Sarah E. Cusick

Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999–2006

BACKGROUND Total body iron calculated from serum ferritin and soluble transferrin receptor concentrations allows for the evaluation of the full range of iron status. OBJECTIVE We described the distribution of total body iron and the prevalence of iron deficiency (ID) on the basis of total body iron in US pregnant women. DESIGN We examined data from the National Health and Nutrition Examination Survey (NHANES) in 1999-2006 for 1171 pregnant women. RESULTS ID prevalence (±SE) in US pregnant women, which was defined as total body iron <0 mg/kg, was 18.0 ± 1.4%. Pregnant women in the first trimester had a higher mean total body iron than did pregnant women in the second or third trimesters. ID prevalence in pregnant women increased significantly with each trimester (6.9 ± 2.2%, 14.3 ± 2.1%, and 29.5 ± 2.7% in the first, second, and third trimesters, respectively). Pregnant women with parity ≥2 had the lowest mean total body iron and the highest prevalence of ID compared with values for pregnant women with parity of 0 or 1. The ID prevalence in non-Hispanic white pregnant women was significantly lower than in Mexican American or non-Hispanic black pregnant women. The mean total body iron and the prevalence of ID did not differ by educational level or by family income. CONCLUSIONS To our knowledge, these are the first data on total body iron distributions for a representative sample of US pregnant women. Low total body iron is more prevalent in pregnant women in the second or third trimesters, in Mexican American pregnant women, in non-Hispanic black pregnant women, and in women with parity ≥2.

Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research

A central issue when designing multidimensional biological and psychosocial interventions for children who are exposed to multiple developmental risks is identification of the age period(s) in which such interventions will have the strongest and longest lasting effects (sensitive periods). In this paper, we review nutritional, neuroscientific, and psychological evidence on this issue. Nutritional evidence is used to identify nutrient‐sensitive periods of age‐linked dimensions of brain development, with specific reference to iron deficiency. Neuroscience evidence is used to assess the importance of timing of exposures to environmental stressors for maintaining neural, neuroendocrine, and immune systems integrity. Psychological evidence illustrates the sensitivity of cognitive and social–emotional development to contextual risk and protective influences encountered at different ages. Evidence reviewed documents that the early years of life are a sensitive period when biological or psychosocial interventions or exposure to risk or protective contextual influences can produce unique long‐term influences upon human brain, neuroendocrine, and cognitive or psychosocial development. However, the evidence does not identify the early years as the sole sensitive time period within which to have a significant influence upon development. Choice of age(s) to initiate interventions should be based on what outcomes are targeted and what interventions are used.

Issues in the timing of integrated early interventions

A central issue when designing multidimensional biological and psychosocial interventions for children who are exposed to multiple developmental risks is identification of the age period(s) in which such interventions will have the strongest and longest lasting effects (sensitive periods). In this paper, we review nutritional, neuroscientific, and psychological evidence on this issue. Nutritional evidence is used to identify nutrient‐sensitive periods of age‐linked dimensions of brain development, with specific reference to iron deficiency. Neuroscience evidence is used to assess the importance of timing of exposures to environmental stressors for maintaining neural, neuroendocrine, and immune systems integrity. Psychological evidence illustrates the sensitivity of cognitive and social–emotional development to contextual risk and protective influences encountered at different ages. Evidence reviewed documents that the early years of life are a sensitive period when biological or psychosocial interventions or exposure to risk or protective contextual influences can produce unique long‐term influences upon human brain, neuroendocrine, and cognitive or psychosocial development. However, the evidence does not identify the early years as the sole sensitive time period within which to have a significant influence upon development. Choice of age(s) to initiate interventions should be based on what outcomes are targeted and what interventions are used.

Unexplained decline in the prevalence of anemia among US children and women between 1988–1994 and 1999–2002

BACKGROUND The current anemia burden among US preschool children and women of childbearing age has not been documented. OBJECTIVE We used data from National Health and Nutrition Examination Surveys 1988-1994 and 1999-2002 to examine recent anemia changes. DESIGN We calculated the prevalence of anemia (hemoglobin < 11.0 g/dL at <24 mo, <11.1 g/dL at 24-59 mo, and <12.0 g/dL for women), iron deficiency anemia (anemia plus abnormal value >or=2: serum ferritin, transferrin saturation, and erythrocyte protoporphyrin), and high blood lead (>or=10 microg/dL) with anemia among children 12-59 mo and women 20-49 y in both surveys. Among women, we also calculated the prevalence of folate deficiency (erythrocyte folate < 317.2 nmol/L) with anemia and high C-reactive protein (>10 mg/L) with anemia. Multiple logistic regression was used to compare anemia prevalence between surveys, with control for race and age. RESULTS Anemia declined significantly in children (from 8.0% to 3.6%; OR: 0.4; 95% CI: 0.3, 0.7) and women (10.8% to 6.9%; OR: 0.6; CI: 0.4, 0.7), but the prevalence of iron deficiency anemia did not change significantly in children (1.5% compared with 1.2%; OR: 0.7; 95% CI: 0.4, 1.5) or women (4.9% compared with 4.1%; OR: 0.8; 95% CI: 0.6, 1.1). Folate deficiency with anemia declined significantly in women (from 4.1% to 0.5%; OR: 0.1; 95% CI: 0.1, 0.2), but logistic regression models and standardization indicated that none of the known possible anemia causes could account for the decline in total anemia in children or women. CONCLUSIONS The prevalence of anemia declined significantly among US women and children between 1988-1994 and 1999-2002, but this decline was not associated with changes in iron or folate deficiency, inflammation, or high blood lead.

