High Prevalence of Iron Deficiency Despite Standardized High-Dose Iron Supplementation During Recombinant Erythropoietin Therapy in Extremely Low Gestational Age Newborns

Anemia remains a condition with high prevalence in populations worldwide, and the prevalence of anemia among children under five years old in Brazil is approximately 40%, being higher in communities marked by social inequities. Diverse government programs during recent decades targeted iron-deficiency anemia, considering its impacts throughout the lifetime. The objective of this study was to investigate the effects of two government iron supplementation programs on health outcomes related to iron-deficiency anemia among children up to 4 years old in Brazilian municipalities. A longitudinal panel encompassing data from 5570 municipalities from 1998 to 2019 was investigated using a difference-in-differences framework with multiple interventions and distinct times of adhesion, and fixed-effects models were estimated to control for invariant municipal characteristics throughout the period in order to ensure comparability. The results indicate significant effects of the federal programs in reducing hospitalizations and lengths of stay due to iron-deficiency anemia, especially in non-poor municipalities. There was complementarity in the effects of the programs; however, neither of the programs influenced mortality rates. Thus, it is important to consider possible improvements in the operationalization of the programs, in order to achieve better results in the reduction of severe iron-deficiency anemia among children up to 4 years old.

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Risk Factors for Iron Deficiency in Very Preterm Infants at 4-6 Months Corrected Age

Blood ◽

10.1182/blood-2020-142442 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-28

Author(s):

Carmen Landry ◽

Jon Dorling ◽

Ketan Kulkarni ◽

Marsha Campbell-Yeo ◽

Michael Vincer ◽

...

Keyword(s):

Risk Factors ◽

Iron Deficiency ◽

Preterm Infants ◽

Serum Ferritin ◽

Gestational Age ◽

Iron Supplementation ◽

Gestational Hypertension ◽

Univariate Analysis ◽

P Value

Background: Iron is an essential micronutrient, especially in infants and young children and is required for erythropoiesis and development of the central nervous system. However, iron deficiency (ID) is the most common micronutrient deficiency worldwide. ID and iron deficiency anemia (IDA) have been associated with poor neurodevelopmental and behavioural outcomes later in life. Preterm infants are particularly at risk of developing ID in early life due to lower iron stores at birth, accelerated growth in the first weeks of life and multiple phlebotomies while in hospital. Therefore, international recommendations suggest prophylactic iron therapy of 2-4 mg/kg/day starting at 2-6 weeks of age until at least 6-12 months in preterm and low birth weight infants. This prophylactic iron supplementation has been shown to be effective at reducing the incidence of ID and IDA. However, the published work mainly involves moderate to late preterm infants and the research is lacking on iron status after discharge in very preterm infants (VPI, <31 weeks gestational age). Based on our previous work, 32% of the VPIs were iron deficient at 4-6 months corrected age despite this early supplementation. Since the development of ID may have permanent detrimental effects on the developing brain of these high-risk preterm infants, a knowledge of risk factors for ID is also important to identify strategies focused on its prevention. Objective: To investigate the risk factors associated with development of ID Methods: A retrospective cohort study was conducted at the IWK Health Centre using a population based provincial Perinatal Follow-Up Program database. All live-born VPIs born in Nova Scotia between 2005-2018 were included. Patients with congenital malformations, chromosomal anomalies, or who died prior to outcome assessment were excluded. As a standard of care, all these infants were started on prophylactic iron supplements (2-3 mg/kg/day) at 2-4 weeks of chronological age. Iron dosage was regularly adjusted during the hospital stay as guided by serum ferritin levels. At discharge, it was recommended to continue iron prophylaxis until 9-12 months corrected age. All these infants underwent a blood test during their first neonatal follow-up visit at 4-6 months corrected age to check for hemoglobin, reticulocyte count and serum ferritin. ID was defined as serum ferritin <20g/l or <12g/l at 4 and 6 months respectively. A univariate analysis was performed by using a series of single variable logistic regression models to identify the factors associated with presence of ID. Factors with a p-value < 0.20 in the univariate analysis were entered into a multivariable risk model for occurrence of ID using a backwards selection procedure. Variables with a p-value < 0.05 were retained. Results: Of 411 infants included in the study, 32.1% (n=132) had ID. The prevalence of ID decreased over time (37.6% in 2005-2011 vs 25.8% in 2012-2018 cohort). Table 1 compares the antenatal and neonatal characteristics of the ID and non-ID groups. Table 2 compares sociodemographic variables and clinical variables at the time of follow up of the two groups. Independent risk factors for ID were: gestational age (<27 weeks to >27 weeks) (OR:1.7 (1.0-2.9), p=0.04) and gestational hypertension (OR: 2.1(1.2-3.7), p=0.009). Independent factors protective for ID were: mixed feeding (breast milk and formula compared to formula alone) (OR: 0.5 (0.2-0.9), p=0.021) and iron supplementation at follow-up (OR:0.5 (0.3-0.9), p=0.02). Conclusion(s): Despite prophylactic iron supplementation, one-third of VPIs had ID at 4-6 months corrected age. Gestational hypertension in mother and gestational age < 27 weeks were independent risk factors for ID. In addition, despite adjusting for iron supplementation at follow-up, the formula feeding group was more likely to have ID compared to the mixed feeding group. This may be because of the sub-therapeutic iron intake in the formula fed infants. It is often thought that formula milk may have sufficient iron to meet the demands of growing infants and thus, they are less likely to receive higher doses of supplemental iron beyond what is contained in the formula. However, this may not be true since the iron present in formula may not have the same bioavailability as breast milk. Future prospective studies are required to further validate these observations. Nonetheless, the study identified important areas to mitigate ID in VPIs. Disclosures No relevant conflicts of interest to declare.

