Alexandria Kristensen-Cabrera was the lead author and organized the case study through interviews with Dr. Juan Pablo Peña-Rosas who provided substantial additions to the case study. Dr. Luis Gabriel Cuervo as a mentor provided guidance and inspiration and reviewed and approved the final version. Ruben Grajeda, Michele Gilbert and Louisa Stuwe reviewed and edited the final drafts. Louisa Stuwe translated the document into Spanish, which was reviewed by María Medina. Christopher Khanoyan assisted with formatting. The photos illustrating the case study are from the exhibit "Research on the Move" by photographer Jane Isabelle Dempster, and are part of PAHO's Art for Research Project (www.paho.org/artforresearch) ©PAHO/WHO
What's the issue?
It is estimated that about half of the anemia in populations is due to iron deficiency. Although iron deficiency is the most common cause, other vitamin and mineral deficiencies, chronic inflammation, parasitic infections, and inherited disorders can all cause anemia. Both anemia and iron deficiency have severe economic and health costs.
Iron deficiency anemia compromises a child's ability to learn, further compromises its future prospects and, in aggregate terms, hinders the development of the population.
The World Health Organization's (WHO) most recent estimates suggest that anemia affects around 800 million children and women. In fact, 528.7 million women and 273.2 million children under 5 years of age were anemic in 2011, and about half of them were also iron deficient . Under-nutrition and micronutrient malnutrition have severe economic consequences, costing an estimated US$1.4-2.1 trillion or 2-3 percent of global gross domestic product (GDP) per year. Investment in preventing and managing micronutrient malnutrition results in improved health, a reduction in child and maternal mortality, and better earnings with a 'benefit-to-cost ratio' of almost 13 to 1 . The estimated distribution of anemia prevalence for infants/ children and pregnant women is shown in figure 1.
Iron deficiency is the world's most widespread micronutrient deficiency often resulting in chronic iron deficiency or iron deficiency anemia (defined by the WHO as hemoglobin levels ? 11g/dl). The cut-off values vary by age, sex, altitude, smoking, and pregnancy status1. To replenish iron stores, men require 0.9 mg, women of childbearing age require 1.3 mg, and pregnant women require 3.0 mg per day of iron. High iron intake is also required for growth. Another estimate from the University of Toronto found that total (cognitive and physical) loss due to iron deficiency is around 4.05% of GDP per year while physical losses alone are around 0.57% of GDP (calculated based on 10 developing countries) .
Anemia has severe health consequences in pregnant women, infants, and children. Anemia in pregnancy has numerous health effects for the baby including increased risks of stunting, blindness, severe illnesses, decreased cognitive performance, spinal, and brain defects. Anemia in pregnancy also increases the risk of miscarriage, stillbirth, and low-birth-weight thus increasing risks of infant mortality as well as birth complications causing hemorrhaging corresponding to an increased risk of maternal depression and maternal mortality. Iron deficiency anemia contributes to an estimated 115,000 maternal deaths/ year worldwide. Additionally, infants and young children with iron deficiency anemia are more likely to have attention deficits, reduced motor coordination, and language difficulties. For school age children, this type of anemia also decreases school participation . There is strong evidence showing that iron treatment for school age children can improve low-test scores of cognitive ability and education achievement5.
Research in practice
It is critical to diagnose the cause of iron deficiency for appropriate treatment. Iron deficiency may be the result of unsatisfied needs (pregnancy, growth, inadequate diet), and/or increased losses (chronic inflammation, parasitic infections).
One option to add iron to the diet is the iron fortification (the addition of micronutrients to food) of staple foods such as wheat flour, maize flour, and rice with iron and other vitamins and minerals.Some condiments, such as salt, fish sauces, and soy sauces can also be fortified with iron. Studies have shown that iron fortification corresponds with the reduction of anemia prevalence ,. For example, the Food Fortification Initiative found evidence that suggests, but does definitively conclude, that anemia prevalence has significantly decreased in countries which utilize micronutrient fortification of flour while has not changed in countries that do not. Another study looked at the effects of iron fortification of wheat and corn flour and found that fortification had a 'protective effect' against gestational anemia . Fortification of cornmeal and maize flour can improve nutritional status if mandated at the national level in countries where these staples are frequently consumed. High sensory acceptability has been found for a number of iron fortificants,. Two COCHRANE reviews are being conducted on the effects of the fortification of maize flour, wheat flour, and rice with iron and other vitamins and minerals for anemia,,. A review on bioavailability of different iron compounds used in food fortification is available.
