Benefits and Risks of Iron Interventions in Infants in Rural Bangladesh.

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.).

Supplementation With Iron Syrup or Iron-Containing Multiple Micronutrient Powders Alters Resting Brain Activity in Bangladeshi Children.

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.

Effects of iron supplementation on neural indices of habituation in Bangladeshi children.

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.

Adapting Reach Up and Learn in Crisis and Conflict Settings: An Exploratory Multiple Case Study.

OBJECTIVES: In 2019, >71 million children aged <5 had spent their entire lives in conflict-affected settings. Compounding adversities including violence, poverty, and displacement have immediate and long-term effects on early childhood development, health, behavior, and well-being. In response, adaptations of Reach Up have been implemented in conflict and crisis settings. METHODS: This article uses exploratory multiple case study methodology, drawing from implementation and qualitative data from 3 interventions: a mobile phone-based intervention promoting nurturing care among Rohingya and crisis-affected host communities in Bangladesh; Reach Up amid acute violence and displacement in Northeast Syria; and Reach Up group sessions and home visits integrated with health services for an indigenous population in Venezuela. RESULTS: In Bangladesh, tailoring interactive voice response messages improved responsiveness to the developmental needs of young children, yet complementary in-person services were identified as a key program enhancement. In Syria, rapid adaptations of Reach Up addressed the needs of families in acute crisis, including social-emotional learning games for school-aged children. In Venezuela, Reach Up, coupled with complementary lactation counseling, yielded high rates of uptake and satisfaction, and children's language development was highlighted as a key area of growth. CONCLUSIONS: Recommendations to promote early childhood development in crisis and conflict settings include: (1) cultural adaptation based on a holistic understanding of children and caregivers' needs; (2) the integration of child and family safety and linkages with complementary services on the basis of community needs and priorities, and (3) the importance of designing for scale through blended models and costing analyses.

Integrating a Group-Based, Early Childhood Parenting Intervention Into Primary Health Care Services in Rural Bangladesh: A Cluster-Randomized Controlled Trial.

Background: Over 250 million children globally do not reach their developmental potential. We tested whether integrating a group-based, early childhood parenting program into government healthcare clinics improved children's development, growth, and behavior. Methods: We conducted a cluster-randomized controlled trial in 40 community clinics in the Kishorganj district of Bangladesh. We randomly assigned clinics (1:1) to deliver a group-based parenting interventions or to a comparison group that received no intervention. Participants were children aged 5-24 months, with weight-for-age z-score of ≤ -1.5 SDs of the WHO standards, living within a thirty-minute walking distance from the clinic (n = 419 intervention, 366 control). Government health staff facilitated parenting sessions in the clinic with groups of four mother/child dyads fortnightly for one year as part of their routine duties. Primary outcomes measured at baseline and endline were child development assessed using the Bayley scales, child behaviors during the test by tester ratings, and child growth. The trial is registered at ClinicalTrials.gov, NCT02208531. Findings: 91% of children were tested at endline (396 intervention, 319 control). Multilevel analyses showed significant benefits of intervention to child cognition (effect size 0.85 SDs, 95% CI: 0.59, 1.11), language (0.69 SDs, 0.43, 0.94), and motor development (0.52 SDs, 0.31, 0.73), and to child behaviors during the test (ranging from 0.36 SDs, 0.14, 0.58, to 0.53 SDs, 0.35, 0.71). There were no significant effects on growth. Conclusion: A scalable parenting intervention, integrated into existing government health services and implemented by government health staff, led to significant benefits to child development and behavior.

The Benefits and Risks of Iron interventionS in Children (BRISC) trial: Statistical analysis plan.

Background: The Benefits and Risks of Iron interventionS in Children (BRISC) trial will evaluate the impact of universal supplementation with iron supplements or iron-containing multiple micronutrient powders (MNPs) compared with placebo given for 3 months on child development, growth, morbidity, laboratory indices of anaemia, iron deficiency, and inflammation at end of intervention and after a further 9 months post intervention in children aged 8 months living in rural Bangladesh. This paper describes the statistical analysis plan. Methods: BRISC is a multi-site, three-arm, double-dummy blinded, parallel group, randomised control superiority trial in 3300 children. The statistical analysis plan was developed by the trial statistician in consultation with the trial steering committee and trial management committee based on the protocol, data collection forms, and study outcomes available in the blinded study database.   Conclusion: This detailed statistical analysis plan published prior to unblinding the allocated treatments will support the statistical analyses and reporting of the BRISC trial to be undertaken after unblinding. It allows for transparency as well as reproducibility of statistical analyses and reporting. Registration: Australian New Zealand Clinical Trials Registry ACTRN12617000660381 (registered on 8 May 2017); World Health Organization Universal Trial Number U1111-1196-1125.

