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Jai K Das, Sajid Soofi, Zulfiqar A Bhutta from the Division of Women & Child Health, The Aga Khan University, Pakistan,
Nutrition in India
Globally around two billion people are anemic with iron deficiency being the leading cause. Iron deficiency is highly prevalent among preschool and school children, adolescent females and pregnant women. Around 600 million preschool and school-age children are anemic, and an estimated half of these are attributable to iron deficiency (1); this deficiency is highly prevalent in developing countries with 40% to 50% of children under 5 years of age being iron-deficient (2). Iron deficiency is also estimated to cause 726,000 deaths in the perinatal and childhood periods (3).

Iron is an essential nutrient required for infant growth and development and is also a potent pro-oxidant. The storage pool of iron is considerably mobile, and reserves can quickly become depleted when dietary iron is inadequate or when there is reduced absorption and increased utilization during growth and increased loss due to parasitic infections such as malaria and soil-transmitted helminthic infestations (4). Iron deficiency anemia during childhood results in impaired physical and mental development and work performance and is also associated with reduced appetite and a poor immune system all of which consequently have negative impacts on social and economic development (5).

An array of interventions exists to ameliorate this deficiency including promotion of dietary diversification, supplementation, mass fortification, micronutrient powders and treatment of underlying causes including malabsorption and worm infestation. Iron supplementation is one of the effective ways to prevent and treat iron deficiency however; there are differences in opinion regarding its frequency and dosage. Routine iron supplementation is sometimes also advised to prevent iron deficiency during infancy, even in populations with a relatively low prevalence of iron deficiency anemia. Fortification of infant formulas and consumption of fortified and iron rich products by lactating women and young infants have also been associated with reduced prevalence in the developed countries, but the overall picture is less convincing because of poverty, illiteracy and poor health care systems (6). Another emerging intervention is the removal of phytic acid from maize and beans which increases the bioavailability of the micronutrient (7).

Iron supplementation is effective, but at the cost of variable gastrointestinal side effects which can lead to poor compliance, and there is controversy over whether iron supplements result in increased growth (8, 9, 10), decreased growth (11) or has no effect on growth (12), in young children (13). Similarly, there is debate about the possibility that iron supplements or iron-fortified foods may increase the incidence of certain types of infections, particularly gastrointestinal infections (14, 15, 16). The World Health Organization (WHO) recommends intermittent iron supplementation as a public health intervention in preschool and school-age children to improve the iron status and reduce the risk of anemia (17). Various trials have been conducted to evaluate the effectiveness of iron supplementation and its impact on a range of outcomes from improving serum levels of iron, and reducing anemia to its impact on anthropometric indices, morbidity, mortality and neurodevelopmental outcomes. A review concluded that iron supplementation does not have any significant effect on anthropometric outcomes in children (18). A Cochrane review (19) found that intermittent iron supplementation reduces the risk of anemia by 49% and iron deficiency by 76% and significantly improves hemoglobin and serum ferritin concentration. The findings further suggest that intermittent iron supplementation may be a viable public health intervention in settings where daily supplementation has failed or has not been implemented. A review (20) of iron supplementation in children and its impact on mental and motor development indicates that iron supplementation improves mental development score modestly, with effects apparent for intelligence tests above 7 years of age and in initially iron-deficient children. There is no convincing evidence that iron treatment has an effect on mental development in children below 27 months of age or on motor development. Another systematic review (21) indicates that iron supplementation increases hemoglobin levels in children significantly and this increase is greater in children who were anemic at baseline and lower in malarial endemic areas and in those consuming iron-fortified food. This clearly projects the need for additional area-specific interventions, particularly in malaria-prone regions.