Picture 1. Institute of Nutrition of Central America and Panama (INCAP)
Children receive breakfast, lunch and two snacks per day, a diet set up by nutritionists at INCAP that control the development of children.
Another option to prevent and treat anemia is iron supplementation. This is an effective technique, including as a preventive method to reduce the likelihood of maternal anemia in pregnant women. An intervention in rural Vietnam measured the effects of iron supplementation and iron fortified milk on the hemoglobin status of pregnant women. The study found that the "hemoglobin concentrations in both treatment groups were not significantly different" but hemoglobin levels were lower in the comparison groups with iron supplementation .
Iron fortification is a cost-effective option: the cost of iron fortification of wheat flour is often less than 1% of the wholesale cost or less than US $1.00 per metric ton. Thus it is incredibly efficient:US$4.40/Disability adjusted life year (DALY) for iron fortification of flour versus US$12.80/DALY for iron supplementation and US$29.00/ DALY for vitamin A fortification.
Excessive iron consumption or overload can be harmful, potentially leading to iron overload and blood disorders . However, iron overload due to extended iron supplement ingestion or fortification of flour is very rare,,. Possible side effects of iron include diarrhea, constipation, and nausea with higher doses.
What is next?
To deploy efficient, feasible strategies for iron fortification as a solution to iron deficiency anemia, it is important for each country to address the recommendations of iron nutrition experts and the WHO in a systematic manner including legislation and research, address the bioavailability and the supply of iron fortification, educate the population on iron deficiency, and test individuals using clinical pathways for serum or plasma ferritin concentration as an index of iron deficiency and overload, as indicated in the figures 3 and 4.
There are three main types of fortification recognized by the WHO: commercial, universal, and targeting high-risk populations . Universal iron fortification, when there are no non-fortified options available, potentially puts those with hemochromatosis (caused by an increase in iron intake) at a greater risk for iron overload. Thus, targeted or market-driven approaches are often favored22. Groups at highest risk include pregnant women, infants, and school age children.
While there is substantial evidence of the effectiveness of iron fortification and supplements to reduce iron deficiency anemia, the benefits are hindered due to low usage of preventive health services in developing countries, lack of infrastructure and national political drive for larger scale fortification of popular local foods, and incomplete enactment of preventive treatments. It is critical to address these barriers, using research, to effectively prevent iron deficient anemia.
Figure 3. Clinical pathway for iron deficiency
Figure 4. Clinical pathway for iron overload
According to a review on iron fortification of wheat flour, "most current iron fortification programs are likely to be ineffective. Legislation needs updating in many countries so that flour is fortified with adequate levels of the recommended iron compounds" . Thus, countries where flour is an ingredient in staple foods, should adhere to WHO recommendations on levels of iron fortification in wheat and maize flour. It is important for countries to fortify staple foods in their respective countries.
Quality, targeted research is a critical component to addressing iron deficient anemia. "Despite the high incidence and burden of disease associated with this condition, there is a paucity of good quality trials assessing clinical maternal and neonatal effects of iron administration in women with anaemia… variable or inadequate reporting of data from trials which can inform health equity decisions could contribute to waste in research and may not serve the needs of people who are experiencing health inequities.". Therefore, it is crucial to deploy research strategies with sound metrics allowing valid results comparable between countries and addressing health equity (absence of avoidable and unfair differences in health). According PAHO's Policy on Research for Health (CD49.R10) all activities to improve health should be informed on evidence therefore more effectively strengthening public health and improving health care outcomes.
