Protocol 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.

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.

Developmental outcomes in Malawian children with retinopathy-positive cerebral malaria.

OBJECTIVE: To assess children with retinopathy-positive cerebral malaria (CM) for neurocognitive sequelae. METHODS: Participants were selected from an ongoing exposure-control study. Eighty-three Malawian children averaging 4.4 years of age and diagnosed with retinopathy-positive CM were compared to 95 controls. Each child was classified as delayed or not using age-based norms for the Malawi Developmental Assessment Tool (MDAT) for developmental delay on the total scale and for the domains of gross motor, fine motor, language and social skills. Groups were also compared on the Achenbach Child Behaviour Checklist (CBCL) (1.5-5 years). RESULTS: Children with retinopathy-positive CM were delayed, relative to the comparison group, on MDAT total development (P = 0.028; odds ratio or OR = 2.13), with the greatest effects on language development (P = 0.003; OR = 4.93). The two groups did not differ significantly on the Achenbach CBCL internalizing and externalizing symptoms total scores. Stepwise regression demonstrated that coma duration, seizures while in hospital, platelet count and lactate level on admission were predictive of assessment outcomes for the children with retinopathy-positive CM. CONCLUSIONS: Children who suffer retinopathy-positive CM at preschool age are at greater risk of developmental delay, particularly with respect to language development. This confirms previous retrospective study findings with school-age children evaluated years after acute illness. The MDAT and the Achenbach CBCL proved sensitive to clinical indicators of severity of malarial illness.

Common mental disorder and associated factors amongst women with young infants in rural Malawi.

BACKGROUND: Common mental disorder (CMD) affecting women during the childbearing years is an important health problem in low and middle income countries. This study investigates CMD and associated factors amongst women with young infants in rural Malawi. METHODS: In this cross-sectional study, mothers of infants due for measles vaccination were recruited from a district hospital child health clinic. Maternal CMD was measured using a Chichewa version of the Self-Reporting Questionnaire (SRQ). DSM-IV diagnoses of major and minor depressive disorder were made using the structured clinical interview for DSM-IV (SCID). Socio-demographic, maternal and infant variables were measured and associations with CMD were determined. RESULTS: Of 519 eligible women, 501 were included in the analysis. Mean age was 24.4 years and median infant age was 9.9 months. The weighted prevalence of any current depressive episode (minor or major) was 30.4% (95% CI 22.8-38.1%). The weighted prevalence of current major depressive episode was 13.9% (95% CI 8.2-19.5%). Mean SRQ score for the total sample was 5.71 (SD 4.42). On multivariate analysis, SRQ score was significantly associated with lower socioeconomic status, lack of a confiding relationship with partner or relative, and recent infant illness. Amongst the women who knew their HIV status (n = 314), SRQ score was also associated with HIV infection. CONCLUSIONS: This study demonstrates that CMD is a significant health burden among women with infants in rural Malawi, and is associated with poverty, relationship difficulties, HIV infection and infant health problems.

Validation of a Chichewa version of the self-reporting questionnaire (SRQ) as a brief screening measure for maternal depressive disorder in Malawi, Africa.

BACKGROUND: Depressive disorder affecting women during the perinatal period is common in low-income countries. The detection and study of maternal depression in a resource-poor setting requires a brief screening tool that is both accurate and practical to administer. METHOD: A Chichewa version of the Self Reporting Questionnaire (SRQ) was developed through a rigorous process of forward and back translation, focus-group discussion and piloting. Criterion validation was conducted as part of a larger study in a sample of women who had brought their infants to a child health clinic in rural Malawi, using DSM-IV major and minor depressive episode as the gold standard diagnoses. RESULTS: The criterion validation was conducted on 114 subjects who did not differ on health and sociodemographic characteristics from the total study sample (n=501). Test characteristics for each possible SRQ cut-off were calculated and Receiver Operator Characteristic (ROC) curves derived. Area under the ROC curve (AUROC) for detection of current major depressive disorder was 0.856 (95% CI 0.813 to 0.900), and for current major or minor depressive disorder was 0.826 (95% CI 0.783 to 0.869). Internal consistency of the SRQ was high (Cronbach's alpha 0.85). LIMITATION: Inter-rater reliability testing was not conducted. CONCLUSION: This Chichewa version of the SRQ shows utility as a brief screening measure for detection of probable maternal depression in rural Malawi.

Early and middle childhood developmental, cognitive, and psychiatric outcomes of Malawian children affected by retinopathy positive cerebral malaria.

