Risk factors for moderate acute malnutrition among children with acute diarrhoea in India and Tanzania: a secondary analysis of data from a randomized trial.

BACKGROUND: Moderate acute malnutrition (MAM) affects over 30 million children aged < 5 years worldwide. MAM may confer a greater risk of developing severe malnutrition and even mortality in children. Assessing risk factors for MAM may allow for earlier recognition of children at risk of deleterious health outcomes. OBJECTIVE: To determine risk factors associated with the prevalence and development of MAM among children aged 6 to 59 months with acute diarrhoea who received treatment with oral rehydration solution and zinc supplementation. METHODS: We conducted a secondary analysis of data from a randomized, dose-finding trial of zinc among children with acute diarrhoea in India and Tanzania. We used regression models to assess risk factors for prevalent MAM at the start of diarrhoea treatment and to identify risk factors associated with the development of MAM at 60 days. MAM was defined as weight for length (or height) Z score ≤-2 and > -3 or mid-upper arm circumference < 12.5 and ≥ 11.5 cm. RESULTS: A total of 4,500 children were enrolled; 593 (13.2%) had MAM at the baseline. MAM at baseline was significantly less common among children in Tanzania than in India (adjusted risk ratio [aRR] 0.37, 95% confidence interval [CI]: 0.30, 0.44, P < 0.001), in children aged 24- < 60 months versus 6- < 12 months (aRR 0.46, 95% CI: 0.38, 0.56, P < 0.001), and in families with household wealth index higher than the median (aRR 0.79, 95% CI: 0.68, 0.92, P = 0.002). Sixty days after outpatient treatment and follow-up, 87 (2.5%) children developed MAM. When compared to children aged 6- < 12 months, children aged 24- < 60 months had a 52% lower risk of developing MAM. Every one unit increase in weight for length (or height) Z score at enrolment was associated with a 93% lower risk of developing MAM during follow-up. CONCLUSIONS: Among children with diarrhoea, younger children and those from households with lower wealth were at greater risk of MAM. These children may benefit from targeted interventions focusing on feeding (targeted nutrition support for at-risk households) and follow up in order to reduce the occurrence of MAM and its consequences.

Effect of dose reduction of supplemental zinc for childhood diarrhoea: study protocol for a double-masked, randomised controlled trial in India and Tanzania.

BACKGROUND: Diarrhoea-associated mortality and morbidity are highest in infants and young children in low-income and middle-income countries (LMICs). Zinc supplementation during acute diarrhoea has been shown to reduce the duration of illness and the risk of persistent diarrhoea. However, vomiting with zinc supplementation is a common side effect that may interfere with compliance and programmatic scale-up, and may be related to the dose prescribed. METHODS/DESIGN: The Zinc Therapeutic Dose Trial (ZTDT) is a two-centre (Tanzania and India), three-arm randomised, double-blind controlled non-inferiority trial. Children 6-59 months of age with acute diarrhoea are eligible to participate. Enrolled children (1500 per arm; 4500 total) will be randomly allocated to receive 5, 10 or 20 mg of zinc sulfate daily for 14 days and will be followed up for 60 days after enrolment. All children will receive WHO/Unicef Integrated Management of Childhood Illness standard of care (oral or intravenous rehydration and zinc as indicated and feeding advice). The primary efficacy outcomes of the trial are the percentage of subjects with diarrhoea duration >5 days, the mean total number of loose or watery stools after enrolment and the proportion of children vomiting within 30 min of zinc administration. DISCUSSION: The ZTDT trial will determine the optimal dose of therapeutic zinc supplements for treatment of acute diarrhoea in children aged 6-59 months in two LMICs. The results of the trial are likely to be generalisable to childhood acute diarrhoea in similar resource-limited settings and may influence global policy about zinc supplementation dosage during acute diarrhoea. TRIAL REGISTRATION NUMBER: NCT03078842. TRIAL STATUS: Enrolment began in January 2017 and follow-up is estimated to be completed by April 2019. As of 1 February 2019, 742 children are still contributing data to the ZTDT study.

Efficacy of high zinc biofortified wheat in improvement of micronutrient status, and prevention of morbidity among preschool children and women - a double masked, randomized, controlled trial.