Two WHO/PAHO supported studies conducted in 2015 are paving the way:
- Considerations regarding the elaboration and deployment of the Nutritional Directives of WHO, and
- Protocol for development of CONSORT-equity guideline to improve reporting of health equity in randomized trials (see figure 5) .
Figure 5. CONSORT-equity: study phases
One efficient way to address lack of iron supply and bioavailability of iron in diets is iron fortification . Iron fortification may help to reduce iron deficiency anemia, which can have positive development effects across populations including improved cognitive and academic performance as well as decreased child birth defects, maternal and child mortality rates. Improved cognitive and academic performance as well as less days of school missed can translate into a better-trained workforce resulting in economic gains. Decrease of negative health effects leads to a reduction of health care costs. In summary, there is a potential for efficient, viable conquer of iron deficiency and lack of iron supply which can result in improved health and development.
 The prevalence of anaemia in 2011. Geneva: World Health Organization; 2015. ( https://www.who.int/nutrition/publications/micronutrients/global_prevalence_anaemia_2011/en/, accessed 7 September 2015)
Bailey RL, West KP Jr, Black RE. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015;66 Suppl 2:22-33.
WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and
Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (https://www.who.int/nutrition/publications/micronutrients/indicators_haemoglobin/en/, accessed 7 September 2015)
Horton S, Ross J. The economics of iron deficiency. Food Policy 2003;28: 51-75.
 Black MM. Integrated strategies needed to prevent iron deficiency and to promote early child development. Journal of Trace Elements in Medicine and Biology 2012;26(2-3): 120—3.
 Christian P, Mullany LC, Hurley KM, Katz J, Black RE. Nutrition and maternal, neonatal, and child health. Semin Perinatol. 2015 Aug;39(5):361-72
 Nokes C, Bosch C, Bundy D. The effects of iron deficiency and anemia on mental and motor performance, education achievement, and behavior in children. International Nutritional Anemia Consultative Group. 1998. http://www.ilsi.org/ResearchFoundation/Publications/1998_anemia_mental_motor.pdf
 Bobonis G, Miguel E, Puri Sharma C. Iron deficiency anemia and school participation. Poverty Action Lab Paper No. 7. March 2004. Poverty Action Lab.
 Barkley J, Wheeler K, Pachon H. Anaemia prevalence may be reduced among countries that fortify flour. British Journal of Nutrition 2015;114(2): 2665-273)
 Gera T, Sachdev HS, Boy E.Effect of iron-fortified foods on hematologic and biological outcomes: systematic review of randomized controlled trials. Am J Clin Nutr. 2012 Aug;96(2):309-24.
 Kongkachuichai R, Kounhawej A, Chavasit V, Charoensiri R. Effects of various iron fortificants on sensory acceptability and shelf-life stability of instant noodles. Food and Nutrition Bulletin, vol. 28, no. 2. 2007. The United Nations University.
 Beinner, Mark Anthony, Soares, Anne Danieli Nascimento, Barros, Ana Laura Antunes, & Monteiro, Marlene Azevedo Magalhães. (2010). Sensory evaluation of rice fortified with iron. Food Science and Technology (Campinas), 30(2), 516-519 ://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-20612010000200034&lng=en&tlng=en. 10.1590/S0101-20612010000200034.
 Peña-Rosas JP, Field MS, Burford BJ, De-Regil LM. Wheat flour fortification with iron for reducing anaemia and improving iron status in populations (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 9.
 Pasricha SR, De-Regil LM, Garcia-Casal MN, Burford BJ, Gwirtz JA, Peña-Rosas JP. Fortification of maize flour with iron for preventing anaemia and iron deficiency in populations (Protocol). Cochrane Database of Systematic Reviews 2012, Issue 11.
 Ashong J, Muthayya S, De-Regil LM, Laillou A, Guyondet C, Moench-Pfanner R, Burford BJ, Peña-Rosas JP. Fortification of rice with vitamins and minerals for addressing micronutrient malnutrition (Protocol). Cochrane Database of Systematic Reviews 2012, Issue 6.
