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Assessment of iron status in settings of inflammation: challenges and potential approaches.
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Assessment of iron status in settings of inflammation: challenges and potential approaches.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1626S-1633S

Authors: Suchdev PS, Williams AM, Mei Z, Flores-Ayala R, Pasricha SR, Rogers LM, Namaste SM

Abstract
The determination of iron status is challenging when concomitant infection and inflammation are present because of confounding effects of the acute-phase response on the interpretation of most iron indicators. This review summarizes the effects of inflammation on indicators of iron status and assesses the impact of a regression analysis to adjust for inflammation on estimates of iron deficiency (ID) in low- and high-infection-burden settings. We overviewed cross-sectional data from 16 surveys for preschool children (PSC) (n = 29,765) and from 10 surveys for nonpregnant women of reproductive age (WRA) (n = 25,731) from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Effects of C-reactive protein (CRP) and α1-acid glycoprotein (AGP) concentrations on estimates of ID according to serum ferritin (SF) (used generically to include plasma ferritin), soluble transferrin receptor (sTfR), and total body iron (TBI) were summarized in relation to infection burden (in the United States compared with other countries) and population group (PSC compared with WRA). Effects of the concentrations of CRP and AGP on SF, sTfR, and TBI were generally linear, especially in PSC. Overall, regression correction changed the estimated prevalence of ID in PSC by a median of +25 percentage points (pps) when SF concentrations were used, by -15 pps when sTfR concentrations were used, and by +14 pps when TBI was used; the estimated prevalence of ID in WRA changed by a median of +8 pps when SF concentrations were used, by -10 pps when sTfR concentrations were used, and by +3 pps when TBI was used. In the United States, inflammation correction was done only for CRP concentrations because AGP concentrations were not measured; regression correction for CRP concentrations increased the estimated prevalence of ID when SF concentrations were used by 3 pps in PSC and by 7 pps in WRA. The correction of iron-status indicators for inflammation with the use of regression correction appears to substantially change estimates of ID prevalence in low- and high-infection-burden countries. More research is needed to determine the validity of inflammation-corrected estimates, their dependence on the etiology of inflammation, and their applicability to individual iron-status assessment in clinical settings.

PMID: 29070567 [PubMed - indexed for MEDLINE]




U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation.
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U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1694S-1702S

Authors: Dewey KG, Oaks BM

Abstract
Both iron deficiency (ID) and excess can lead to impaired health status. There is substantial evidence of a U-shaped curve between the risk of adverse birth outcomes and maternal hemoglobin concentrations during pregnancy; however, it is unclear whether those relations are attributable to conditions of low and high iron status or to other mechanisms. We summarized current evidence from human studies regarding the association between birth outcomes and maternal hemoglobin concentrations or iron status. We also reviewed effects of iron supplementation on birth outcomes among women at low risk of ID and the potential mechanisms for adverse effects of high iron status during pregnancy. Overall, we confirmed a U-shaped curve for the risk of adverse birth outcomes with maternal hemoglobin concentrations, but the relations differ by trimester. For low hemoglobin concentrations, the link with adverse outcomes is more evident when hemoglobin concentrations are measured in early pregnancy. These relations generally became weaker or nonexistent when hemoglobin concentrations are measured in the second or third trimesters. Associations between high hemoglobin concentration and adverse birth outcomes are evident in all 3 trimesters but evidence is mixed. There is less evidence for the associations between maternal iron status and adverse birth outcomes. Most studies used serum ferritin (SF) concentrations as the indicator of iron status, which makes the interpretation of results challenging because SF concentrations increase in response to inflammation or infection. The effect of iron supplementation during pregnancy may depend on initial iron status. There are several mechanisms through which high iron status during pregnancy may have adverse effects on birth outcomes, including oxidative stress, increased blood viscosity, and impaired systemic response to inflammation and infection. Research is needed to understand the biological processes that underlie the U-shaped curves seen in observational studies. Reevaluation of cutoffs for hemoglobin concentrations and indicators of iron status during pregnancy is also needed.

