Infectious Diseases - Research Publications
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ItemProtocol for a randomised, multicentre, four-arm, double-blinded, placebo-controlled trial to assess the benefits and safety of iron supplementation with malaria chemoprevention to children in Malawi: IRMA trial(BMJ PUBLISHING GROUP, 2023-10)INTRODUCTION: Approximately 40% of children aged 6-59 months worldwide are anaemic. Iron-containing multiple micronutrient powders (MNPs) and iron supplements (syrup/drops) are used to combat anaemia in children in different parts of the world. However, evidence for functional benefits of iron supplementation in children is scarce, and potential risks remain poorly defined, particularly concerning diarrhoea and malaria. This trial aims to determine if: (1) the efficacy of iron supplements or MNPs (containing iron) given with malaria chemoprevention is superior to malaria chemoprevention alone, or (2) if the efficacy of malaria chemoprevention alone is superior to placebo on child cognitive development. METHODS AND ANALYSIS: IRMA is a four-arm, parallel-group, double-blinded, placebo-controlled, triple-dummy, randomised trial in Southern Malawi. The study recruits 2168 infants aged 6 months, with an intervention period of 6 months and a post-intervention period of a further 6 months. Children are randomised into four arms: (1) No intervention (placebo); (2) malaria chemoprevention only; (3) MNPs and malaria chemoprevention; and (4) iron syrup and malaria chemoprevention. The primary outcome, cognitive development (Cognitive Composite Score (CogCS)), is measured at the end of the 6 months intervention. Secondary outcomes include CogCS at a further 6 months post-intervention, motor, language and behavioural development, physical growth and prevalence of anaemia and iron deficiency. Safety outcomes include incidence of malaria and other infections, and prevalence of malaria parasitaemia during and post-intervention period. ETHICS AND DISSEMINATION: The trial is approved by the National Health Sciences Research Committee (#19/01/2213) (Malawi) and the Human Research Ethics Committee (WEHI: 19/012) (Australia). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders. TRIAL REGISTRATION NUMBER: ACTRN12620000386932.
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ItemNo Preview AvailableIron Supplementation May Selectively Reprofile the Gut Microbiome in Iron-Deficient Bangladeshi Infants(AMER SOC HEMATOLOGY, 2022-11-15)
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ItemThe role of fingernail selenium in the association between arsenic, lead and mercury and child development in rural Vietnam: a cross-sectional analysis(CAMBRIDGE UNIV PRESS, 2023-05-14)As, Pb and Hg are common environmental contaminants in low- and middle-income countries. We investigated the association between child toxicant exposure and growth and development and determined if this association was mitigated by Se concentration. Toxicant concentrations in fingernail samples, anthropometry and Bayley's Scales of Infant Development, 3rd edition domains were assessed in 36-month-old children whose mothers had been part of a randomised controlled trial in rural Vietnam. Multivariable regression analyses were performed to estimate the effect of toxicant exposure on clinical outcomes with adjustments for potential confounders and interaction with fingernail Se concentration. We analysed 658 children who had data for at least one physical or developmental outcome, and at least one toxicant measurement, and each of the covariates. Fingernail As concentration was negatively associated with language (estimate per 10 % increase in As: -0·19, 95 % CI: (-0·32, -0·05)). Pb was negatively associated with cognition (estimate per 10 % increase in Pb: -0·08 (-0·15, -0·02)), language (estimate per 10 % increase in Pb: -0·18 (-0·28, -0·10)) and motor skills (estimate per 10 % increase in Pb: -0·12 (-0·24, 0·00)). Hg was negatively associated with cognition (estimate per 10 % increase in Hg: -0·48, (-0·72, -0·23)) and language (estimate per 10 % increase in Hg -0·51, (-0·88, -0·13)) when Se concentration was set at zero in the model. As Se concentration increased, the negative associations between Hg and both cognition and language scores were attenuated. There was no association between toxicant concentration and growth. As, Pb and Hg concentrations in fingernails of 3-year-old children were associated with lower child development scores. The negative association between Hg and neurological development was reduced in magnitude with increasing Se concentration. Se status should be considered when assessing heavy metal toxicants in children and their impact on neurodevelopmental outcomes.
