Iodine deficiency: Consequences and progress toward elimination

Glen F. Maberly, David P. Haxton, and Frits van der Haar

Abstract Consequences of iodine deficiency

While traditionally associated with cretinism and goiter, The trace nutrient iodine is of fundamental importance iodine deficiency has broad effects on central nervous in human biology. Iodine deficiency is particularly system development that can occur in the absence of damaging during pregnancy, because it retards fetal either condition. Any maternal iodine deficiency results development, especially development of the brain in a range of intellectual, motor, and hearing deficits in [1, 2]. Through the past millennia, the loss of human offspring. This loss in intellectual capacity limits edu- intellectual, physical, and social potential caused by cational achievement of populations and the economic iodine deficiency has been enormous [3, 4]. prowess of nations. Progress made since the historic The thyroid gland requires iodine for biosynthesis World Summit for Children in 1990 has been outstand- of the thyroid hormones thyroxin (T4) and trii- ing. Approximately 70% of households in the world used odothyronine (T3). Iodine available to form thyroid iodized salt by 2000, compared with less than 20% in hormones is dependent upon iodine intake from foods 1990. It is estimated that at least 85 million newborns out as well as interaction with possible goitrogens—other of 130 million annual births are protected from a loss in food substances that may interfere with the ability of learning ability that would otherwise have occurred. The the thyroid gland to make thyroid hormones and/or elimination of iodine deficiency, by expedient production, increase urinary iodine excretion. Soils are generally marketing, and universal consumption of iodized salt, deficient in iodine, so iodine needs to be added to the represents a significant development effort in public diet to achieve sufficiency. With adequate iodine intake nutrition. Although globally iodine nutrition has greatly the inhibiting effect of most goitrogens can usually be improved, 20% to 30% of pregnancies and thus newborns overcome. Normal development of the central nervous still do not fully benefit from the use of iodized salt. Coun- tissues is dependent on an adequate supply of thyroid tries where success is in evidence could rapidly revert back hormones. Thus, iodine is an essential micronutrient to deficiency if vigilance is not maintained. Just as suc- for normal intellectual development and functioning. cess came through concerted public-private-civic actions, T4 and T3, when released by the thyroid gland making sure that this is expanded and will steadily go on into the blood circulation, are predominantly bound requires continuous collaboration. to binding proteins. The unbound hormones, once released, enter the cells throughout the body where their ultimate metabolic impact is chiefly regulated Key words: Brain development, elimination of iodine by the type and activity of several deiodinase enzymes deficiency disorders, iodine deficiency, salt iodization, found within the cells. Certain tissue cells actively sustained iodine nutrition, thyroid hormone action convert T4 to T3 while others predominantly convert T4 to an inactive isomer of T3, reverse triiodothyronine (rT3). More peripheral tissues like liver, kidney, and muscles obtain T3 directly from the blood T3, while Glen F. Maberly, David P. Haxton, and Frits van der Haar are affiliated with the Department of International Health, the pituitary and other brain cells derive most of Rollins School of Public Health, Emory University, Atlanta, their cellular T3 from blood T4. Once within the cell, Georgia, USA. Please direct queries to the corresponding T3 becomes biologically active through binding to author: Glen F. Maberly, Department of International Health, the nuclear T3 receptors, where it regulates growth, Rollins School of Public Health, 1518 Clifton Road NE, Atlanta, GA 30322, USA; email: [email protected]. development, and specialization [2]. Mention of names of firms and commercial products does The iodine-replete pregnant woman is normally able not imply endorsement by the United Nations University. to make available a ready supply of T4 to the devel-

Food and Nutrition Bulletin, vol. 24, no. 4 (supplement) © 2003, The United Nations University. S91 S92 G. F. Maberly et al. oping fetus by transferring T4 through the placenta. approaches. The urgency and extent of the problem The availability of T4 is enhanced during pregnancy were yet to become evident. In the past 25 years, a more through increases in binding proteins and the deiodi- realistic understanding of the nature and magnitude nase enzyme system that favors the transfer of free T4 of the problem has emerged. Hetzel [6] introduced over free T3 to the fetus. It is of interest that new fetal the term “iodine deficiency disorders” (IDD) in 1983 tissue has a form of tissue deiodinase that converts the to encompass the broad range of the various clini- free T4 to intracellular active T3 rather than reverse T3. cal manifestations, including fetal damage and loss, When the nuclear T3 receptors become more highly endemic cretinism, impaired mental function, as well occupied, they