PMID: 29070565 [PubMed - indexed for MEDLINE]




Development of iron homeostasis in infants and young children.
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Development of iron homeostasis in infants and young children.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1575S-1580S

Authors: Lönnerdal B

Abstract
Healthy, term, breastfed infants usually have adequate iron stores that, together with the small amount of iron that is contributed by breast milk, make them iron sufficient until ≥6 mo of age. The appropriate concentration of iron in infant formula to achieve iron sufficiency is more controversial. Infants who are fed formula with varying concentrations of iron generally achieve sufficiency with iron concentrations of 2 mg/L (i.e., with iron status that is similar to that of breastfed infants at 6 mo of age). Regardless of the feeding choice, infants' capacity to regulate iron homeostasis is important but less well understood than the regulation of iron absorption in adults, which is inverse to iron status and strongly upregulated or downregulated. Infants who were given daily iron drops compared with a placebo from 4 to 6 mo of age had similar increases in hemoglobin concentrations. In addition, isotope studies have shown no difference in iron absorption between infants with high or low hemoglobin concentrations at 6 mo of age. Together, these findings suggest a lack of homeostatic regulation of iron homeostasis in young infants. However, at 9 mo of age, homeostatic regulatory capacity has developed although, to our knowledge, its extent is not known. Studies in suckling rat pups showed similar results with no capacity to regulate iron homeostasis at 10 d of age when fully nursing, but such capacity occurred at 20 d of age when pups were partially weaned. The major iron transporters in the small intestine divalent metal-ion transporter 1 (DMT1) and ferroportin were not affected by pup iron status at 10 d of age but were strongly affected by iron status at 20 d of age. Thus, mechanisms that regulate iron homeostasis are developed at the time of weaning. Overall, studies in human infants and experimental animals suggest that iron homeostasis is absent or limited early in infancy largely because of a lack of regulation of the iron transporters DMT1 and ferroportin.

PMID: 29070561 [PubMed - indexed for MEDLINE]




Serum ferritin as an indicator of iron status: what do we need to know?
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Serum ferritin as an indicator of iron status: what do we need to know?

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1634S-1639S

Authors: Daru J, Colman K, Stanworth SJ, De La Salle B, Wood EM, Pasricha SR

Abstract
Determination of iron status in pregnancy and in young children is essential for both clinical and public health practice. Clinical diagnosis of iron deficiency (ID) through sampling of bone marrow to identify the absence of body iron stores is impractical in most cases. Serum ferritin (SF) concentrations are the most commonly deployed indicator for determining ID, and low SF concentrations reflect a state of iron depletion. However, there is considerable variation in SF cutoffs recommended by different expert groups to diagnose ID. Moreover, the cutoffs used in different clinical laboratories are heterogeneous. There are few studies of diagnostic test accuracy to establish the sensitivity and specificity of SF compared with key gold standards (such as absent bone marrow iron stores, increased intestinal iron absorption, and hemoglobin response to SF) among noninflamed, outpatient populations. The limited data available suggest the commonly recommended SF cutoff of <15 μg/L is a specific but not sensitive cutoff, although evidence is limited. Data from women during pregnancy or from young children are especially uncommon. Most data are from studies conducted >30 y ago, do not reflect ethnic or geographic diversity, and were performed in an era for which laboratory methods no longer reflect present practice. Future studies to define the appropriate SF cutoffs are urgently needed and would also provide an opportunity to compare this indicator with other established and emerging iron indexes. In addition, future work would benefit from a focus on elucidating cutoffs and indexes relevant to iron adequacy.

PMID: 29070560 [PubMed - indexed for MEDLINE]




Iron status of toddlers, nonpregnant females, and pregnant females in the United States.
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Iron status of toddlers, nonpregnant females, and pregnant females in the United States.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1640S-1646S

Authors: Gupta PM, Hamner HC, Suchdev PS, Flores-Ayala R, Mei Z

Abstract
Background: Total-body iron stores (TBI), which are calculated from serum ferritin and soluble transferrin receptor concentrations, can be used to assess the iron status of populations in the United States.Objective: This analysis, developed to support workshop discussions, describes the distribution of TBI and the prevalence of iron deficiency (ID) and ID anemia (IDA) among toddlers, nonpregnant females, and pregnant females.Design: We analyzed data from NHANES; toddlers aged 12-23 mo (NHANES 2003-2010), nonpregnant females aged 15-49 y (NHANES 2007-2010), and pregnant females aged 12-49 y (NHANES 1999-2010). We used SAS survey procedures to plot distributions of TBI and produce prevalence estimates of ID and IDA for each target population. All analyses were weighted to account for the complex survey design.Results: According to these data, ID prevalences (± SEs) were 15.1% ± 1.7%, 10.4% ± 0.5%, and 16.3% ± 1.3% in toddlers, nonpregnant females, and pregnant females, respectively. ID prevalence in pregnant females increased significantly with each trimester (5.3% ± 1.5%, 12.7% ± 2.3%, and 27.5% ± 3.5% in the first, second, and third trimesters, respectively). Racial disparities in the prevalence of ID among both nonpregnant and pregnant females exist, with Mexican American and non-Hispanic black females at greater risk of ID than non-Hispanic white females. IDA prevalence was 5.0% ± 0.4% and 2.6% ± 0.7% in nonpregnant and pregnant females, respectively.Conclusions: Available nationally representative data suggest that ID and IDA remain a concern in the United States. Estimates of iron-replete status cannot be made at this time in the absence of established cutoffs for iron repletion based on TBI. The study was registered at clinicaltrials.gov as NCT03274726.

