title: Efficacy of micronutrient powder (MNP) with low-dose of iron supplementation in Bangladeshi children living in areas of high level of iron in groundwater
Creators: name: Rahman, Sabuktagin
Publisher: name: Griffith University
Year: 2022
Subjects: subject: Anaemia
subject: Iron deficiency
subject: Groundwater iron
subject: Low-iron MNP
subject: Gut microbiota
subject: Bangladesh

description: Background Anaemia is a public health concern in Bangladesh, affecting 30-50% of the children under-5 years of age. Iron deficiency (ID) is thought to be the primary cause of anaemia in the country. However, a national micronutrient survey revealed that the prevalence of ID in under-five children is quite low (10.7%) and drinking iron-containing groundwater from tube wells was reported to be linked with low ID. Despite the low burden of ID, due to the high prevalence of anaemia, the national policy for childhood anaemia prevention recommended iron supplementation through distributing micronutrient powder (MNP) containing 12.5 mg of iron. The MNP programmes have been implemented over the decades to prevent anaemia in children. Physiologically, in an iron-replete state, usage of iron supplement (MNP) might induce side effects such as, diarrhoea, nausea, and vomiting is common. Hence, the present study was conducted in Bangladeshi children drinking from groundwater with high level of iron to assess the effect of the low iron MNP (5 mg iron) against the standard MNP (12.5 mg iron) on haemoglobin concentration and to compare the relative side-effects of the competing MNP treatments. Methods: The RCT was conducted in children 2-5 years old who drank water from groundwater with a high concentration of iron (≥2 mg/L) in Belkuchi—a rural district of Bangladesh. A total of 435 children were screened for eligibility, with 327 enrolled in the trial and randomly allocated to receive either the standard MNP (12.5 mg iron per sachet) or the low-iron MNP (5 mg iron per sachet). The trial assessed if low-iron MNP, after consumption of one sachet every day for 60 days, was non-inferior to the standard MNP in regard to haemoglobin concentration of the children. A priori non-inferior margin (-0.5 g/dl) was set; and non-inferiority was concluded if the lower bound of the one-sided 95% CI for the difference in the treatment effect of the low iron MNP was higher than the non-inferiority margin. The treatment effect of the low iron MNP on haemoglobin was examined by Generalized Linear Modelling through controlling for the pertinent baseline covariates. Furthermore, the study assessed the comparative incidence of iron-induced side effect such as diarrhoea, loose stools, nausea, fever, and vomiting between the treatment groups. Incidence Rate Ratio (IRR) which compares incidence rates of an event between two groups was calculated using the poisson regression to assess the incidence of the side effects in the groups. On a subsample (n=53) of the enrolled children representing both MNP groups, gut microbiome was assessed by sequencing of 16sRNA at baseline and the endpoint. The effects of the intake of MNPs on the composition of gut microbiota were compared between the groups and between endpoint and baseline. Additionally, to assess the effect of thalassaemia in the background of high groundwater iron and MNP consumption, a sub-sample analysis from the trial was conducted to compare haemoglobin and ferritin status among the thalassaemia carriers and non-carriers. Another sub-study was conducted to examine the haemoglobin status of the children whose drinking groundwater contained low level of iron (0--&lt;2 mg/) for hypothesizing the utility of the low iron MNP in the low groundwater iron setting. Further, the trial was preceded by three sub studies leading up to the preparation of the trial—such as the taste-rating of the groundwater sample for semi quantitative assessment of iron content (annex 1); validation of a semi quantitative food frequency questionnaire (annex 2); and assessment of temporal concentration of groundwater iron (annex 3). Results: The results of the RCT revealed that the low-dose iron MNP was non-inferior to the standard MNP on haemoglobin outcome (β = −0.14, 95% CI: −0.30, 0.013; p = 0.07). The lower bound of the 95% CI for the difference in the treatment effect on haemoglobin was higher than -0.5 g/dl, thus confirming the non-inferiority of the low iron MNP. It resulted in a lower incidence of diarrhoea (IRR = 0.29, p = 0.01, 95% CI: 0.11–0.77), nausea (IRR = 0.24, p = 0.002, 95% CI: 0.09–0.59) and fever (IRR = 0.26, p &lt; 0.001, 95% CI: 0.15–0.43) compared to the standard MNP. The 16sRNA sequencing revealed that overall; there was no significant treatment effect of the low-iron MNP on microbiota compared to the standard MNP. However, an apparent treatment effect was observed in children with a relative adultlike microbiota, with a higher relative abundance of potentially pathogenic Enterobacteriaceae after receiving the standard MNP compared to the low-iron MNP (p=0.07). The results of the sub-sample of the thalassaemia carriers showed that the haemoglobin concentration of the children with thalassaemia at the end-point remained unchanged relative to the baseline value; 11.56±0.59 (Endpoint) vs. 11.6±0.54 (Baseline), p=0.83. In the children without thalassaemia haemoglobin tended to increase; 12.54±0.72 (Endpoint) vs. 12.41±0.72 (baseline), p=0.06. Baseline reserve of body iron was significantly higher in the thalassaemia carriers compared to their non-carrier peers; 594 mg vs. 558 mg; p=0.03. The increase of the infection adjusted ferritin level from baseline to the endpoint was 7.37% (p=0.7) and 10.17% (p=0.009) in the carrier and non-carrier groups respectively. The sub-study examining the effect of the low iron MNP in a low groundwater iron setting revealed that the ccombined intake of iron from dietary, groundwater and low-iron MNP in children was 5.8±2.0 and 6.9±2.5 mg/day comprising 193% and 169% of the Estimated Average Requirement in the 2-3 year-old and 4-5 year-old subgroups, respectively. The mean concentration of haemoglobin in children exposed to groundwater concentration 0.8-&lt;2.0 mg/L and 0.0-&lt;0.8 mg/L subgroups was 12.17±0.94 mg/dl and 11.91±0.91 mg/dl (p=0.30) respectively. Conclusion: The low iron MNP (5 mg iron) was non-inferior to the standard MNP (12.5 mg) in preventing the low level of haemoglobin in Bangladeshi children exposed to high content of iron from drinking groundwater. It caused fewer incidence of side effects, such as diarrhoea, nausea and fever. Overall, there was no treatment effect of the low iron MNP on composition of gut microbiota. Further, a low iron MNP can be potentially beneficial to the thalassaemia carriers. Low iron MNP has the potential to curb the childhood anaemia in settings where groundwater iron is low. The combined findings of the trial and the sub studies demonstrated beneficial role of the low iron MNP in Bangladesh to control childhood anaemia.