promote more active cellular growth as goiter. This concept helped public policymakers to and development. This system is also more activated understand the broad extent of the dangers and aided in the brain than in other tissues. After the major part in elevating a discussion of the problem on the agenda of brain development has taken place, these systems of governments and development agencies. become less active [5]. The damage from iodine deficiency in a society soon When people are iodine deficient, their circulating was shown to extend beyond the burden of people levels of T4 decline while the blood levels of T3 actually affected by the various clinical syndromes. A series of increase. This has several important consequences. studies prior to the early 1990s comparing groups of Peripheral tissues, which rely predominantly on apparently healthy people in iodine-deficient areas with circulating T3 rather than T4, are relatively spared from those from neighboring areas and from groups where the consequences of iodine deficiency, so the affected iodine deficiency was being corrected, showed a reduc- individuals appear as if they have normal thyroid status, tion of the entire distribution of cognitive ability in the and they grow relatively normally. On the other hand, deficient population by as much as 10 to 15 intelligence the brain at the same time receives multiple insults quotient (IQ) points [7]. Ultimately, the realization of from thyroid hormone deficiency. First, the maternal the nature of the public nutrition problem arose from T4 supply is limited so the fetal brain does not develop evidence that all members of an iodine-deficient popu- normally. Second, because of the short supply of iodine lation are affected even if the burden on the individual from the mother to the fetus, when the fetus starts to is not perceived or clinically demonstrable [8]. Cov- develop its own thyroid hormone supply during the ertly, iodine deficiency saps the cognitive performance second trimester it also makes predominantly T3 rather and the productivity of humans and undermines their than T4. reproduction and survival. By using the term “hidden Endemic cretinism, arising from severe dietary iodine hunger,” the late executive director of the United deficiency, is the most severe manifestation of maternal Nations Children’s Fund (UNICEF), James P. Grant, and fetal thyroid hormone deficiency. The hallmarks voiced the new understanding: “Like the iceberg, its of endemic cretinism include mental retardation and bulk lies beneath the surface” [9]. a brain disorder. These symptoms are best described as By 1990, iodine deficiency was documented in 118 spastic (pyramidal) signs in the upper limb distribution countries with more than 1.5 billion people—more and rigidity (extrapyramidal) signs. These subjects than one-third of the world’s population, living in have a diagnostic gait, which is not only related to the iodine-deficient areas [10]. It now has become evident neurologic disorder, but also contributed to by joint that this was an underestimate. Improved criteria for laxity and deformity. Other frequently encountered population indicators of iodine deficiency [11] showed clinical features include squinting, deafness, and the real extent in, for instance, China [12], thus adding primitive brain reflexes. In some populations there 800 million people to the global total. Also, data on is the additional manifestation of endemic cretinism iodine deficiency in the former USSR were not easily resulting from continuing thyroid hormone deficiency available at that time and subsequent information early in life. This results in additional clinical features showed that the populations in the newly Independ- of hypothyroidism: severe stunting of growth, skeletal ent States were iodine deficient, adding a further 250 retardation, and sexual immaturity. A prevalence of million people to the global total [13, 14]. There is no cretinism from 3% to 15% was commonly found in exact calculation of what proportion of the world’s severely affected rural populations in many places populations at the start of the decade had a diet with around the world [3]. insufficient iodine, but it would be realistic to estimate that between half and three-quarters of the world’s population were affected. Iodine nutrition moves onto the stage

Although the benefits of iodized salt have been sug- Policy formulation to programs gested since its introduction during the 1920s, options for programs to address iodine deficiency during The history of progress toward global elimination of the 1970s still involved a selection among various iodine deficiency, from the age of ignorance, through Iodine deficiency: Progress toward elimination S93 a half century of discovery, and to a decade of action, food-grade salt in all of the country, the Government of provides the insight that different elements of society the People’s Republic of China, supported by UNICEF had to learn to work together in new ways to tackle the and UNDP and with participation of ICCIDD, the problem through mutually supportive actions. Micronutrient Initiative (MI), the Program Against Member states at the World Health Assembly in May Micronutrient Malnutrition (PAMM), WHO, and the 1990 urged that