PMID: 29070559 [PubMed - indexed for MEDLINE]




Harmonization of blood-based indicators of iron status: making the hard work matter.
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Harmonization of blood-based indicators of iron status: making the hard work matter.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1615S-1619S

Authors: Hoofnagle AN

Abstract
Blood-based indicators that are used in the assessment of iron status are assumed to be accurate. In practice, inaccuracies in these measurements exist and stem from bias and variability. For example, the analytic variability of serum ferritin measurements across laboratories is very high (>15%), which increases the rate of misclassification in clinical and epidemiologic studies. The procedures that are used in laboratory medicine to minimize bias and variability could be used effectively in clinical research studies, particularly in the evaluation of iron deficiency and its associated anemia in pregnancy and early childhood and in characterizing states of iron repletion and excess. The harmonization and standardization of traditional and novel bioindicators of iron status will allow results from clinical studies to be more meaningfully translated into clinical practice by providing a firm foundation for clinical laboratories to set appropriate cutoffs. In addition, proficiency testing monitors the performance of the methods over time. It is important that measures of iron status be evaluated, validated, and performed in a manner that is consistent with standard procedures in laboratory medicine.

PMID: 29070558 [PubMed - indexed for MEDLINE]




Iron status of North American pregnant women: an update on longitudinal data and gaps in knowledge from the United States and Canada.
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Iron status of North American pregnant women: an update on longitudinal data and gaps in knowledge from the United States and Canada.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1647S-1654S

Authors: O'Brien KO, Ru Y

Abstract
Pregnant women are particularly vulnerable to iron deficiency due to the high iron demands of pregnancy. To avoid the adverse birth outcomes that are associated with maternal iron deficiency anemia, both Canada and the United States recommend universal iron supplementation for pregnant women. Although the benefits of iron supplementation in anemic women are well recognized, insufficient data are currently available on the maternal and neonatal benefits and harms of universal iron supplementation in developed countries as evidenced by the recent conclusions of the US Preventive Services Task Force on the need for further data that address existing gaps. As part of an effort to evaluate the impact of the current North American prenatal iron supplementation policy, this review highlights the lack of national data on longitudinal changes in iron status in pregnant North American women, emphasizes possible limitations with the original longitudinal hemoglobin data used to inform the current CDC reference hemoglobin values, and presents additional normative data from recent longitudinal research studies of iron status in North American pregnant women. Further longitudinal data in North American pregnant women are needed to help identify those who may benefit most from supplementation as well as to help determine whether there are adverse effects of iron supplementation in iron-replete women.

PMID: 29070557 [PubMed - indexed for MEDLINE]




Integrating themes, evidence gaps, and research needs identified by workshop on iron screening and supplementation in iron-replete pregnant women and young children.
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Integrating themes, evidence gaps, and research needs identified by workshop on iron screening and supplementation in iron-replete pregnant women and young children.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1703S-1712S

Authors: Brannon PM, Stover PJ, Taylor CL

Abstract
This report addresses the evidence and the uncertainties, knowledge gaps, and research needs identified by participants at the NIH workshop related to iron screening and routine iron supplementation of largely iron-replete pregnant women and young children (6-24 mo) in developed countries. The workshop presentations and panel discussions focused on current understanding and knowledge gaps related to iron homeostasis, measurement of and evidence for iron status, and emerging concerns about supplementing iron-replete members of these vulnerable populations. Four integrating themes emerged across workshop presentations and discussion and centered on 1) physiologic or developmental adaptations of iron homeostasis to pregnancy and early infancy, respectively, and their implications, 2) improvement of the assessment of iron status across the full continuum from iron deficiency anemia to iron deficiency to iron replete to iron excess, 3) the linkage of iron status with health outcomes beyond hematologic outcomes, and 4) the balance of benefit and harm of iron supplementation of iron-replete pregnant women and young children. Research that addresses these themes in the context of the full continuum of iron status is needed to inform approaches to the balancing of benefits and harms of screening and routine supplementation.