Short-term effects of vitamin A and antimalarial treatment on erythropoiesis in severely anemic Zanzibari preschool children

BACKGROUND The pathophysiology of anemia in coastal East Africa is complex. Impaired erythropoietin production is one possible mechanism. Plasmodium falciparum malaria has been found to blunt erythropoietin production, whereas vitamin A stimulates erythropoietin production in vitro. OBJECTIVE We investigated the 72-h effects of vitamin A and the antimalarial drug sulfadoxine pyramethamine (SP) on erythropoietin production in severely anemic (hemoglobin < or = 70 g/L) preschool children in Zanzibar, a region of known vitamin A deficiency. We hypothesized that both treatments would stimulate erythropoietin production directly, within 72 h, before a change in hemoglobin would occur. DESIGN One hundred forty-one severely anemic children were identified during the baseline assessment of a morbidity substudy of a community-based micronutrient supplementation trial. All severely anemic children were randomly assigned to receive either vitamin A (100,000 or 200,000 IU depending on age) or SP at baseline; 72 h later they received the opposite treatment plus daily hematinic syrup for 90 d. Erythropoietic and parasitic indicators were assessed at baseline and again after 72 h. RESULTS After 72 h, SP reduced the malaria parasite density (by 5029 parasites/microL; P < 0.001), CRP concentrations (by 10.6 mg/L; P = 0.001), and the proportion of children infected with malaria (by 32.4%; P < 0.001). Vitamin A reduced CRP (by 9.6 mg/L; P = 0.011), serum ferritin (by 18.1 microg/L; P = 0.042), and erythropoietin (by 194.7 mIU/mL; P = 0.011) concentrations and increased the reticulocyte production index (by 0.40; P = 0.041). CONCLUSIONS Contrary to our hypothesis, vitamin A significantly decreased erythropoietin concentration. The most important effect of both vitamin A and SP was the rapid reduction of inflammation. Vitamin A also mobilized iron from stores and stimulated the production of new erythrocytes.

The Role of Nutrition in Brain Development: The Golden Opportunity of the “First 1000 Days”

Journal of Pediatrics, The - In Press.Proof corrected by the author Available online since lundi 6 juin 2016

Vitamin D Insufficiency Is Common in Ugandan Children and Is Associated with Severe Malaria

Vitamin D plays an increasingly recognized role in the innate and adaptive immune response to infection. Based on demonstrated roles in up-regulating innate immunity, decreasing inflammation, and reducing the severity of disease in illnesses such as tuberculosis and influenza, we hypothesized that poor vitamin D status would be associated with severe malaria. We measured 25-hydroxyvitamin D [25(OH)D] by immunoassay in a sample of Ugandan children aged 18 months –12 years with severe malaria (cerebral malaria or severe malarial anemia, n = 40) and in healthy community children (n = 20). Ninety-five percent of children with severe malaria (n = 38) and 80% of control children (n = 16) were vitamin D-insufficient [plasma 25(OH)D <30 ng/mL]. Mean plasma 25(OH)D levels were significantly lower in children with severe malaria than in community children (21.2 vs. 25.3 ng/mL, p = 0.03). Logistic regression revealed that for every 1 ng/mL increase in plasma 25(OH)D, the odds of having severe malaria declined by 9% [OR = 0.91 (95% CI: 0.84, 1.0)]. These preliminary results suggest that vitamin D insufficiency may play a role in the development of severe malaria. Further prospective studies in larger cohorts are indicated to confirm the relationship of vitamin D levels to severity of malaria infection and to investigate causality.

Decline in childhood iron deficiency after interruption of malaria transmission in highland Kenya.

