Jane Kvalsvig

Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study

Abstract Objective: To measure the effects of iron supplementation and anthelmintic treatment on iron status, anaemia, growth, morbidity, and development of children aged 6–59 months. Design: Double blind, placebo controlled randomised factorial trial of iron supplementation and anthelmintic treatment. Setting: Community in Pemba Island, Zanzibar. Participants: 614 preschool children aged 6–59 months. Main outcome measures: Development of language and motor skills assessed by parental interview before and after treatment in age appropriate subgroups. Results: Before intervention, anaemia was prevalent and severe, and geohelminth infections were prevalent and light—Plasmodium falciparum infection was nearly universal. Iron supplementation significantly improved iron status, but not haemoglobin status. Iron supplementation improved language development by 0.8 (95% confidence interval 0.2 to 1.4) points on the 20 point scale. Iron supplementation also improved motor development, but this effect was modified by baseline haemoglobin concentrations (P=0.015 for interaction term) and was apparent only in children with baseline haemoglobin concentrations <90 g/l. In children with a baseline haemoglobin concentration of 68 g/l (one standard deviation below the mean value), iron treatment increased scores by 1.1 (0.1 to 2.1) points on the 18 point motor scale. Mebendazole significantly reduced the number and severity of infections caused by Ascaris lumbricoides and Trichuris trichiura, but not by hookworms. Mebendazole increased development scores by 0.4 (−0.3 to 1.1) points on the motor scale and 0.3 (−0.3 to 0.9) points on the language scale. Conclusions: Iron supplementation improved motor and language development of preschool children in rural Africa. The effects of iron on motor development were limited to children with more severe anaemia (baseline haemoglobin concentration <90 g/l). Mebendazole had a positive effect on motor and language development, but this was not statistically significant. What is already known on this topic Iron is needed for development and functioning of the human brain Anaemic children show developmental delays, but it is not yet clear whether iron deficiency causes these deficits or whether iron supplementation can reverse them Helminth infections in schoolchildren are associated with cognitive deficits, but few studies have been made of helminth infection and early child development What this study adds Low doses of oral iron supplementation given daily improved language development in children aged 1–4 years in Zanzibar Iron supplementation improved motor development, but only in children with initial haemoglobin concentrations below 90 g/l The effects of routine anthelmintic treatment on motor and language milestones were positive, but non-significant, with our sample size

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.

Effects of iron and n−3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa

BACKGROUND Little is known about the combined effects of iron and n-3 (omega-3) fatty acid (FA) supplementation on cognitive performance. The provision of either DHA/EPA or iron alone in rats with combined iron and n-3 FA deficiency has been reported to exacerbate cognitive deficits associated with deficiency. OBJECTIVE We investigated the effects of iron and DHA/EPA supplementation, alone and in combination, in children with poor iron and n-3 FA status. DESIGN In a 2-by-2 factorial trial, children with iron deficiency (ID) (n = 321; aged 6-11 y) were allocated to receive 1) iron (50 mg) plus DHA/EPA (420/80 mg), 2) iron plus placebo, 3) placebo plus a mixture of DHA and EPA (DHA/EPA), or 4) placebo plus placebo as oral supplements (4/wk) for 8.5 mo. Cognition was assessed at baseline and endpoint by using the Hopkins Verbal Learning Test (HVLT) and subscales of the Kaufman Assessment Battery for Children. RESULTS Both iron and DHA/EPA significantly increased weight-for-age z scores. Iron increased the number of words recalled at HVLT recall 2 (intervention effect: 0.90; 95% CI: 0.18, 1.62), and in anemic children, iron increased scores in the Atlantis Delayed test (1.51; 95% CI: 0.03, 2.99) and HVLT recall 2 (2.02; 95% CI: 0.55, 3.49). DHA/EPA showed no benefit in any of the cognitive tests but decreased Atlantis test scores (-2.48; 95% CI: -3.99, -0.96) in children who were anemic at baseline and decreased Atlantis delayed scores (-0.9; 95% CI: -1.45, -0.36) in girls with ID, whereas boys tended to perform better. CONCLUSIONS In children with poor iron and n-3 FA status, iron supplementation improved verbal and nonverbal learning and memory, particularly in children with anemia. In contrast, DHA/EPA supplementation had no benefits on cognition and impaired working memory in anemic children and long-term memory and retrieval in girls with ID.

S. haematobium as a common cause of genital morbidity in girls: a cross-sectional study of children in South Africa.

Background Schistosoma (S.) haematobium infection is a common cause of genital morbidity in adult women. Ova in the genital mucosal lining may cause lesions, bleeding, pain, discharge, and the damaged surfaces may pose a risk for HIV. In a heterogeneous schistosomiasis endemic area in South Africa, we sought to investigate if young girls had genital symptoms and if this was associated with urinary S. haematobium. Methodology In a cross-sectional study of 18 randomly chosen primary schools, we included 1057 schoolgirls between the age of 10 and 12 years. We interviewed assenting girls, whose parents had consented to their participation and examined three urines from each of them for schistosome ova. Principal findings One third of the girls reported to have a history of genital symptoms. Prior schistosomal infection was reported by 22% (226/1020), this was associated with current genital symptoms (p<0.001). In regression analysis the genital symptoms were significantly associated both with urinary schistosomiasis (p<0.001) and water contact (p<0.001). Conclusions Even before sexually active age, a relatively large proportion of the participating girls had similar genital symptoms to those reported for adult genital schistosomiasis previously. Anti-schistosomal treatment should be considered at a young age in order to prevent chronic genital damage and secondary infections such as HIV, sexually transmitted diseases and other super-infections.