There is a complex interplay between malaria and iron metabolism, as iron supplementation increases individual’s susceptibility to malaria in vulnerable areas where malaria surveillance is not sufficient. (22) While on the other hand, malaria infections cause anemia and reduce iron absorption. Data from Tanzania also indicates that malaria contributes to 60% of all cases of severe anemia in infants, whereas iron deficiency contributes to only 30% (23). A trial of iron and folic acid supplementation in preschool children in Zanzibar, a malaria endemic area, was stopped prematurely as it resulted in a significant increased risk of severe illness, hospitalization and death among children who were not iron deficient (24). These findings compelled the World Health Organization (WHO) to revise its recommendations on iron supplementation for young children from universal to target towards children who are iron-deficient in malaria-endemic areas. A Cochrane review on oral iron supplements for children in malaria-endemic areas was published which concluded that iron alone or with antimalarial treatment did not increase the risk of clinical malaria (RR: 0.99, 95% CI: 0.90-1.09) or death (RD: +1.93 per 1000 children (95% CI -1.78-5.64)) when regular malaria surveillance and treatment services are provided (25). It further suggested that iron with antimalarial treatment significantly reduced malaria incidence. It also suggested that there is no need to screen for anemia prior to supplementation. But controversies exist regarding the review findings that it has further clouded the original issue rather than bringing any clarity to it, as the review suggests that iron supplementation is safe when regular malaria surveillance and treatment services are provided. This may well be true, but it drifted from the real issue of iron and malaria interactions under certain common real world conditions and that the conclusion was based on the incidence of malaria rather than its severity, which could have been more meaningful. Issues were also cited regarding studies being included from non-malaria endemic areas (26).

These research findings and the revised guidelines have irked debate and uncertainty among the clinicians, academicians and policy makers, and hence stalled the progress on this potential beneficial intervention and resulted in years of inaction. A number of initiatives including research on the mechanism of the negative effects have so far been futile. This has left millions of children at risk of impaired nutritional, cognitive, development and other negative consequences of iron deficiency. One option is prior screening for underlying deficiency before supplementation but this has its own strings attached including logistical difficulties, costs and possible technical errors (27).

The dilemma that still holds ground is the consensus on the strategy to move forward that not only prevents iron deficiency and its consequences in young children, but also minimizes the risks to malaria endemic populations. While new research findings continue to increase our understanding, there are ways which can, in the interim, move us forward with the existing knowledge. Two complementary strategies proposed by Stoltzfus et al are to shift interventions from supplements to lower-dose, food-based interventions and to coordinate iron interventions with malaria control efforts (28). Iron supplementation could be given in combination with key malaria interventions, including indoor residual spraying, insecticide treated bed nets, prophylactic treatment, or education and community awareness about malaria prevention and treatment. Food fortification is also a feasible option as it has the potential to reach larger sections of the society, are cost effective and compliance is not dependent at the individual level (29). While fortification could be a viable strategy, good-quality field trials are required to unequivocally demonstrate and quantify the actual impacts of food fortification and to determine any untoward effects associated with this strategy.

Despite gaps in the existing knowledge on the risks and benefits of iron supplementation in children especially in malaria-endemic areas, various research communities and relevant stakeholders together with policy makers should work together with the single and foremost goal of reaching a consensus on the best possible approach. It is understandable that this won’t be easy and would take time to conform to the existing realities of the scientific and research gaps, but at the same time we should not underestimate the loss that is occurring in this interim period, and should propose a strategy which is effective, widely agreed upon and is functional until the real picture unfolds.