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Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.18841220 ◽

2021 ◽

Vol 16 (6) ◽

pp. 862-869

Author(s):

Sangeeta Hingorani ◽

Robert H. Schmicker ◽

Patrick D. Brophy ◽

Patrick J. Heagerty ◽

Sandra E. Juul ◽

...

Keyword(s):

Confidence Interval ◽

Gestational Age ◽

Regression Models ◽

Cox Regression ◽

Controlled Trial ◽

Hazard Ratio ◽

Time Dependent ◽

Recombinant Erythropoietin ◽

The Relationship ◽

Extremely Low Gestational Age

Background and objectivesAKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates.Design, setting, participants, & measurementsThe Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by <7 days before death. Landmark analyses examined the relationship of death with development of severe AKI.ResultsSevere AKI occurred in 168 of 900 (19%, 95% confidence interval, 17% to 20%) neonates, and stage 3 AKI occurred in 60 (7%, 95% confidence interval, 5% to 8%). Stage 3 AKI occurring 7 days before death (hazard ratio, 3.88; 95% confidence interval, 1.26 to 11.96), intraventricular hemorrhage (hazard ratio, 2.01; 95% confidence interval, 1.01 to 3.99) and sepsis (hazard ratio, 2.85; 95% confidence interval, 1.12 to 7.22) were all independently associated with death. Severe AKI occurring 7 days before death (hazard ratio, 2.21; 95% confidence interval, 0.92 to 5.26) was associated with death but not statistically significant. In a landmark analysis, after adjusting for potential confounders, late (after day 14 and before day 28) severe AKI was strongly associated with higher hazard of death (hazard ratio, 4.57; 95% confidence interval, 1.82 to 11.5).ConclusionsSevere AKI occurs frequently in extremely low gestational age neonates. Stage 3 AKI is associated with mortality, and this association is present 7 days before death.