PMID: 29070556 [PubMed - indexed for MEDLINE]




Ethnic and genetic factors of iron status in women of reproductive age.
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Ethnic and genetic factors of iron status in women of reproductive age.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1594S-1599S

Authors: Gordeuk VR, Brannon PM

Abstract
Background: African Americans are at increased risk of iron deficiency (ID) but also have higher serum ferritin (SF) concentrations than those of the general population. The Hemochromatosis and Iron Overload Screening (HEIRS) Study was a multicenter study of ethnically diverse participants that tested for the hemochromatosis (HFE) C282Y genotype and iron status.Objective: We sought to determine the prevalence and predictors of ID (SF concentration ≤15 μg/L) and elevated iron stores (SF concentration >300 μg/L) in HEIRS women of reproductive age (25-44 y).Design: The HEIRS Study was a cross-sectional study of iron status and HFE mutations in primary care patients at 5 centers in the United States and Canada. We analyzed data for women of reproductive age according to whether or not they were pregnant or breastfeeding at the time of the study.Results: ID was present in 12.5% of 20,080 nonpregnant and nonbreastfeeding women compared with 19.2% of 1962 pregnant or breastfeeding women (P < 0.001). Asian American ethnicity (OR ≤0.9; P ≤ 0.049) and HFE C282Y (OR ≤0.84; P ≤ 0.060) were independently associated with a decreased risk of ID in nonpregnant and nonbreastfeeding women and in pregnant or breastfeeding women. Hispanic ethnicity (OR: 1.8; P < 0.001) and African American ethnicity (OR: 1.6; P < 0.001) were associated with an increased risk of ID in nonpregnant and nonbreastfeeding women. Elevated iron stores were shown in 1.7% of nonpregnant and nonbreastfeeding women compared with 0.7% of pregnant or breastfeeding women (P = 0.001). HFE C282Y homozygosity had the most marked independent association with elevated iron stores in nonpregnant and nonbreastfeeding women and in pregnant or breastfeeding women (OR >49.0; P < 0.001), but African American ethnicity was also associated with increased iron stores in both groups of women (OR >2.0; P < 0.001). Asian American ethnicity (OR: 1.8; P = 0.001) and HFE C282Y heterozygosity (OR: 1.9; P = 0.003) were associated with increased iron stores in nonpregnant and nonbreastfeeding women.Conclusions: Both ID and elevated iron stores are present in women of reproductive age and are influenced by ethnicity and HFE C282Y. Efforts to optimize iron status should keep these findings in view. This study was registered at clinicaltrials.gov as NCT03276247.

PMID: 29070555 [PubMed - indexed for MEDLINE]




Dietary iron intake, iron status, and gestational diabetes.
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Dietary iron intake, iron status, and gestational diabetes.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1672S-1680S

Authors: Zhang C, Rawal S

Abstract
Pregnant women are particularly vulnerable to iron deficiency and related adverse pregnancy outcomes and, as such, are routinely recommended for iron supplementation. Emerging evidence from both animal and population-based studies, however, has raised potential concerns because significant associations have been observed between greater iron stores and disturbances in glucose metabolism, including increased risk of type 2 diabetes among nonpregnant individuals. Yet, the evidence is uncertain regarding the role of iron in the development of gestational diabetes mellitus (GDM), a common pregnancy complication which has short-term and long-term adverse health ramifications for both women and their children. In this review, we critically and systematically evaluate available data examining the risk of GDM associated with dietary iron, iron supplementation, and iron status as measured by blood concentrations of several indicators. We also discuss major methodologic concerns regarding the available epidemiologic studies on iron and GDM.

PMID: 29070554 [PubMed - indexed for MEDLINE]




Introduction to workshop on iron screening and supplementation in iron-replete pregnant women and young children.
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Introduction to workshop on iron screening and supplementation in iron-replete pregnant women and young children.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1547S-1554S

Authors: Taylor CL, Brannon PM

Abstract
The NIH Office of Dietary Supplements convened a public workshop on iron screening and supplementation in iron-replete pregnant women and young children in 2016 in Bethesda, Maryland. The starting point for the workshop was the recent reports from the US Preventive Services Task Force concluding that there was insufficient evidence to evaluate the benefits and harms associated with iron screening and routine supplementation among asymptomatic pregnant women and young children (6-24 mo old) in the United States. The goal of the workshop was to explore and refine understanding about the existing knowledge gaps and research needs associated with these preventive services for these groups. Given the focus on the United States, planning for the workshop took into account the higher iron status in the United States compared with developing countries and, in turn, included a focus on iron-replete individuals consistent with the U-shaped risk curve for nutrient-health relations. Topic areas included adaptations in iron homeostasis associated with pregnancy and young childhood, the impact of inflammation, measurement of iron status, current estimates of iron status for pregnant women and young children in the United States and in Europe, and emerging evidence suggesting adverse effects associated with iron supplementation of iron-replete individuals. A crosscutting dialogue conducted at the close of the workshop formed the basis for a workshop summary that specified evidence gaps and research needs in a range of areas centered on the relation of these adaptations of iron homeostasis with the response to and risk from iron supplementation as well as the need for indicators informative of the full continuum of iron status and based on health outcomes, not just erythropoiesis.