BACKGROUND: Biofortification of staple food crops with zinc (Zn) can be one of the cost-effective and sustainable strategies to combat zinc deficiency and prevent morbidity among the target population. Agronomic approaches such as application of Zn fertilizers to soil and/or foliar spray seem to be a practical tool for Zn biofortification of wheat. However, there is a need to evaluate its efficacy from randomized controlled trials. This study aimed to evaluate the efficacy of zinc biofortified wheat flour on zinc status and its impact on morbidity among children aged 4-6 years and non-pregnant non lactating woman of child bearing age (WCBA) in Delhi, India. METHODS: In a community based, double-masked randomized controlled trial, 6005 participants (WCBA and child pairs) were enrolled and randomly allocated to receive either high zinc biofortified wheat flour (HZn, 30 ppm zinc daily) or low zinc biofortified wheat flour (LZn, 20 ppm zinc daily) for 6 months (WCBA @ 360 g/day and children @ 120 g/day). Baseline and endline blood samples were obtained for assessing hematological markers; zinc status and data on compliance and morbidity were collected. RESULTS: Compliance rates were high; ~ 88% of the WCBAs in both the groups consumed 50% or more of recommended amount of biofortfied wheat flour during the follow up. Similarly 86.9% children in HZn and 87.5% in LZn consumed 50% or more of recommended wheat flour intake. There was no significant difference in mean zinc levels between the groups at end study. This observation might be due to a marginal difference in zinc content (10 ppm) between the HZn and LZn wheat flour, and a short intervention period. However a positive impact of bio-fortification on self-reported morbidity was observed. Compared to children in LZn group, children in HZn group had 17% (95% CI: 6 to 31%, p = 0.05) and 40% (95% CI: 16 to 57%; p = 0.0019) reduction in days with pneumonia and vomiting respectively. WCBA in the HZn group also showed a statistically significant 9% fewer days with fever compared to LZn group. CONCLUSIONS: Biofortified wheat flour had a good compliance among children and WCBAs. Significant improvement on some of the self-reported morbidity indicators suggests that evaluating longer-term effects of biofortification with higher grain zinc content would be more appropriate. TRIAL REGISTRATION: http://ctri.nic.in/Clinicaltrials/ , CTRI/2014/04/004527, Registered April 7, 2014.

Compliance with home-based fortification strategies for delivery of iron and zinc: its effect on haematological and growth markers among 6-24 months old children in north India.

Compliance is a key component in successful implementation of the delivery of micronutrients among children. The present study evaluates the compliance with two home-based food fortification strategies (fortified complementary food or sprinkle) for providing iron and zinc among children aged 6-24 months. A total of 292 children were randomly allocated to receive either rice-based fortified complementary food and nutrition education (Cf = 101), sprinkle and nutrition education (Mp = 97), or nutrition education alone as control (Ed = 94). All the enrolled children were breastfed at the beginning of the study and were advised to continue breastfeeding. Biweekly information on compliance and anthropometry was collected. Complete haemogram estimation was conducted at baseline and end of the study. Compliance with the fortified complementary food was higher compared to sprinkle (Cf = 81%, Mp = 64% child-days). Consumption of the fortified complementary food for 6 months resulted in a significant increase in mean haemoglobin in the intervention group compared to control group (Cf 1.29 +/- 1.6 g/dL; Ed 0.23 +/- 1.3 g/dL; p < 0.001). Our results showed that fortified complementary food had higher compliance than sprinkle and is a suitable delivery mechanism for iron and zinc in preschool children.

Impact of micronutrient fortification of yoghurt on micronutrient status markers and growth - a randomized double blind controlled trial among school children in Bangladesh.

