Penny Holding

Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants

Background In-home iron fortification for infants in developing countries is recommended for control of anaemia, but low absorption typically results in >80% of the iron passing into the colon. Iron is essential for growth and virulence of many pathogenic enterobacteria. We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation. Methods We performed two double-blind randomised controlled trials in 6-month-old Kenyan infants (n=115) consuming home-fortified maize porridge daily for 4 months. In the first, infants received a micronutrient powder (MNP) containing 2.5 mg iron as NaFeEDTA or the MNP without iron. In the second, they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron. The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR (qPCR). Secondary outcomes included faecal calprotectin (marker of intestinal inflammation) and incidence of diarrhoea. We analysed the trials separately and combined. Results At baseline, 63% of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens, including Salmonella Clostridium difficile, Clostridium perfringens, and pathogenic Escherichia coli. Using pyrosequencing, +FeMNPs increased enterobacteria, particularly Escherichia/Shigella (p=0.048), the enterobacteria/bifidobacteria ratio (p=0.020), and Clostridium (p=0.030). Most of these effects were confirmed using qPCR; for example, +FeMNPs increased pathogenic E. coli strains (p=0.029). +FeMNPs also increased faecal calprotectin (p=0.002). During the trial, 27.3% of infants in +12.5 mgFeMNP required treatment for diarrhoea versus 8.3% in −12.5 mgFeMNP (p=0.092). There were no study-related serious adverse events in either group. Conclusions In this setting, provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome, increasing pathogen abundance and causing intestinal inflammation. Trial registration number NCT01111864.

Paediatric HIV and neurodevelopment in sub-Saharan Africa: a systematic review

Objective  To determine the degree of motor, cognitive, language and social‐emotional impairment related to HIV infection in children living in sub‐Saharan Africa (SSA).

Monitoring psychomotor development in a resource-limited setting: an evaluation of the Kilifi Developmental Inventory.

Abstract Background: Modifications made to the Kilifi Developmental Checklist and the psychometric characteristics of the new measure (The Kilifi Developmental Inventory) which assess the psychomotor functioning of children aged 6– 35 months are described. Methods: Two groups of community children (319 rural and 104 urban dwellers) and nine children with neurodevelopmental disorders were recruited for a cross-sectional study. Results: In both a rural and urban reference population, the inventory showed excellent internal consistency, interobserver agreement, test-retest reliability and sensitivity to maturational changes. Children with neurodevelopmental impairment and those who were underweight had significantly lower scores than the community sample, attesting to the sensitivity of the measure. Mothers found the assessment procedures acceptable and informative. Conclusions: The Kilifi Developmental Inventory is a culturally appropriate measure that can be used to monitor and describe the development of at-risk children in resource-limited settings in Kenya.

Socioeconomic status, anthropometric status, and psychomotor development of Kenyan children from resource-limited settings: A path-analytic study

BACKGROUND Sub-optimal physical growth has been suggested as a key pathway between the effect of environmental risk and developmental outcome. AIM To determine if anthropometric status mediates the relation between socioeconomic status and psychomotor development of young children in resource-limited settings. STUDY DESIGN A cross-sectional study design was used. SUBJECTS A total of 204 (105 girls) children from two resource-limited communities in the Coast Province, Kenya. The mean age of these children was 29 months (SD = 3.43; range: 24-35 months). OUTCOME MEASURE Psychomotor functioning was assessed using a locally developed and validated measure, the Kilifi Developmental Inventory. RESULTS A significant association was found between anthropometric status (as measured by weight-for-age, height-for-age, mid-upper arm circumference, and head circumference) and psychomotor functioning and also between socioeconomic status and anthropometric status; no direct effects were found between socioeconomic status and developmental outcome. The models showed that weight, height and to a lesser extent mid-upper arm circumference mediate the relation between socioeconomic status and developmental outcome, while head circumference did not show the same effect. CONCLUSION Among children under 3 years living in poverty, anthropometric status shows a clear association with psychomotor development while socioeconomic status may only have an indirect association.