PMID: 29070553 [PubMed - indexed for MEDLINE]




The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review.
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The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1688S-1693S

Authors: Paganini D, Zimmermann MB

Abstract
In infants and young children in Sub-Saharan Africa, iron-deficiency anemia (IDA) is common, and many complementary foods are low in bioavailable iron. In-home fortification of complementary foods using iron-containing micronutrient powders (MNPs) and oral iron supplementation are both effective strategies to increase iron intakes and reduce IDA at this age. However, these interventions produce large increases in colonic iron because the absorption of their high iron dose (≥12.5 mg) is typically <20%. We reviewed studies in infants and young children on the effects of iron supplements and iron fortification with MNPs on the gut microbiome and diarrhea. Iron-containing MNPs and iron supplements can modestly increase diarrhea risk, and in vitro and in vivo studies have suggested that this occurs because increases in colonic iron adversely affect the gut microbiome in that they decrease abundances of beneficial barrier commensal gut bacteria (e.g., bifidobacteria and lactobacilli) and increase the abundance of enterobacteria including entropathogenic Escherichia coli These changes are associated with increased gut inflammation. Therefore, safer formulations of iron-containing supplements and MNPs are needed. To improve MNP safety, the iron dose of these formulations should be reduced while maximizing absorption to retain efficacy. Also, the addition of prebiotics to MNPs is a promising approach to mitigate the adverse effects of iron on the infant gut.

PMID: 29070552 [PubMed - indexed for MEDLINE]




Current understanding of iron homeostasis.
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Current understanding of iron homeostasis.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1559S-1566S

Authors: Anderson GJ, Frazer DM

Abstract
Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron concentrations within the optimal physiologic range. In the diet, iron is either sequestered within heme or in various nonheme forms. Although the absorption of heme iron is poorly understood, nonheme iron is transported across the apical membrane of the intestinal enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1). Newly absorbed iron binds to plasma transferrin and is distributed around the body to sites of utilization with the erythroid marrow having particularly high iron requirements. Iron-loaded transferrin binds to transferrin receptor 1 on the surface of most body cells, and after endocytosis of the complex, iron enters the cytoplasm via DMT1 in the endosomal membrane. This iron can be used for metabolic functions, stored within cytosolic ferritin, or exported from the cell via FPN1. Cellular iron concentrations are modulated by the iron regulatory proteins (IRPs) IRP1 and IRP2. At the whole-body level, dietary iron absorption and iron export from the tissues into the plasma are regulated by the liver-derived peptide hepcidin. When tissue iron demands are high, hepcidin concentrations are low and vice versa. Too little or too much iron can have important clinical consequences. Most iron deficiency reflects an inadequate supply of iron in the diet, whereas iron excess is usually associated with hereditary disorders. These disorders include various forms of hemochromatosis, which are characterized by inadequate hepcidin production and, thus, increased dietary iron intake, and iron-loading anemias whereby both increased iron absorption and transfusion therapy contribute to the iron overload. Despite major recent advances, much remains to be learned about iron physiology and pathophysiology.

PMID: 29070551 [PubMed - indexed for MEDLINE]




Iron assessment to protect the developing brain.
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Iron assessment to protect the developing brain.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1588S-1593S

Authors: Georgieff MK

Abstract
Iron deficiency (ID) before the age of 3 y can lead to long-term neurological deficits despite prompt diagnosis of ID anemia (IDA) by screening of hemoglobin concentrations followed by iron treatment. Furthermore, pre- or nonanemic ID alters neurobehavioral function and is 3 times more common than IDA in toddlers. Given the global prevalence of ID and the enormous societal cost of developmental disabilities across the life span, better methods are needed to detect the risk of inadequate concentrations of iron for brain development (i.e., brain tissue ID) before dysfunction occurs and to monitor its amelioration after diagnosis and treatment. The current screening and treatment strategy for IDA fails to achieve this goal for 3 reasons. First, anemia is the final state in iron depletion. Thus, the developing brain is already iron deficient when IDA is diagnosed owing to the prioritization of available iron to red blood cells over all other tissues during negative iron balance in development. Second, brain ID, independently of IDA, is responsible for long-term neurological deficits. Thus, starting iron treatment after the onset of IDA is less effective than prevention. Multiple studies in humans and animal models show that post hoc treatment strategies do not reliably prevent ID-induced neurological deficits. Third, most currently used indexes of ID are population statistical cutoffs for either hematologic or iron status but are not bioindicators of brain ID and brain dysfunction in children. Furthermore, their relation to brain iron status is not known. To protect the developing brain, there is a need to generate serum measures that index brain dysfunction in the preanemic stage of ID, assess the ability of standard iron indicators to detect ID-induced brain dysfunction, and evaluate the efficacy of early iron treatment in preventing ID-induced brain dysfunction.