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ItemEffects of iron supplementation on neural indices of habituation in Bangladeshi children(ELSEVIER SCIENCE INC, 2023-01)BACKGROUND: Iron deficiency and anemia have been associated with poor cognition in children, yet the effects of iron supplementation on neurocognition remain unclear. OBJECTIVE: We aimed to examine the effects of supplementation with iron on neural indices of habituation using auditory event-related brain potentials (ERPs). METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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ItemSupplementation With Iron Syrup or Iron-Containing Multiple Micronutrient Powders Alters Resting Brain Activity in Bangladeshi Children(ELSEVIER SCIENCE INC, 2023-01)BACKGROUND: Anemia and iron deficiency have been associated with poor child cognitive development. A key rationale for the prevention of anemia using supplementation with iron has been the benefits to neurodevelopment. However, little causal evidence exists for these gains. OBJECTIVES: We aimed to examine effects of supplementation with iron or multiple micronutrient powders (MNPs) on brain activity measures using resting electroencephalography (EEG). METHODS: Children included in this neurocognitive substudy were randomly selected from the Benefits and Risks of Iron Supplementation in Children study, a double-blind, double-dummy, individually randomized, parallel-group trial in Bangladesh, in which children, starting at 8 mo of age, received 3 mo of daily iron syrup, MNPs, or placebo. Resting brain activity was recorded using EEG immediately after intervention (month 3) and after a further 9-month follow-up (month 12). We derived EEG band power measures for delta, theta, alpha, and beta frequency bands. Linear regression models were used to compare the effect of each intervention with that of placebo on the outcomes. RESULTS: Data from 412 children at month 3 and 374 at month 12 were analyzed. At baseline, 43.9% were anemic and 26.7% were iron deficient. Immediately after intervention, iron syrup, but not MNPs, increased the mu alpha-band power, a measure that is associated with maturity and the production of motor actions (iron vs. placebo: mean difference = 0.30; 95% CI: 0.11, 0.50 μV2; P = 0.003; false discovery rate adjusted P = 0.015). Despite effects on hemoglobin and iron status, effects were not observed on the posterior alpha, beta, delta, and theta bands, nor were effects sustained at the 9-month follow-up. CONCLUSIONS: The effect size for immediate effects on the mu alpha-band power is comparable in magnitude with psychosocial stimulation interventions and poverty reduction strategies. However, overall, we did not find evidence for long-lasting changes in resting EEG power spectra from iron interventions in young Bangladeshi children. This trial was registered at www.anzctr.org.au as ACTRN12617000660381.
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ItemCost-effectiveness of universal iron supplementation and iron-containing micronutrient powders for anemia among young children in rural Bangladesh: analysis of a randomized, placebo-controlled trial(ELSEVIER SCIENCE INC, 2022-11-03)BACKGROUND: Universal provision of iron supplements or iron-containing multiple micronutrient powders (MNPs) is widely used to prevent anemia in young children in low- and middle-income countries. The BRISC (Benefits and Risks of Iron Interventions in Children) trial compared iron supplements and MNPs with placebo in children <2 y old in rural Bangladesh. OBJECTIVES: We aimed to assess the cost-effectiveness of iron supplements or iron-containing MNPs among young children in rural Bangladesh. METHODS: We did a cost-effectiveness analysis of MNPs and iron supplements using the BRISC trial outcomes and resource use data, and programmatic data from the literature. Health care costs were assessed from a health system perspective. We calculated incremental cost-effectiveness ratios (ICERs) in terms of US$ per disability-adjusted life-year (DALY) averted. To explore uncertainty, we constructed cost-effectiveness acceptability curves using bootstrapped data over a range of cost-effectiveness thresholds. One- and 2-way sensitivity analyses tested the impact of varying key parameter values on our results. RESULTS: Provision of MNPs was estimated to avert 0.0031 (95% CI: 0.0022, 0.0041) DALYs/child, whereas iron supplements averted 0.0039 (95% CI: 0.0030, 0.0048) DALYs/child, over 1 y compared with no intervention. Incremental mean costs were $0.75 (95% CI: 0.73, 0.77) for MNPs compared with no intervention and $0.64 ($0.62, $0.67) for iron supplements compared with no intervention. Iron supplementation dominated MNPs because it was cheaper and averted more DALYs. Iron supplementation had an ICER of $1645 ($1333, $2153) per DALY averted compared with no intervention, and had a 0% probability of being the optimal strategy at cost-effectiveness thresholds of $200 (reflecting health opportunity costs in Bangladesh) and $985 [half of gross domestic product (GDP) per capita] per DALY averted. Scenario and sensitivity analyses supported the base case findings. CONCLUSIONS: These findings do not support universal iron supplementation or micronutrient powders as a cost-effective intervention for young children in rural Bangladesh. This trial was registered at anzctr.org.au as ACTRN1261700066038 and trialsearch.who.int as U1111-1196-1125.