the elimination of iodine deficiency World Bank, held a meeting in 1993 of governors from be given priority nationally. Political commitment to all provinces and key national ministries at the Great the issue was made at the World Summit for Children Hall of the People [18] and declared national com- in September 1990 at the United Nations (UN) when mitment to USI as the strategy for virtual elimination the virtual elimination of IDD was among 27 health of IDD. The government then moved to borrow US and social development goals for the decade of the $29 million from the World Bank to modernize the 1990s [15]. In 1991, a policy conference on hidden salt industry, a key factor for the successful household hunger translated the political goal into realistic policy utilization rate in China today [19]. Similar national guidelines and in 1992, the International Conference “dialogues” were held in the Republic of Georgia, on Nutrition agreed upon a framework of action that Mongolia, Indonesia, Zimbabwe, Thailand, Pakistan, would be incorporated in national plans. Russian Federation, Botswana, and Bangladesh. Policy decision makers and other leaders were slow to Experience of these national policy events shows that recognize the nature and magnitude of problems aris- forging the alliances needed to seek mutual agreement ing from iodine deficiency, as well as to acknowledge on a range of factors in national diligence—from that addressing the deficiency would require more than general standards of quality and conduct to specific a mere Ministry-of-Health-led intervention. By the start quality assurance needs—assured access to raw of the 1990s, UNICEF, the World Health Organization materials, fair market prices, internal and external (WHO), and the International Council for the Con- monitoring systems, key components of a national trol of Iodine Deficiency Disorders (ICCIDD) had all communication strategy, appropriate legislative argued for a multi-sectoral approach, but inter-agency and regulatory processes, overriding political will, agreement on guidelines for collaboration and stand- and sustained public demand for improved iodine ards of conduct in engaging the private sector needed nutrition. sorting out. National and international coalitions for To accelerate and support the emerging interna- blending the public- and private-sector interests were tional and national efforts, development agencies of needed. The experience of how to foster and manage donor countries such as Australia, Belgium, Canada, these coalitions, however, was limited. Germany, Japan, the Netherlands, Sweden, and United Meanwhile, many studies had documented the effi- States adjusted their allocation and technical assistance cacy of appropriate daily delivery of iodine through procedures to the budding new realities. In convincing common salt [16]. This set the stage for WHO and donors, such as governments and other national lead- UNICEF to agree upon the strategy of universal salt ers, that the solution was feasible, it was important to iodization (USI) [17] as the prime method to be pro- assure consistency of the policy message by evidence moted and supported through their global networks. that the agreed-upon strategy leads to success. ICCIDD UNICEF amplified its commitment through a variety had been created in part to pull the many scientific of approaches including support to national advocacy, opinions together as a forum for resolution hitherto procurement of equipment and supplies, technical not available to agencies and governments. The UN assistance, and training. Sub-Committee on Nutrition provided a platform for To acquire evidence of national political and other development agencies to exchange views and experi- commitments, national advocacy events of various ences that supported IDD elimination. Nongovern- kinds were organized. In South Asia, India’s Prime mental technical organizations, such as ICCIDD, MI, Minister initiated a national discussion on the need and PAMM, provided expertise, expanded the number for USI, and His Majesty the King of Bhutan decreed of trained professionals in many countries, and assisted the need for iodized salt in the small nation. In Bolivia, in advocacy activities. To this was added the solid sup- UNICEF and the government arranged a meeting of port of a civic group, Kiwanis International, as it members of the Cabinet to outline roles each Ministry undertook its first-ever international service project played in national elimination programs, including and agreed to raise US $75 million to eliminate iodine key representatives of the productive sector. In the deficiency and to channel those resources through Philippines, the President chaired a meeting in the UNICEF to national endeavors. Malacannang Palace where the Secretaries of Educa- After the initial government-led and public sector– tion, Trade, Agriculture, Health, and others outlined dominated meetings that focused on elimination of sectoral commitments in the presence of producers, IDD, an archetype change began to occur in the mid- food processors, and the public. 1990s based on the recognition that neither the agen- To accentuate the point that “universal” meant all cies nor governments owned, produced, or sold salt. S94 G. F. Maberly et al.