BACKGROUND: Interventions providing foods fortified with multiple micronutrients can be a cost-effective and sustainable strategy to improve micronutrient status and physical growth of school children. We evaluated the effect of micronutrient-fortified yoghurt on the biochemical status of important micronutrients (iron, zinc, iodine, vitamin A) as well as growth indicators among school children in Bogra district of Bangladesh. METHODS: In a double-masked randomized controlled trial (RCT) conducted in 4 primary schools, 1010 children from classes 1-4 (age 6-9 years) were randomly allocated to receive either micronutrient fortified yoghurt (FY, n = 501) or non-fortified yoghurt (NFY, n = 509). For one year, children were fed with 60 g yoghurt everyday providing 30% RDA for iron, zinc, iodine and vitamin A. Anthropometric measurements and blood/urine samples were collected at base-, mid- and end-line. All children (FY, n = 278, NFY, n = 293) consenting for the end-line blood sample were included in the present analyses. RESULTS: Both groups were comparable at baseline for socio-economic status variables, micronutrient status markers and anthropometry measures. Compliance was similar in both the groups. At baseline 53.4% of the population was anemic; 2.1% was iron deficient (ferritin <15.0 µg/L and TfR > 8.3 mg/L). Children in the FY group showed improvement in Hb (mean difference: 1.5; 95% CI: 0.4-2.5; p = 0.006) as compared to NFY group. Retinol binding protein (mean diff: 0.05; 95% CI: 0.002-0.09; p = 0.04) and iodine levels (mean difference: 39.87; 95% CI: 20.39-59.35; p < 0.001) decreased between base and end-line but the decrease was significantly less in the FY group. Compared to NFY, the FY group had better height gain velocity (mean diff: 0.32; 95% CI: 0.05-0.60; p = 0.02) and height-for-age z-scores (mean diff: 0.18; 95% CI: 0.02-0.33; p = 0.03). There was no difference in weight gain velocity, weight-for-age z-scores or Body Mass Index z-scores. CONCLUSION: In the absence of iron deficiency at baseline the impact on iron status would not be expected to be observed and hence cannot be evaluated. Improved Hb concentrations in the absence of a change in iron status suggest improved utilization of iron possibly due to vitamin A and zinc availability. Fortification improved height gain without affecting weight gain. TRIAL REGISTRATION: ClinicalTrial.gov: NCT00980733.

Micronutrient fortified milk improves iron status, anemia and growth among children 1-4 years: a double masked, randomized, controlled trial.

BACKGROUND: Multiple micronutrient deficiencies are highly prevalent among preschool children and often lead to anemia and growth faltering. Given the limited success of supplementation and health education programs, fortification of foods could be a viable and sustainable option. We report results from a community based double-masked, randomized trial among children 1-4 years evaluating the effects of micronutrients (especially of zinc and iron) delivered through fortified milk on growth, anemia and iron status markers as part of a four group study design, running two studies simultaneously. METHODS AND FINDINGS: Enrolled children (n = 633) were randomly allocated to receive either micronutrients fortified milk (MN = 316) or control milk (Co = 317). Intervention of MN milk provided additional 7.8 mg zinc, 9.6 mg iron, 4.2 microg selenium, 0.27 mg copper, 156 microg vitamin A, 40.2 mg vitamin C, and 7.5 mg vitamin E per day (three serves) for one year. Anthropometry was recorded at baseline, mid- and end-study. Hematological parameters were estimated at baseline and end-study. Both groups were comparable at baseline. Compliance was over 85% and did not vary between groups. Compared to children consuming Co milk, children consuming MN milk showed significant improvement in weight gain (difference of mean: 0.21 kg/year; 95% confidence interval [CI] 0.12 to 0.31, p<0.001) and height gain (difference of mean: 0.51 cm/year; 95% CI 0.27 to 0.75, p<0.001). Mean hemoglobin (Hb) (difference of 13.6 g/L; 95% CI 11.1 to 16.0, p<0.001) and serum ferritin levels (difference of 7.9 microg/L; 95% CI 5.4 to 10.5, p<0.001) also improved. Children in MN group had 88% (odds ratio = 0.12, 95% CI 0.08 to 0.20, p<0.001) lower risk of iron deficiency anemia. CONCLUSIONS/SIGNIFICANCE: Milk provides an acceptable and effective vehicle for delivery of specific micronutrients, especially zinc and iron. Micronutrient bundle improved growth and iron status and reduced anemia in children 1-4 years old.

Effects of Bifidobacterium lactis HN019 and prebiotic oligosaccharide added to milk on iron status, anemia, and growth among children 1 to 4 years old.