Assessing Developmental Outcomes in Children from Kilifi, Kenya, Following Prophylaxis for Seizures in Cerebral Malaria

The purpose of the study was to develop a culture-informed measure of developmental outcome and to apply it to detect differences in developmental level between children with cerebral malaria enrolled in a clinical trial to control seizures during the acute phase of the illness. The instrument was administered to a sample of 180 children, three and 12 months after discharge from hospital. The measure demonstrated high internal consistency, good inter-observer reliability, age sensitivity and strong relations with parental report of child functioning. No association was found between performance, or change in performance, with the prophylactic regime administered. The results suggested that the use of Phenobarbital in controlling provoked seizures has no observable effect on cognitive function.

Impaired everyday memory associated with encephalopathy of severe malaria: the role of seizures and hippocampal damage

BackgroundSeizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage.MethodsAn everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition.ResultsCM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures.DiscussionThe findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.

The role of weight for age and disease stage in poor psychomotor outcome of HIV-infected children in Kilifi, Kenya

Aim  We aimed to investigate the contribution of disease stage and weight for age to the variability in psychomotor outcome observed among children with human immunodeficiency virus (HIV) infection.

Constructing Tests of Cognitive Abilities for Schooled and Unschooled Children

It is frequently necessary to assess children with little or no schooling to determine their level of cognitive functioning, especially in developing countries. It is not possible, however, to assume that assessments will hold equal validity for children with and without the experience of schooling. The authors, therefore, set out to create a battery of tests suitable for both schooled and unschooled children. They assessed 973 schooled and 645 unschooled children in rural coastal Kenya using culturally adapted cognitive tests. Significant effects of age and schooling were found on all tests. On some tests (verbal knowledge, speeded figure matching, and pattern copying), unschooled children did not improve as much with age as schooled children. The effects of length of exposure to schooling and of age were greater than that of initial enrollment in school. The authors conclude that it is possible to assess unschooled children, but test batteries must be carefully constructed and standardized.

Developmental monitoring using caregiver reports in a resource‐limited setting: the case of Kilifi, Kenya

Aim:  The main aim of the current study was to evaluate the reliability, validity and acceptability of developmental monitoring using caregiver reports among mothers in a rural African setting.

Iron status and systemic inflammation, but not gut inflammation, strongly predict gender-specific concentrations of serum hepcidin in infants in rural Kenya.

Hepcidin regulation by competing stimuli such as infection and iron deficiency has not been studied in infants and it’s yet unknown whether hepcidin regulatory pathways are fully functional in infants. In this cross-sectional study including 339 Kenyan infants aged 6.0±1.1 months (mean±SD), we assessed serum hepcidin-25, biomarkers of iron status and inflammation, and fecal calprotectin. Prevalence of inflammation, anemia, and iron deficiency was 31%, 71%, 26%, respectively. Geometric mean (±SD) serum hepcidin was 6.0 (±3.4) ng/mL, and was significantly lower in males than females. Inflammation (C-reactive protein and interleukin-6) and iron status (serum ferritin, zinc protoporphyrin and soluble transferrin receptor) were significant predictors of serum hepcidin, explaining nearly 60% of its variance. There were small, but significant differences in serum hepcidin comparing iron deficient anemic (IDA) infants without inflammation to iron-deficient anemic infants with inflammation (1.2 (±4.9) vs. 3.4 (±4.9) ng/mL; P<0.001). Fecal calprotectin correlated with blood/mucus in the stool but not with hepcidin. Similarly, the gut-linked cytokines IL-12 and IL-17 did not correlate with hepcidin. We conclude that hepcidin regulatory pathways are already functional in infancy, but serum hepcidin alone may not clearly discriminate between iron-deficient anemic infants with and without infection. We propose gender-specific reference values for serum hepcidin in iron-replete infants without inflammation.