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ItemChild linear growth trajectories during the first three years of life in relation to infant iron status: a prospective cohort study in rural Vietnam(BMC, 2022-02-15)BACKGROUND: Early childhood growth patterns have long-term consequences for health and disease. Little is known about the interplay between growth and iron status during childhood. We explored the interplay between linear growth and iron status during early childhood, by assessing child growth trajectories between 6 and 36 months (m) of age in relation to infant iron status at 6 months of age. METHODS: A cohort study of infants born to women who had previously participated in a cluster randomized controlled trial of antenatal micronutrient supplementation, conducted in rural Vietnam. The relationship between child linear growth trajectories and infant iron status (ferritin concentration) was examined using latent growth curve modeling. Primary outcomes were height for age z scores (HAZ) and growth trajectory between 6 and 36 m of age. RESULTS: A total of 1112 infants were included in the study. Mean [SD] HAZ scores decreased over time from -0·58 [0·94] at 6 m, to -0·97 [0·99] at 18 m, to -1·14 [0·89] at 36 m of age. There was a steep linear decline in the HAZ scores between 6 and 18 m of age, followed by a slower linear decline from 18 to 36 m of age. Ferritin concentration at 6 m of age was inversely associated with HAZ score at 6 m of age (-0·145, 95% CI [-0.189, -0.101]). There was no association between infant ferritin at 6 m of age and child growth trajectory between 6 and 36 m of age. CONCLUSIONS: Iron status at six months of age did not influence a child's later linear growth trajectory in this cohort of rural Vietnamese children. Longitudinal studies with repeated ferritin and height measurements are required to better delineate this relationship and inform public health interventions.
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ItemNo Preview AvailableAgreement Between Venous and Capillary Haemoglobin Concentrations in Bangladeshi Children (P10-105-19).(Elsevier BV, 2019-06)Objectives: There are concerns that capillary haemoglobin (Hb) concentrations do not agree with venous Hb, which has implications for global estimates of anaemia largely derived from capillary Hb. In children enrolled in the Benefits and Risks of Iron Supplementation in Children (BRISC) trial, we examined differences between Hb concentrations collected from venous and capillary blood samples, and predictors of these differences. Methods: Hb concentrations were measured in 3300 children at 8 months of age. Capillary Hb concentrations were measured during screening of children for inclusion in the trial. Venous Hb was measured up to 10 days after screening, during enrolment. All Hb measurements used the HemoCue® 301. In children who received both capillary and venous measurements, Hb means, standard deviations, and anaemia prevalence statistics were derived. Paired t-tests were used to compare means across groups. Pearson's correlation coefficients and a Bland-Altman plot were used to examine agreement between capillary and venous Hb. A kappa coefficient was used to examine agreement in diagnosis of anaemia between the two methods. Lastly, differences in mean venous and capillary Hb concentrations between phlebotomists were calculated using ANOVA. Results: All 3300 children will have completed baseline Hb measurements by February 2019. The current abstract presents preliminary data up to December 2018 for 2485 children. Venous and capillary Hb concentrations were moderately correlated (r = 0.62). Prevalence of anaemia using venous samples was 44.8% and using capillary samples was 69.5%. Accounting for chance, the % agreement (kappa coefficient) between the methods for diagnosis of anaemia was 34.8%. Mean Hb concentrations were significantly higher in venous than capillary samples (mean ± SD: 11.0 ± 1.0 vs 10.4 ± 1.0 g/dL, P < 0.001). This is confirmed in the Bland-Altman plot. No differences in Hb were observed between phlebotomists. Conclusions: Significant differences exist in the diagnosis of anaemia using capillary vs venous samples. Capillary Hb measurements should not be used as a surrogate for venous Hb as they may incorrectly estimate the prevalence of anaemia. Results indicated that global estimates of anaemia based on capillary Hb may be misrepresenting true estimates. Funding Sources: NHMRC.