PMID: 29070550 [PubMed - indexed for MEDLINE]




Iron status of young children in Europe.
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Iron status of young children in Europe.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1663S-1671S

Authors: van der Merwe LF, Eussen SR

Abstract
Iron deficiency (ID) is common in young children aged 6-36 mo. Although the hazards associated with iron deficiency anemia (IDA) are well known, concerns about risks associated with excess iron intake in young children are emerging. To characterize iron status in Europe, we describe the prevalence of ID, IDA, iron repletion, and excess stores with the use of published data from a systematic review on iron intake and deficiency rates, combined with other selected iron status data in young European children. Various definitions for ID and IDA were applied across studies. ID prevalence varied depending on socioeconomic status and type of milk fed (i.e., human or cow milk or formula). Without regard to these factors, ID was reported in 3-48% of children aged ≥12 mo across the countries. For 6- to 12-mo-old infants, based on studies that did not differentiate these factors, ID prevalence was 4-18%. IDA was <5% in most studies in Northern and Western Europe but was considerably higher in Eastern Europe (9-50%). According to current iron status data from a sample of healthy Western European children aged 12-36 mo, 69% were iron replete, and the 97.5th percentile for serum ferritin (SF) was 64.3 μg/L. In another sample, 79% of 24-mo-old children were iron replete, and the 97.5th percentile for SF was 57.3 μg/L. Average iron intake in most countries studied was close to or below the UK's Recommended Dietary Allowance. In conclusion, even in healthy European children aged 6-36 mo, ID is still common. In Western European populations for whom data were available, approximately three-quarters of children were found to be iron replete, and excess iron stores (SF >100 μg/L) did not appear to be a concern. Consensus on the definitions of iron repletion and excess stores, as well as on ID and IDA, is needed.

PMID: 29070549 [PubMed - indexed for MEDLINE]




Excess iron: considerations related to development and early growth.
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Excess iron: considerations related to development and early growth.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1600S-1605S

Authors: Wessling-Resnick M

Abstract
What effects might arise from early life exposures to high iron? This review considers the specific effects of high iron on the brain, stem cells, and the process of erythropoiesis and identifies gaps in our knowledge of what molecular damage may be incurred by oxidative stress that is imparted by high iron status in early life. Specific areas to enhance research on this topic include the following: longitudinal behavioral studies of children to test associations between iron exposures and mood, emotion, cognition, and memory; animal studies to determine epigenetic changes that reprogram brain development and metabolic changes in early life that could be followed through the life course; and the establishment of human epigenetic markers of iron exposures and oxidative stress that could be monitored for early origins of adult chronic diseases. In addition, efforts to understand how iron exposure influences stem cell biology could be enhanced by establishing platforms to collect biological specimens, including umbilical cord blood and amniotic fluid, to be made available to the research community. At the molecular level, there is a need to better understand stress erythropoiesis and changes in iron metabolism during pregnancy and development, especially with respect to regulatory control under high iron conditions that might promote ineffective erythropoiesis and iron-loading anemia. These investigations should focus not only on factors such as hepcidin and erythroferrone but should also include newly identified interactions between transferrin receptor-2 and the erythropoietin receptor. Finally, despite our understanding that several key micronutrients (e.g., vitamin A, copper, manganese, and zinc) support iron's function in erythropoiesis, how these nutrients interact remains, to our knowledge, unknown. It is necessary to consider many factors when formulating recommendations on iron supplementation.

PMID: 29070548 [PubMed - indexed for MEDLINE]




Emerging understanding and measurement of plasma volume expansion in pregnancy.
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Emerging understanding and measurement of plasma volume expansion in pregnancy.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1620S-1625S

Authors: Vricella LK

Abstract
Plasma volume expansion is an important component of a successful pregnancy. The failure of maternal plasma volume expansion has been implicated in adverse obstetric outcomes such as pre-eclampsia, fetal growth restriction, and preterm birth. Altered iron homeostasis and elevated maternal hemoglobin concentrations have also been associated with adverse pregnancy outcomes; limited data have suggested that these effects may be mediated by inadequate plasma volume expansion. In addition, it has been noted that pregnant, obese women, compared with lean subjects, have decreased plasma volume expansion along with impaired iron homeostasis and increased inflammation. Current estimates of plasma volume expansion are outdated and do not necessarily reflect contemporary obstetric populations. Moreover, the validation of clinically applicable methods of plasma volume determination as well as enhanced methodologies should be a priority. Further study is needed to characterize diminished plasma volume expansion during pregnancy and to understand the potential role of impaired iron homeostasis and inflammation in adverse obstetric outcomes, especially in obese women.