 Maria Nieves Garcia-Casal, Juan Pablo Pena-Rosas, Diego Moretti, Richard Hurrell, Monica Flores-Urrutia, Hala Boukerdenna. Bioavailability of iron compounds for use in food fortification. PROSPERO 2015: CRD42015024693. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024693 .
 Peña-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Daily iron supplementation during pregnancy (Review). The Cochrane Collaboration. 20012. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004736.pub4/epdf/standard
 Hoa P, Khan N, Beusekom C, Gross R, Conde W, Khoi H. Milk fortified with iron or iron supplementation to improve nutritional status of pregnant women: An intervention trial from rural Vietnam. Food and Nutrition Bulletin, vol. 26, no. 1. 2005. The United Nations University. http://apiycna.org/wp-content/uploads/2014/01/2005_Vietnam-study_MUM_iron.pdf
 Nestel P, Naluboa R. Manual for wheat fortification with iron. USAID. 2000.
 NIH. How is iron deficiency anemia treated? National Heart, Lung, and Blood Institute. 2011.
 Martins, J. M. (2012). Universal iron fortification of foods: the view of a hematologist. Revista Brasileira de Hematologia E Hemoterapia, 34(6), 459—463. http://doi.org/10.5581/1516-8484.20120113
 Brittenham G. Safety of flour fortification with iron. Columbia University. 2004. http://www.ffinetwork.org/why_fortify/documents/IronSafety2004.pdf
 Iron tablets: indications, side effects, warnings. Drugs.com. Clinical Drug Information. LLC. 2015.
 Garcia-Casal MN, Pasricha SR, Martinez RX, Lopez-Perez L, Peña-Rosas JP. Serum or plasma ferritin concentration as an index of iron deficiency and overload. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD011817. DOI: 10.1002/14651858.CD011817. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011817/full
 Allen L, Beloist B, Dary O, Hurrell R. Guidelines on food fortification with micronutrients. World Health Organization/ Food and Agricultural Organization. 2006. https://www.who.int/nutrition/publications/guide_food_fortification_micronutrients.pdf.
 Osungbade K and Oladunjoye A, "Preventive Treatments of Iron Deficiency Anaemia in Pregnancy: A Review of Their Effectiveness and Implications for Health System Strengthening," Journal of Pregnancy, vol. 2012, Article ID 454601, 2012. doi:10.1155/2012/454601.
 Hurrell R1, Ranum P, De Pee S, Biebinger R, Hulthen L, Johnson Q, Lynch S. Revised recommendations for iron fortification of wheat flour and an evaluation of the expected impact of current national wheat flour fortification programs. Food Nutrition Bulletin, 2010.
 WHO, FAO, UNICEF, GAIN, MI, & FFI. Recommendations on wheat and maize flour fortification. Meeting Report: Interim Consensus Statement. Geneva, World Health Organization, 2009 https://www.who.int/nutrition/publications/micronutrients/wheat_maize_fort.pdf
 Reveiz L, Gyte GML, Cuervo LG, Casasbuenas A. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD003094, DOI:10.1002/14651858.CD003094.pub3. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003094.pub3/abstract.
 PAHO/WHO. Final Report. 2 Oct 2009. CD49/FR. 49th Directing Council. 61st Session of the Regional Committee.
 Zamora, Gerardo et al. Consideraciones sobre la elaboración de las directrices de nutrición de la Organización Mundial de la Salud y su implementación.ALAN [online]. 2015, vol.65, n.1 [citado 2016-01-24], pp. 1-11 . Disponible en: <http://www.scielo.org.ve/scielo.php?script=sci_arttext&pid=S0004-06222015000100001&lng=es&nrm=iso>. ISSN 0004-0622.
 Petkovic J, Jull J, Armstrong R, Boyer Y, Cuervo LG, and 20 more. Protocol for the development of a CONSORT-equity guideline to improve reporting of health equity in randomized trials. Implementation Science, 2015-10-21. http://dx.doi.org/10.1186/s13012-015-0332-z
 Dary O, Freire W, Kim S. Iron compounds for food fortification: guidelines for Latin America and the Caribbean 2002. Nutr Rev. 2002 Jul;60(7 Pt 2): S50-61.