References

1- WHO. Guideline (2011). Intermittent iron supplementation in preschool and school-age children. Geneva, World Health Organization, 2011.
2- Stoltzfus RJ, Mullany L, Black RE, (2004). Iron deficiency anaemia. In: Ezzati M, Lopez AD, Rodgers A, Murray CJL editor(s). Comparative quantification of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. Volume 1. Geneva: World Health Organization, 2004.
3- ibid.
4- Tapiero H, Gate L, Tew KD, (2001). Iron: deficiencies and requirements. Biomed Pharmacother. 2001;55(6):324-32.
5- Ahmed F. Khan MR. Jackson AA, (2001). Concomitant supplemental vitamin A enhances the response to weekly supplemental iron and folic acid in anemic teenagers in urban Bangladesh. Am J Clin Nutr 2001:74:108-15.
6- Ibid.
7- Ibid.
8- Aukett, M. A., Parks, Y. A., Scott, P. H. & Wharton, B. A. (1986) Treatment with iron increases weight gain and psychomotor development. Arch.Dis. Child. 61: 849/857.
9- Bhatia, D. & Seshadri, S. (1993) Growth performance in anemia and following iron supplementation. Indian Pediatr. 30: 195/200.
10- Angeles, I. T., Schultink, W. J., Matulessi, P., Gross, R. and Sastroamidjojo, S. (1993). Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Am. J. Clin. Nutr. 58: 339/342.
11- Idjradinata, P., Watkins, W. & Pollitt, E. (1994). Adverse effect of iron supplementation on weight gain of iron-replete young children. Lancet 343:1252/1254.
12- Rahman, M. M., Akramussaman, S. M., Mitra, A. K., Fuchs, G. J. & Mahalanabis, D. (1999). Long-term supplementation with iron does not enhance growth in malnourished Bangladeshi children. J. Nutr. 129: 1319/1322.
13- Morley, R., Abbott, R., Fairweather-Tait, S., MacFadyen, U., Stephenson, T. & Lucas, A. (1999). Iron fortified follow on formula from 9 to 18 months improves iron status but not development or growth: a randomised trial. Arch. Dis.Child. 81: 247252.
14- Javaid, N., Haschke, F., Pietschnig, B., Schuster, E., Huemer, C., Shebaz,A., Ganesh, P., Steffan, I., Hurrel, R. and Secretin, M. C. (1991). Interactions between infections, malnutrition and iron nutritional status in Pakistani infants.Acta. Paediatr. Scand. 374: 141/150.
15- Oppenheimer, S. J. (2001). Iron and its relation to immunity and infectious disease. J. Nutr. 131: 616S/635S.
16- Berger, J., Dyck, J. L., Galan, P., Aplogan, A., Schneider, D., Traissac, P.and Hercberg, S. (2000). Effect of daily iron supplementation on iron status, cell-mediated immunity, and incidence of infections in 6-36 month old Togolese children. Eur. J. Clin. Nutr. 2000. 54: 29-35.
17- WHO (2011) op. cit.
18- Sachdev HPS, Gera T, Nestel P. (2006). Effect of iron supplementation on physical growth in children: systematic review of randomised controlled trials. Public health nutrition. 2006;9(7):904-20.
19- De-Regil LM, Jefferds MED, Sylvetsky AC, Dowswell T. (2011). Intermittent iron supplementation for improving nutrition and development in children under 12 years of age (Review). Cochrane Database Syst Rev. 2011;12: Issue 12. Art. No.: CD009085.
20- Sachdev H, Gera T, Nestel P. (2005). Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutr. 2005 Apr;8(2):117-32.
21- Gera T, Sachdev HPS, Nestel P, Sachdev SS. (2007). Effect of iron supplementation on haemoglobin response in children: systematic review of randomised controlled trials. Journal of pediatric gastroenterology and nutrition. 2007;44(4):468-86.
22- Stoltzfus et al (2004) op. cit.
23- Menendez C, Kahigwa E, Hirt R, et al. (1997). Randomised placebocontrolled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet 1997;350:844-50.
24- Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. (2006). Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006;367(9505):133-43.
25- Ojukwu JU, Okebe JU, Yahav D, Paul M. (2010). Cochrane review: Oral iron supplementation for preventing or treating anaemia among children in malaria‐endemic areas. Evidence-Based Child Health: A Cochrane Review Journal. 2010;5(2):967-1183
. 26- Roth DE, Black RE, Ojukwu JU, Okebe JU, Yahav D, Paul M. (2010). Commentary on Oral iron supplementation for preventing or treating anaemia among children in malariaendemic aeas - with a response from the review authors. Evidence-Based Child Health: A Cochrane Review Journal. 2010;5(2):1186-8.
27- Crowley CR, Solomons NW, Schaumann K. (2012). Targeted provision of oral iron: the evolution of a practical screening option.
28- Advances in Nutrition: An International Review Journal. 2012;3(4):560-9.
30- Stoltzfus RJ. (2012). Iron and malaria interactions: programmatic ways forward. Advances in Nutrition: An International Review Journal. 2012;3(4):579-82.
31- Walter T, Olivares M, Pizarro F, et al. (2001). Fortification. In: Ramakrishnan U (ed). Nutritional Anemias. Boca Raton, FL: CRC Press; 2001. pp. 153-84.