PMID: 29070547 [PubMed - indexed for MEDLINE]




Impact of chronic and acute inflammation on extra- and intracellular iron homeostasis.
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Impact of chronic and acute inflammation on extra- and intracellular iron homeostasis.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1581S-1587S

Authors: Ross AC

Abstract
Inflammation has a major impact on iron homeostasis. This review focuses on acute and chronic inflammation as it affects iron trafficking and, as a result, the availability of this essential micronutrient to the host. In situations of microbial infection, not only the host is affected but also the offending microorganisms, which, in general, not only require iron for their own growth but have evolved mechanisms to obtain it from the infected host. Key players in mammalian iron trafficking include several types of cells important to iron acquisition, homeostasis, and hematopoiesis (enterocytes, hepatocytes, macrophages, hematopoietic cells, and in the case of pregnancy, placental syncytiotrophoblast cells) and several forms of chaperone proteins, including, for nonheme iron, the transport protein transferrin and the intracellular iron-storage protein ferritin, and for heme iron, the chaperone proteins haptoglobin and hemopexin. Additional key players are the cell membrane-associated iron transporters, particularly ferroportin (FPN), the only protein known to modulate iron export from cells, and finally, the iron-regulatory hormone hepcidin, which, in addition to having antibacterial activity, regulates the functions of FPN. Interestingly, the impact of infection on iron homeostasis differs among pathogens whose mode of infection is mainly intracellular or extracellular. Understanding how inflammation affects each of these processes may be crucial for understanding how inflammation affects iron status, indicators of iron sufficiency, and iron supplementation during inflammation and how it may potentially result in a beneficial or detrimental impact on the host.

PMID: 29070546 [PubMed - indexed for MEDLINE]




Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges.
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Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1606S-1614S

Authors: Pfeiffer CM, Looker AC

Abstract
Biochemical assessment of iron status relies on serum-based indicators, such as serum ferritin (SF), transferrin saturation, and soluble transferrin receptor (sTfR), as well as erythrocyte protoporphyrin. These indicators present challenges for clinical practice and national nutrition surveys, and often iron status interpretation is based on the combination of several indicators. The diagnosis of iron deficiency (ID) through SF concentration, the most commonly used indicator, is complicated by concomitant inflammation. sTfR concentration is an indicator of functional ID that is not an acute-phase reactant, but challenges in its interpretation arise because of the lack of assay standardization, common reference ranges, and common cutoffs. It is unclear which indicators are best suited to assess excess iron status. The value of hepcidin, non-transferrin-bound iron, and reticulocyte indexes is being explored in research settings. Serum-based indicators are generally measured on fully automated clinical analyzers available in most hospitals. Although international reference materials have been available for years, the standardization of immunoassays is complicated by the heterogeneity of antibodies used and the absence of physicochemical reference methods to establish "true" concentrations. From 1988 to 2006, the assessment of iron status in NHANES was based on the multi-indicator ferritin model. However, the model did not indicate the severity of ID and produced categorical estimates. More recently, iron status assessment in NHANES has used the total body iron stores (TBI) model, in which the log ratio of sTfR to SF is assessed. Together, sTfR and SF concentrations cover the full range of iron status. The TBI model better predicts the absence of bone marrow iron than SF concentration alone, and TBI can be analyzed as a continuous variable. Additional consideration of methodologies, interpretation of indicators, and analytic standardization is important for further improvements in iron status assessment.

PMID: 29070545 [PubMed - indexed for MEDLINE]




Excess iron intake as a factor in growth, infections, and development of infants and young children.
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Excess iron intake as a factor in growth, infections, and development of infants and young children.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1681S-1687S

Authors: Lönnerdal B

Abstract
The provision of iron via supplementation or the fortification of foods has been shown to be effective in preventing and treating iron deficiency and iron deficiency anemia in infants and young children. However, iron is a pro-oxidative element and can have negative effects on biological systems even at moderate amounts. An increasing number of studies have reported adverse effects of iron that was given to infants and young-children populations who initially were iron replete. These effects include decreased growth (both linear growth and weight), increased illness (usually diarrhea), interactions with other trace elements such as copper and zinc, altered gut microbiota to more pathogenic bacteria, increased inflammatory markers, and impaired cognitive and motor development. If these results can be confirmed by larger and well-controlled studies, it may have considerable programmatic implications (e.g., the necessity to screen for iron status before interventions to exclude iron-replete individuals). A lack of understanding of the mechanisms underlying these adverse outcomes limits our ability to modify present supplementation and fortification strategies. This review summarizes studies on the adverse effects of iron on various outcomes; suggests possible mechanisms that may explain these observations, which are usually made in clinical studies and intervention trials; and gives examples from animal models and in vitro studies. With a better understanding of these mechanisms, it may be possible to find novel ways of providing iron in a form that causes fewer or no adverse effects even when subjects are iron replete. However, it is apparent that our understanding is limited, and research in this area is urgently needed.