Immediate impact of stay-at-home orders to control COVID-19 transmission on socioeconomic conditions, food insecurity, mental health, and intimate partner violence in Bangladeshi women and their families: an interrupted time series.

BACKGROUND: Stay-at-home orders (lockdowns) have been deployed globally to control COVID-19 transmission, and might impair economic conditions and mental health, and exacerbate risk of food insecurity and intimate partner violence. The effect of lockdowns in low-income and middle-income countries must be understood to ensure safe deployment of these interventions in less affluent settings. We aimed to determine the immediate impact of COVID-19 lockdown orders on women and their families in rural Bangladesh. METHODS: An interrupted time series was used to compare data collected from families in Rupganj upazila, rural Bangladesh (randomly selected from participants in a randomised controlled trial), on income, food security, and mental health a median of 1 year and 2 years before the COVID-19 pandemic to data collected during the lockdown. We also assessed women's experiences of intimate partner violence during the pandemic. RESULTS: Between May 19 and June 18, 2020, we randomly selected and invited the mothers of 3016 children to participate in the study, 2424 of whom provided consent. 2414 (99·9%, 95% CI 99·6-99·9) of 2417 mothers were aware of, and adhering to, the stay-at-home advice. 2321 (96·0%, 95·2-96·7) of 2417 mothers reported a reduction in paid work for the family. Median monthly family income fell from US$212 at baseline to $59 during lockdown, and the proportion of families earning less than $1·90 per day rose from five (0·2%, 0·0-0·5) of 2422 to 992 (47·3%, 45·2-49·5) of 2096 (p<0·0001 comparing baseline with lockdown period). Before the pandemic, 136 (5·6%, 4·7-6·6) of 2420 and 65 (2·7%, 2·1-3·4) of 2420 families experienced moderate and severe food insecurity, respectively. This increased to 881 (36·5%, 34·5-38·4) of 2417 and 371 (15·3%, 13·9-16·8) of 2417 during the lockdown; the number of families experiencing any level of food insecurity increased by 51·7% (48·1-55·4; p<0·0001). Mothers' depression and anxiety symptoms increased during the lockdown. Among women experiencing emotional or moderate physical violence, over half reported it had increased since the lockdown. INTERPRETATION: COVID-19 lockdowns present significant economic, psychosocial, and physical risks to the wellbeing of women and their families across economic strata in rural Bangladesh. Beyond supporting only the most socioeconomically deprived, support is needed for all affected families. FUNDING: National Health and Medical Research Council, Australia.

Effects of adding psychosocial stimulation for children of lactating mothers using an unconditional cash transfer platform on neurocognitive behavior of children in rural Bangladesh: protocol for a cluster randomized controlled trial.

BACKGROUND: There is sufficient evidence that psychosocial stimulation (PS) benefits children's neurocognitive behavior, however, there is no information on how it works when delivered through an Unconditional Cash Transfer (UCT) platform for poor rural population in developing countries. The objective of this study is to measure effects of adding PS for children of lactating mothers enrolled to receive UCT with health education (HE) on neurocognitive behavior of children in rural Bangladesh. METHODS: The study will be conducted at 11 unions of Ullapara sub-district in Bangladesh. The study is a cluster randomized controlled trial with three-arms; (i) PS and UCT with HE (ii) UCT with HE and iii) Comparison arm. The cluster will be considered as an old Ward of a Union, the lowest tier of local government system in rural Bangladesh. There are three old Wards in a union. These three clusters will be randomized to one of the three arms. Similarly, randomization will be done for each 11 Unions and then 11 clusters will be assigned to an arm. Eighteen participants will be recruited from each cluster randomly (n = 196 in each arm). The intervention designed for one year includes UCT with HE for the poor as a safety net program in rural Bangladesh with or without PS. An age-based curriculum of PS is already available for Bangladeshi children and this will be administered by trained local women; play leaders (PL) in intervention clusters. The government of Bangladesh is providing UCT of taka 500 ($6.25) as maternity allowance per month with HE. The primary outcomes will be cognitive, motor and language composite scores measured by Bayley-III and behavior using Wolke's behavior rating scale. The secondary outcomes will be children and mothers' growth, family food security status, health seeking behavior, mothers' depressive symptoms and self-esteem and violence against mothers. DISCUSSION: The study will provide a unique opportunity to assess an integrated early childhood development intervention using UCT platform to mitigate developmental delays in poor vulnerable children of rural Bangladesh. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03281980, registered on September 13, 2017.