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.

Ecological covariates of Ascaris lumbricoides infection in schoolchildren from rural KwaZulu-Natal, South Africa.

Objectives  To identify environmental factors that could serve to predict Ascaris lumbricoides infection patterns and thus guide control efforts in the absence of epidemiological information; to assess whether A. lumbricoides infection is positively associated with the soil clay content.

Point-of-use micronutrient fortification: lessons learned in implementing a preschool-based pilot trial in South Africa

This current pilot trial assessed the feasibility of implementing a point-of-use (PoU) micronutrient fortification in preschool settings. Preschool children (n = 151) aged 36–79 months were randomized into intervention (n = 76) and control (n = 75) groups, both receiving breakfast maize-porridge with added micronutrient or placebo powder for 52 school days. Process evaluation and early childhood development indicators were used to assess trial feasibility. Process evaluation results showed that the implementation components were feasible and could be delivered with high fidelity. The improvement in hemoglobin concentration in intervention and control groups were not significantly different (P = 0.250). There was medium likelihood for practical significance for the two global cognitive scores assessed: non-verbal index (intervention effects: 7.20; 95% confidence interval: 2.60, 11.81; P = 0.002, effect size: 0.55) and mental processing index (intervention effects: 2.73; 95% confidence interval: 0.25, 5.70; P = 0.072, effect size: 0.36) on the Kaufman Assessment Battery for Children, Second Edition. The lessons from this trial could help in planning/implementing future PoU micronutrient fortification trial among South African preschool children.

Effects of a multi-micronutrient-fortified beverage, with and without sugar, on growth and cognition in South African schoolchildren: a randomised, double-blind, controlled intervention

Little is known about the effects of combined micronutrient and sugar consumption on growth and cognition. In the present study, we investigated the effects of micronutrients and sugar, alone and in combination, in a beverage on growth and cognition in schoolchildren. In a 2 × 2 factorial design, children (n 414, 6-11 years) were randomly allocated to consume beverages containing (1) micronutrients with sugar, (2) micronutrients with a non-nutritive sweetener, (3) no micronutrients with sugar or (4) no micronutrients with a non-nutritive sweetener for 8.5 months. Growth was assessed and cognition was tested using the Kaufman Assessment Battery for Children version II (KABC-II) subtests and the Hopkins Verbal Learning Test (HVLT). Micronutrients decreased the OR for Fe deficiency at the endpoint (OR 0.19; 95% CI 0.07, 0.53). Micronutrients increased KABC Atlantis (intervention effect: 0.76; 95% CI 0.10, 1.42) and HVLT Discrimination Index (1.00; 95% CI 0.01, 2.00) scores. Sugar increased KABC Atlantis (0.71; 95% CI 0.05, 1.37) and Rover (0.72; 95% CI 0.08, 1.35) scores and HVLT Recall 3 (0.94; 95% CI 0.15, 1.72). Significant micronutrient × sugar interaction effects on the Atlantis, Number recall, Rover and Discrimination Index scores indicated that micronutrients and sugar in combination attenuated the beneficial effects of micronutrients or sugar alone. Micronutrients or sugar alone had a lowering effect on weight-for-age z-scores relative to controls (micronutrients - 0.08; 95% CI - 0.15, - 0.01; sugar - 0.07; 95% CI - 0.14, - 0.002), but in combination, this effect was attenuated. The beverages with micronutrients or added sugar alone had a beneficial effect on cognition, which was attenuated when provided in combination.

Acceptability of community-based growth monitoring in a rural village in South Africa.

In rural areas, a lack of infrastructure often limits the promotion and implementation of community-based nutrition activities. Growth monitoring can potentially provide a platform for the promotion and implementation of community-based nutrition activities, provided that the growth-monitoring program has a high coverage. The aim of this study was to determine the acceptability of a community-based growth-monitoring project in terms of child attendance and maternal attitude. The study was done in a mountainous rural village that lacks health facilities in KwaZulu-Natal, South Africa. Attendance registers from 1996 to 2000 were used to determine the attendance ratio, coverage, adequacy of growth monitoring, and frequency distribution of the age of participating children. In 2001, focus group discussions were used for the qualitative assessment of maternal attitudes. The community-based growth-monitoring project had an estimated coverage of 90%, at least 60% of these children were covered adequately, and attendance was equally distributed over one-year-interval age categories for children aged five years and younger. Community-based growth monitoring can therefore provide a suitable platform for the promotion and implementation of community-based nutrition activities.

A school-based helminth control programme successfully implemented in KwaZulu-Natal

The design of the school-based Parasite Control Programme (referred to below as a helminth control programme) run in the province of KwaZulu-Natal, South Africa, from 1997-2000 is described. Emphasis is given to the role of the Parasite Control Task Group which provided a forum for a wide variety of issues relating to the programme to be debated before they were agreed upon. The programme targeted the three common geohelminths (Trichuris trichiura, Ascaris lumbricoide and hookworm) and the urinary schistosomiasis (bilharzia) fluke, Schistosoma haematobium. It is expected that a national control programme will be setup in South Africa in the future. With this in mind, new opinions and experiences in several aspects of helminth control that have become available since 2000 are included so that they can be considered for any future programme.