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No effect of high dose oral iron supplementation on copper and zinc status in gastric bypass patients undergoing treatment for iron deficiency

Surgery for Obesity and Related Diseases ◽

10.1016/j.soard.2017.09.447 ◽

2017 ◽

Vol 13 (10) ◽

pp. S201

Author(s):

Nana Gletsu MIller ◽

Aisling Mangan

Keyword(s):

Gastric Bypass ◽

Iron Deficiency ◽

Iron Supplementation ◽

Oral Iron ◽

High Dose ◽

Zinc Status ◽

Copper And Zinc ◽

Dose Oral

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Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates

JAMA Pediatrics ◽

10.1001/jamapediatrics.2020.2271 ◽

2020 ◽

Vol 174 (10) ◽

pp. 933 ◽

Cited By ~ 2

Author(s):

Sandra E. Juul ◽

Phuong T. Vu ◽

Bryan A. Comstock ◽

Rajan Wadhawan ◽

Dennis E. Mayock ◽

...

Keyword(s):

Gestational Age ◽

High Dose ◽

Blood Transfusions ◽

Extremely Low Gestational Age

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Optimising Haemoglobin Response to Exogenous Erythropoietin in Anaemic Patients Treated in Routine Haemato-Oncology Practice.

Blood ◽

10.1182/blood.v108.11.5516.5516 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5516-5516

Author(s):

Samir G. Agrawal ◽

Paul Greaves ◽

Christina Lim ◽

Chris D. Poole ◽

Mel D. Walker

Keyword(s):

Iron Deficiency ◽

Disease Progression ◽

Iron Supplementation ◽

Recombinant Erythropoietin ◽

Female Ratio ◽

Functional Iron Deficiency ◽

Use Of Resources ◽

Underlying Malignancy ◽

Iron Deficient ◽

Iv Iron

Abstract Patients’ response to treatment with human recombinant erythropoietin (Epo) for chemotherapy-associated anaemia varies between 50% and 70%. The cost-effectiveness of Epo may be maximized by targeting treatment at patients most likely to respond. In this study, modified ASH/ASCO guidelines were combined with a systematic approach to iron supplementation in order to maximize haemoglobin (Hb) response in iron deficient patients. Patients with haematological malignancy and chemotherapy-associated anaemia received Epo alone (n = 25) or Epo plus intravenous iron sucrose (iv iron) if functional iron deficiency was present (n=24). The cohort had a male/female ratio of 48:52% and a mean age 62.8 years (SD 12.8; range 24 to 81). Baseline measurements were repeated at 4-weekly intervals for a period of 32 weeks. Overall, 80% of cases experienced a Hb response greater than 1g/dl, with 65% of patients achieving a major Hb response (≥ 2g/dl increase above baseline). There was no difference in Hb response between the Epo alone vs. Epo plus iv iron groups (∅ 2.72 vs. 2.84 g/dl; p=0.831), indicating equivalent outcomes for functionally iron deficient patients treated with effective iv iron supplementation and iron replete patients. General Linear Modelling was used to explore the independent contributions of demographics, baseline iron parameters, and disease progression in predicting Hb response to Epo. In the final model three independent variables emerged as significant, which together accounted for 40% of variance in Hb response. Progression of the underlying malignancy was associated with a mean reduction in Hb response of 1.9g/dl (p<0.001). Lower baseline Hb was associated with an increased response - each 1g/dl decrement was associated with a mean increased response of 0.87g/dl (p=0.012). Early change in reticulocyte count (between baseline and early follow up (< 4 weeks) was found to be positively associated with Hb response - each additional 1% change was associated with a 0.016g/dl increase in Hb response (p=0.006). These findings are in contrast to previous reports that the response to Epo was independent of the outcome of the underlying malignancy and diminished at lower Hb levels. Disease progression, baseline Hb and early increases in reticulocytes were all highly significantly correlated with the Hb response to Epo. In fact, in this cohort, all cases of non-response to Epo or loss of a response were associated with disease progression. To maximise response rates to Epo requires detection of functional iron deficiency and supplementation with iv iron. Furthermore, early reticulocyte response and disease progression should be closely followed and can help guide when to stop Epo therapy. This would allow rational use of resources and improve the health economics of Epo therapy by focusing on those most likely to benefit.