BACKGROUND Achieving optimal iron status in children in malaria-endemic areas may increase the risk of malaria. Malaria itself may contribute to iron deficiency, but the impact of an interruption in malaria transmission on the prevalence of iron deficiency is unknown. OBJECTIVES We aimed to determine whether 1) iron status improved in children living in 2 Kenyan villages with a documented cessation in malaria transmission and 2) changes in iron status correlated with changes in hemoglobin. DESIGN We measured iron [hemoglobin, ferritin, soluble transferrin receptor (sTfR)] and inflammatory [C-reactive protein (CRP)] markers in paired plasma samples from 190 children aged 4-59 mo at the beginning (May 2007) and end (July 2008) of a documented 12-mo period of interruption in malaria transmission in 2 highland areas in Kenya with unstable malaria transmission and ongoing malaria surveillance. RESULTS Between May 2007 and July 2008, mean (±SD) hemoglobin increased from 10.8 ± 1.6 to 11.6 ± 1.6 g/dL. Median (25th, 75th percentile) ferritin increased from 17.0 (9.7, 25.6) to 22.6 (13.4, 34.7) μg/L (P < 0.001), whereas median sTfR decreased from 32.4 (26.3, 43.2) to 27.7 (22.1, 36.0) nmol/L (P < 0.001). Median CRP was low (<1 mg/L in both years) and did not change significantly. Iron deficiency prevalence (ferritin <12 μg/L, or <30 μg/L if CRP ≥10 mg/L) decreased from 35.9% (95% CI: 28.9%, 43.0%) to 24.9% (18.5%, 31.2%) (P = 0.005). The prevalence of iron deficiency with anemia (hemoglobin <11.0 g/dL) declined from 27.2% (20.7%, 33.8%) to 12.2% (7.4%, 17.1%) (P < 0.001). Improvement in iron status correlated with an increase in hemoglobin and was greater than explained by physiologic changes expected with age. CONCLUSIONS In this area of unstable malaria transmission, the prevalence of iron deficiency in children decreased significantly after the interruption of malaria transmission and was correlated with an increase in hemoglobin. These findings suggest that malaria elimination strategies themselves may be an effective way to address iron deficiency in malaria-endemic areas.

Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial

BACKGROUND Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution. OBJECTIVE We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery. METHODS We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 μmol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope (57)Fe on day 0 and (58)Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2). RESULTS The percentage of iron incorporation (mean ± SE) was greater at day 28 in the D group (16.5% ± 1.7%) than at day 0 in the I group (7.9% ± 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean ± SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 ± 15.9 compared with 112 ± 12.4 g/L; P = 0.04), ferritin (39.3 μg/L; 23.5, 65.7 μg/L compared with 79.9 μg/L; 58.3, 110 μg/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001). CONCLUSIONS Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.

Comparison of iron status 28 d after provision of antimalarial treatment with iron therapy compared with antimalarial treatment alone in Ugandan children with severe malaria

BACKGROUND The provision of iron with antimalarial treatment is the standard of care for concurrent iron deficiency and malaria. However, iron that is given during a malaria episode may not be well absorbed or used, particularly in children with severe malaria and profound inflammation. OBJECTIVES We aimed to 1) determine baseline values of iron and inflammatory markers in children with severe malarial anemia (SMA), children with cerebral malaria (CM), and community children (CC) and 2) compare markers in iron-deficient children in each group who received 28 d of iron supplementation during antimalarial treatment with those in children who did not receive iron during treatment.. DESIGN Seventy-nine children with CM, 77 children with SMA, and 83 CC who presented to Mulago Hospital, Kampala, Uganda, were enrolled in a 28-d iron-therapy study. Children with malaria received antimalarial treatment. All children with CM or SMA, as well as 35 CC, had zinc protoporphyrin (ZPP) concentrations ≥80 μmol/mol heme and were randomly assigned to receive a 28-d course of iron or no iron. We compared iron markers at day 0 among study groups (CM, SMA, and CC groups) and at day 28 between children in each group who were randomly assigned to receive iron or to not receive iron. RESULTS At day 0, children with CM and SMA had greater values of C-reactive protein, ferritin, and hepcidin than those of CC. At day 28, interactions between study and treatment group were NS. Children in the no-iron compared with iron groups had similar mean values for hemoglobin (115 compared with 113 g/L, respectively; P = 0.73) and ZPP (124 compared with 124 μmol/mol heme, respectively; P = 0.96) but had lower median ferritin [101.0 μg/L (95% CI: 84.2, 121.0 μg/L) compared with 152.9 μg/L (128.8, 181.6 μg/L), respectively; P ≤ 0.001] and hepcidin [45.8 ng/mL (36.8, 56.9 ng/mL) compared with 83.1 ng/mL (67.6, 102.2 ng/mL), respectively; P < 0.011]. CONCLUSIONS Severe inflammation is a characterization of children with CM and SMA. The withholding of iron from children with severe malaria is associated with lower ferritin and hepcidin at day 28 but not a lower hemoglobin concentration. This trial was registered at clinicaltrials.gov as NCT01093989.