OBJECTIVE: To evaluate the effect of Bifidobacterium lactis HN019 and prebiotic-fortified milk on iron status, anemia, and growth among 1- to 4-year-old children. PATIENTS AND METHODS: In a community-based double-masked, controlled trial in a periurban population, 624 children were enrolled and randomly allocated to receive either milk fortified with additional probiotic and prebiotic (n = 312) or control milk (n = 312) for 1 year. Probiotic and prebiotic milk contained an additional 1.9 x 10 colony-forming units per day of probiotic B lactis HN019 and 2.4 g/day of prebiotic oligosaccharides milk. Hematological parameters were estimated at baseline and at the end of the study. Height and weight measurements were recorded at baseline, mid study, and the end of the study. Difference of means and multivariate regression models was used to examine the effect of intervention. RESULTS: Both study groups were similar at baseline. Compliance was high (>85%) and did not vary by intervention groups. As compared with non-fortified milk, consumption of probiotic- and prebiotic-fortified milk for a period of 1 year reduced the risk of being anemic and iron deficient by 45% (95% CI 11%, 66%; P = 0.01) and increased weight gain by 0.13 kg/year (95% CI 0.03, 0.23; P = 0.02). CONCLUSIONS: Preschoolers are usually fed milk, which has good acceptance and can be easily fortified for delivery of probiotics. Consumption of B lactis HN019 and prebiotic-fortified milk resulted in a smaller number of iron-deficient preschoolers and increased weight gain.

Zinc deficiency: descriptive epidemiology and morbidity among preschool children in peri-urban population in Delhi, India.

Community-based data relating to factors influencing zinc deficiency among preschool children in India are inadequate. Data of a large, double-blinded, randomized, controlled zinc-supplementation trial were used for assessing the descriptive epidemiology of zinc deficiency among children aged 6-35 months (n = 940). In total, 609 children were followed up for 120 days for information on morbidity. Of these children, 116 from the control group belonging to the upper and the lower 25th quartile of plasma zinc status at baseline were selected for assessing the association of zinc deficiency with prospective morbidity. At baseline, demographic, socioeconomic and dietary information was collected, and anthropometric measurements and levels of plasma zinc were assessed. At baseline, 73.3% of the children were zinc-deficient (plasma zinc < 70 microg/dL), of which 33.8% had levels of plasma zinc below 60 microg/dL. A significantly higher risk of morbidity was prevalent among the subjects with lower plasma zinc compared to those with higher levels of plasma zinc.

Effects of fortified milk on morbidity in young children in north India: community based, randomised, double masked placebo controlled trial.

OBJECTIVE: To evaluate the efficacy of milk fortified with specific multiple micronutrients on morbidity in children compared with the same milk without fortification. DESIGN: Community based, double masked, individually randomised trial. SETTING: Peri-urban settlement in north India. PARTICIPANTS: Children (n=633) aged 1-3 randomly allocated to receive fortified milk (n=316) or control milk (n=317). INTERVENTION: One year of fortified milk providing additional 7.8 mg zinc, 9.6 mg iron, 4.2 microg selenium, 0.27 mg copper, 156 microg vitamin A, 40.2 mg vitamin C, 7.5 mg vitamin E per day (three feeds). MAIN OUTCOME MEASURES: Days with severe illnesses, incidence and prevalence of diarrhoea, and acute lower respiratory illness. RESULTS: Study groups were comparable at baseline; compliance in the groups was similar. Mean number of episodes of diarrhoea per child was 4.46 (SD 3.8) in the intervention (fortified milk) group and 5.36 (SD 4.1) in the control group. Mean number of episodes of acute lower respiratory illness was 0.62 (SD 1.1) and 0.83 (SD 1.4), respectively. The fortified milk reduced the odds for days with severe illnesses by 15% (95% confidence interval 5% to 24%), the incidence of diarrhoea by 18% (7% to 27%), and the incidence of acute lower respiratory illness by 26% (3% to 43%). Consistently greater beneficial effects were observed in children aged < or =24 months than in older children. CONCLUSION: Milk is well accepted as a means of delivery of micronutrients. Consumption of milk fortified with specific micronutrients can significantly reduce the burden of common morbidities among preschool children, especially in the first two years of life. TRIAL REGISTRATION: NCT00255385 [ClinicalTrials.gov].