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Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2391 ◽

2015 ◽

Vol 100 (9) ◽

pp. 3388-3392 ◽

Cited By ~ 27

Author(s):

Klaus Kapelari ◽

Julia Köhle ◽

Dieter Kotzot ◽

Wolfgang Högler

Keyword(s):

Iron Deficiency ◽

Serum Iron ◽

Iron Supplementation ◽

Autosomal Dominant ◽

Iron Status ◽

Fibroblast Growth Factor 23 ◽

Normal Serum ◽

Hypophosphatemic Rickets ◽

High Dose ◽

Autosomal Dominant Hypophosphatemic Rickets

Context: Autosomal dominant hypophosphatemic rickets (ADHR) is the only hereditary disorder of renal phosphate wasting in which patients may regain the ability to conserve phosphate. Low iron status plays a role in the pathophysiology of ADHR. Objective: This study reports of a girl with ADHR, iron deficiency, and a paternal history of hypophosphatemic rickets that resolved without treatment. The girl's biochemical phenotype resolved with iron supplementation. Subjects: A 26-month-old girl presented with typical features of hypophosphatemic rickets, short stature (79 cm; −2.82 SDS), and iron deficiency. Treatment with elemental phosphorus and calcitriol improved her biochemical profile and resolved the rickets. The girl's father had presented with rickets at age 11 months but never received medication. His final height was reduced (154.3 cm; −3.51 SDS), he had undergone corrective leg surgery and had an adult normal phosphate, fibroblast growth factor 23, and iron status. Father and daughter were found to have a heterozygous mutation in exon 3 of the FGF23 gene (c.536G>A, p.Arg179Gln), confirming ADHR. Intervention: Withdrawal of rickets medication was attempted off and on iron supplementation. Results: Withdrawal of rickets medication in the girl was unsuccessful in the presence of low-normal serum iron levels at age 5.6 years but was later successful in the presence of high-normal serum iron levels following high-dose iron supplementation. Conclusions: We report an association between iron supplementation and a complete loss of biochemical ADHR phenotype, allowing withdrawal of rickets medication. Experience from this case suggests that reduction and withdrawal of rickets medication should be attempted only after iron status has been optimized.

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Iron-Fortified Drinking Water Studies for the Prevention of Children's Anemia in Developing Countries

Anemia ◽

10.1155/2011/815194 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Jose E. Dutra-de-Oliveira ◽

J. Sergio Marchini ◽

Joel Lamounier ◽

Carlos A. N. Almeida

Keyword(s):

Developing Countries ◽

Drinking Water ◽

Iron Deficiency ◽

Iron Supplementation ◽

Iron Intake ◽

Day Care Centers ◽

Small Children ◽

High Prevalence ◽

The Government ◽

Simple Technology

Anemia and iron deficiency should receive special attention considering their high prevalence and serious consequences. For prevention, globally it is recommended to increase dietary iron intake, iron fortification of industrialized foods, and medical iron supplementation. Food fortification for the prevention of iron deficiency in developing countries should consider carriers locally available and consumed daily, requiring limited infrastructure and technology. Drinking water is the iron carrier we have been working for years for the prevention of iron deficiency and anemia in small children in Brazil. It was shown that studies with iron-fortified drinking water were proved to be effective on children's anemia prevention. Water is found everywhere, consumed daily by everyone may be easily fortified with simple technology, is low priced and was effective on the prevention of children's anemia. Fortification of drinking water with iron was locally implemented with the direct participation of the government and community. Government authorities, health personnel and population were part of the project and responsible for its community implementation. The mayor/municipality permitted and supported the proposal to supply it to children at their day-care centers. To keep the children drinking water iron fortified supply an officially authorized legislation was also approved.

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