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ItemNo Preview AvailableUsing a Developmental Test and Electroencephalography to Examine Child Cognition and Its Predictors in Bangladesh (P13-024-19).(Elsevier BV, 2019-06)Objectives: The majority of global health studies use behavioural assessments to measure early child development. Few studies have examined neural indices of cognition using electroencephalography (EEG) in low-income settings. Using data from the Benefits and Risks of Iron Supplementation in Children (BRISC) trial, we examined cognitive development and neural indices of memory and attention in 11 month-old Bangladeshi children and their environmental, socio-demographic, and biological predictors. Methods: At 8 months of age, 3300 children were randomized to iron syrup, multiple micronutrient supplementation, or placebo for 3 months. The main trial outcomes include child development measured using the Bayley Scales of Infant and Toddler Development (BSID)-III, anthropometry, haemoglobin, morbidity, and iron indices. EEG is being conducted to measure event-related brain potentials (ERPs) in a random subset of 250 children at 11 months of age. ERPs are measured in response to auditory and visual stimuli, using roving oddball and attention orienting tasks. Generalized linear mixed models estimated the predictors of BSID-derived cognitive development and EEG-derived neural indices of memory and attention. Potential predictors include psychosocial stimulation, anthropometry, haemoglobin, socio-economic status, food security, sex, and parental education. Additionally, we examined correlations between the BSID cognitive scores and EEG-derived neural indices of cognition. Results: Preliminary BSID data up to December 2018 indicates that 1749 children have completed measurements at 11 months of age. Psychosocial stimulation was significantly associated with BSID cognitive development scores. ERPs in children at 11 months of age are expected to be completed by May 2019 and relevant results will be presented. Conclusions: This study is the first to acquire ERP data in children at 11 months of age in rural Bangladesh. Our findings will identify significant predictors of cognitive functioning measured using the BSID (a well-established developmental test) and using EEG (a sensitive neurophysiological approach) in young children in this setting. Results will indicate the agreement between child cognition outcomes using the BSID and EEG. Funding Sources: NHMRC and The University of Melbourne.
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ItemBenefits and Risks of Iron Interventions in Infants in Rural Bangladesh(MASSACHUSETTS MEDICAL SOC, 2021-09-09)BACKGROUND: Universal provision of iron supplements (drops or syrup) or multiple micronutrient powders to young children in low-to-middle-income countries where anemia is prevalent is recommended by the World Health Organization and widely implemented. The functional benefits and safety of these interventions are unclear. METHODS: We conducted a three-group, double-blind, double-dummy, individually randomized, placebo-controlled trial to assess the immediate and medium-term benefits and risks of 3 months of daily supplementation with iron syrup or iron-containing multiple micronutrient powders, as compared with placebo, in 8-month-old children in rural Bangladesh. The primary outcome was cognitive development, as assessed by the cognitive composite score on the Bayley Scales of Infant and Toddler Development, third edition, immediately after completion of the assigned 3-month regimen; scores range from 55 to 145, with higher scores indicating better cognitive performance. Secondary outcomes included the cognitive composite score at 9 months after completion of the assigned regimen; behavioral, language, and motor development, as well as growth and hematologic markers, immediately after completion and at 9 months after completion; and safety. RESULTS: We randomly assigned 3300 infants to receive iron syrup (1101 infants), multiple micronutrient powders (1099), or placebo (1100) daily. After completion of the assigned 3-month regimen, no apparent effect on the cognitive composite score was observed with iron syrup as compared with placebo (mean between-group difference in change in score from baseline, -0.30 points; 95% confidence interval [CI], -1.08 to 0.48) or with multiple micronutrient powders as compared with placebo (mean between-group difference in change in score from baseline, 0.23 points; 95% CI, -0.55 to 1.00). No apparent effect on any other developmental or growth outcome was observed immediately after completion of the assigned regimen or at 9 months after completion. At 9 months after completion of the assigned regimen, the prevalences of anemia, iron deficiency, and iron deficiency anemia increased in all three trial groups but remained lower among the children who received iron syrup or multiple micronutrient powders than among those who received placebo. The risk of serious adverse events and incidence of symptoms of infection were similar in the three trial groups. CONCLUSIONS: In this trial involving infants in Bangladesh, 3 months of daily supplementation with iron syrup or multiple micronutrient powders did not appear to have an effect on child development or other functional outcomes as compared with placebo. (Funded by the National Health and Medical Research Council of Australia; BRISC Australian New Zealand Clinical Trials Registry number, ACTRN12617000660381.).