restricted cubic spline regression models were also used to determine if alternative SF thresholds should be used t to classify iron deficiency.
A total of 41.5% of WRA had anemia, and 3.0% had severe anemia. Findings from spline analyses suggested a SF cut-off of < 15.0 μg/L, consistent with conventional cut-offs for iron deficiency. 46.3% of WRA had SF < 15.0 μg/L (BRINDA-adjusted: 61.5%), 55.0% had SF < 20.0 μg/L (72.7%), 61.8% had SF < 25.0 μg/L (81.0%), and 30.0% had IDA (34.5%). 17.3% of WRA had CRP > 5.0 mg/L and 22.2% had AGP > 1.0 g/L. The prevalence of ID (rural vs. urban: 49.1% vs. 34.9%; p = 0.0004), iron insufficiency (57.8% vs. 43.8%; p = 0.0005), and IDA (31.8% vs. 22.4%; p = 0.01) were significantly higher in rural areas, although CRP levels were lower and there were no differences in elevated CRP or AGP.
The burden of anemia and iron deficiency in this population was substantial, and increased after adjusting for inflammation, suggesting potential to benefit from screening and interventions.
NCT04048330.

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: Supported by a grant from the National Institutes of Health (R01 HD33487). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest.

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Original ArticleIron Deficiency in Infancy is Associated with Altered Neural Correlates of Recognition Memory at 10 Years

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

Biol Psychol

J Pediatr

Am J Clin Nutr

Electroencephalogr Clin Neurophysiol

Contemp Educ Psychol

Biol Psychol

Brain Cogn

Brain Res Bull

Oligodendrocytes and myelination: the role of iron

GLIA

Recent evidence from human and animal studies regarding iron status and infant development

J Nutr

Long-lasting neural and behavioral effects of iron deficiency in infancy

Nutr Rev

Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain

Pediatr Res

Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus

Hippocampus

Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons

Dev Neurosci

Gestational and neonatal iron deficiency alters apical dendrite structure of CA1 pyramidal neurons in adult rat hippocampus

Dev Neurosci

Original Article
Iron Deficiency in Infancy is Associated with Altered Neural Correlates of Recognition Memory at 10 Years