PMID: 29070544 [PubMed - indexed for MEDLINE]




Iron status in pregnant women and women of reproductive age in Europe.
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Iron status in pregnant women and women of reproductive age in Europe.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1655S-1662S

Authors: Milman N, Taylor CL, Merkel J, Brannon PM

Abstract
Understanding the iron status in pregnant women in Europe provides a foundation for considering the role of iron screening and supplementation. However, available reports and studies have used different approaches that challenge the devising of overall summaries. Moreover, data on pregnant women are limited, and thus, data on women of reproductive age provide useful background information including baseline iron stores in pregnant women. This review considered data that are available from >15 European countries including national surveys and relevant clinical studies. In European women of reproductive age, median or geometric mean serum ferritin (SF) concentrations were estimated at 26-38 μg/L. Approximately 40-55% of this population had small or depleted iron stores (i.e., SF concentration ≤30 μg/L), and 45-60% of this population had apparently replete iron stores. The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) was 10-32% and 2-5%, respectively, depending on the cutoffs used. Approximately 20-35% of European women of reproductive age had sufficient iron stores (SF concentration >70 μg/L) to complete a pregnancy without supplementary iron. During pregnancy, European women in controlled supplementation trials who were not receiving iron supplements displayed increasing prevalences of ID and IDA during pregnancy, which peaked in the middle to late third trimester. Available evidence has suggested that, in gestational weeks 32-39, the median or geometric mean SF concentrations were 6-21 μg/L, and prevalences of ID and IDA were 28-85% and 21-35%, respectively. Women who were taking iron supplements had higher iron status and lower prevalences of ID and IDA, which were dependent on the dose of iron and compliance. The data suggest that, in Europe, the iron status of reproductive-aged women varies by region and worsens in pregnancy without iron supplementation.

PMID: 29070543 [PubMed - indexed for MEDLINE]




Iron homeostasis during pregnancy.
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Iron homeostasis during pregnancy.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1567S-1574S

Authors: Fisher AL, Nemeth E

Abstract
During pregnancy, iron needs to increase substantially to support fetoplacental development and maternal adaptation to pregnancy. To meet these iron requirements, both dietary iron absorption and the mobilization of iron from stores increase, a mechanism that is in large part dependent on the iron-regulatory hormone hepcidin. In healthy human pregnancies, maternal hepcidin concentrations are suppressed in the second and third trimesters, thereby facilitating an increased supply of iron into the circulation. The mechanism of maternal hepcidin suppression in pregnancy is unknown, but hepcidin regulation by the known stimuli (i.e., iron, erythropoietic activity, and inflammation) appears to be preserved during pregnancy. Inappropriately increased maternal hepcidin during pregnancy can compromise the iron availability for placental transfer and impair the efficacy of iron supplementation. The role of fetal hepcidin in the regulation of placental iron transfer still remains to be characterized. This review summarizes the current understanding and addresses the gaps in knowledge about gestational changes in hematologic and iron variables and regulatory aspects of maternal, fetal, and placental iron homeostasis.

PMID: 29070542 [PubMed - indexed for MEDLINE]




Gaps in evidence regarding iron deficiency anemia in pregnant women and young children: summary of US Preventive Services Task Force recommendations.
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Gaps in evidence regarding iron deficiency anemia in pregnant women and young children: summary of US Preventive Services Task Force recommendations.

Am J Clin Nutr. 2017 Dec;106(Suppl 6):1555S-1558S

Authors: Kemper AR, Fan T, Grossman DC, Phipps MG

Abstract
The US Preventive Services Task Force (USPSTF) makes recommendations to primary care providers regarding preventive services for asymptomatic patients. Recommendations are based on the scientific evidence that the delivery of the preventive service leads to improvements in meaningful patient outcomes. After a review of the available evidence, the USPSTF found insufficient evidence to recommend routine iron supplementation for pregnant women or routine screening for iron deficiency anemia in pregnant women or young children. The USPSTF identified a critical evidence gap that is related to whether changing hematologic indexes in otherwise asymptomatic pregnant women or in infants within populations who are reflective of the United States leads to an improvement in maternal or child health outcomes. Future research opportunities are described to address these important evidence gaps.

PMID: 29070541 [PubMed - indexed for MEDLINE]