The objective is to determine the short -and long-term developmental, cognitive, and psychiatric effects of retinopathy positive cerebral malaria (CM-R) among young children in a prospective study assessing them around the onset of disease and again 2 years at preschool and again at school age. In total, 109 children were recruited from the Queen Elizabeth Central Hospital in Blantyre, Malawi, (N = 49) with CM-R and non-malaria controls  (N = 60). Children were assessed for overall motor, language, and social skills using the Malawi Developmental Assessment Tool (MDAT) at preschool age. At school age, the same children were then given the Kaufman Assessment Battery for Children, second edition (KABC-II), which assessed global cognitive performancememory, and learning; as well as the Test of Variables of Attention (TOVA), which assessed attention. The Achenbach Child Development Checklist (CBCL) was administered at both time points to assess emotional and behavioral patterns. Controls scored significantly better on all KABC-II global domains as well as on the mental processing index than their CM-R group counterparts, but showed no performance differences in the TOVA and CBCL assessments at school age, or in the MDAT and CBCL assessments at preschool age. The MDAT total score was significantly correlated with the KABC-II sequential processing, learning, and mental processing index among CM-R survivors but not among controls. Persisting neurocognitive effects of CM can be captured with the KABC-II at school age. The MDAT at preschool age is correlated with the KABC-II among CM-R survivors and can be used to capture early emerging developmental deficits due to CM-R.

Maternal common mental disorder and infant growth--a cross-sectional study from Malawi.

The objective of the study was to investigate the association between maternal common mental disorder (CMD) and infant growth in rural Malawi. A cross-sectional study was conducted at a district hospital child health clinic. Participants were consecutive infants due for measles vaccination, and their mothers. Mean infant weight-for-age and length-for-age z-scores were compared between infants of mothers with and without CMD as measured using the self-reporting questionnaire (SRQ). Of 519 eligible infants/mothers, 501 were included in the analysis. Median infant age was 9.9 months. 29.9% of mothers scored 8 or above on the SRQ indicating CMD. Mean length-for-age z-score for infants of mothers with CMD (-1.50 SD 1.24) was significantly lower than for infants of mothers without CMD (-1.11 SD 1.12) Student's t-test: P = 0.001. This association was confirmed in multivariate analysis. Mean weight-for-age z-score for infants of mothers with CMD (-1.77 SD 1.16) was lower than for infants of mothers without CMD (-1.59 SD 1.09) but this difference was not significant on univariate (Student's t-test: P = 0.097) or multivariate analysis. The study demonstrates an association between maternal CMD and infant growth impairment in rural sub-Saharan Africa.

Can we measure cognitive constructs consistently within and across cultures? Evidence from a test battery in Bangladesh, Ghana, and Tanzania.

We developed a test battery for use among children in Bangladesh, Ghana, and Tanzania, assessing general intelligence, executive functioning, and school achievement. The instruments were drawn from previously published materials and tests. The instruments were adapted and translated in a systematic way to meet the needs of the three assessment contexts. The instruments were administered by a total of 43 trained assessors to 786 children in Bangladesh, Ghana, and Tanzania with a mean age of about 13 years (range: 7-18 years). The battery provides a psychometrically solid basis for evaluating intervention studies in multiple settings. Within-group variation was adequate in each group. The expected positive correlations between test performance and age were found and reliability indices yielded adequate values. A confirmatory factor analysis (not including the literacy and numeracy tests) showed a good fit for a model, merging the intelligence and executive tests in a single factor labeled general intelligence. Measurement weights invariance was found, supporting conceptual equivalence across the three country groups, but not supporting full score comparability across the three countries.

Cerebral malaria retinopathy predictors of persisting neurocognitive outcomes in Malawian children.

BACKGROUND: Neuropsychological sequelae from pediatric cerebral malaria (CM) have been well-documented. Although malaria-specific retinopathy during acute illness has become a defining criterion for CM, its relationship to neurocognitive sequelae has not been documented. This relationship is important if malaria-specific retinopathy reflects the possible brain neuropathogenesis leading to long-term neurocognitive deficits. METHODS: From 2008 to 2012, 49 Malawian children 4.5-12 years of age surviving retinopathy-positive CM (CM-R) were tested 1-6 yrs after illness with the Kaufman Assessment Battery for Children, 2 edition, the tests of variables of attention and the Achenbach Child Behavior Checklist. In an observational study of a cohort of cerebral malaria survivors, these neurocognitive and behavioral outcomes were statistically related to types and severity of retinopathy measures, while controlling for age, sex, body mass index, socioeconomic status and time interval between illness and testing. RESULTS: Worse scores for hemorrhages, papilledema, optic disk hyperemia, retinal whitening of macula and foveal annulus were associated with poorer Kaufman Assessment Battery for Children, 2 edition mental processing index and global scale scores. Disk hyperemia was also predictive of tests of variables of attention D prime overall attention performance (inattention) and commission errors (impulsivity). Few associations were found between retinopathy scores and Achenbach Child Behavior Checklist (emotional and behavioral) outcomes. CONCLUSIONS: We are the first to report the relationship between severity of malaria-specific retinopathy during acute illness in CM survivors and persisting neurocognitive problems. These findings support earlier studies documenting that severity of retinopathy during acute illness is medically prognostic in CM survivors. We extend these findings to include long-term neurocognitive outcomes.