The “industry of salt” was the domain of the private reviews in seven countries of Africa, coordinated by salt producers and their allies. Notwithstanding their ICCIDD, UNICEF, and WHO [27], based upon which commitment to sound business and trade practices, it adjustments of recommended iodization levels were was crucial that salt producers grasped their central introduced [24]. role for the successful elimination of iodine deficiency In China, an additional problem arose when readily [20]. Part of coming to terms with this fact for public available iodized oil capsules containing milligrams health officials was their recognition that a salt situa- rather than micrograms of iodine were promoted to tion assessment and market-based salt supply analysis schoolchildren for daily use. Others promoted iodized were as essential for national program direction as a tea, iodized eggs, and other iodine-fortified products, survey of biologic status of the population. Salt produc- causing an excess intake of iodine in some individuals. To ers needed to become a focus in any discussions that sell these other products, entrepreneurs took advantage were seriously considering how to tackle the problem of the government-sponsored public information efforts of iodine deficiency right from the start. in promoting the use of iodized salt. It has been estimated that during the last decade, From uncovering such issues, it became more evi- the combined public sector investment in eliminating dent that quality assurance and regular oversight were iodine deficiency was US $100 million while private vital but underapplied components of many national investment was over US $1 billion [21]. Throughout management systems. Improved quality assurance the world, salt iodization has provided a trigger for plans were gradually introduced with more attention upgrading and modernizing an industry that was to the three domains of quality assurance, namely the operated on traditional lines. This has led to signifi- essential product, the national process, and the progress cant improvement in quality, hygiene, packaging and in human nutrition (see box 1). Many of the practices presentation of the product to the consumer. indicated have been partly addressed, but more com- prehensive monitoring efforts within production sites by salt producers and external monitoring by govern- Setting standards ment services remain a significant challenge in many places. WHO, in collaboration with ICCIDD and UNICEF, regularly reviewed IDD indicators and published improved standards [11, 22], which permitted a more Tracking progress accurate definition of the damage from iodine defi- ciency in the population, using biologic as well as clini- Information on the global progress being made toward cal evidence. Also, recommended criteria to assess the the elimination of iodine deficiency has been gathered national progress toward sustained elimination were and published gradually, such as UNICEF’s annual discussed and published [23]. In addition to the assess- State of the World’s Children Report. At first, the goiter ment criteria, recommended levels of iodization [24] prevalence was a key indicator [11]. Then, based on a were considered and potassium iodate has been agreed 1999 recommendation by a joint expert consultation upon as safe [25] and the most appropriate additive. among ICCIDD, UNICEF, and WHO [22], the total While the production of iodized salt increased goiter rate was no longer included because goiters do rapidly in a variety of sites in many countries, the not totally regress as rapidly in populations that were regulated levels of iodization were not derived from rigorous experiments. The initial calculations came mostly from salt consumption estimates, combined BOX 1. Three domains of quality assurance with the experience in countries like Switzerland and Essential National Progress in human the United States, where voluntary iodization had been product process nutrition practiced since the 1920s. National officials often set the raw material tax incentives periodic monitoring standards on the advice of international consultants processing education of iodine excretion and national advisors. Advice from salt experts and packaging communication public reporting of producers began slowly to be perceived as required. testing management results The levels of salt iodization observed at the midpoint shipping training application of new of the decade of action varied as widely as from 15 to retailing laboratories techniques 100 mg iodine per kg of salt. political com- mitment At the mid decade, a review of practices revealed legislation that in some countries batches of iodized salt were enforcement of reaching the market with varying levels of iodine con- standards tent, in some instances of more than several times the inter-sectoral permitted level. The appearance of an increased rate collaboration of thyrotoxicosis in Zimbabwe [26] led to national Iodine deficiency: Progress toward elimination S95 iodine deficient, even though urinary iodine levels nations with solid successes in USI during the 1990s. increased to normal levels with the consumption of This information comes from official government data iodized salt [28–30]. To track progress, emphasis has received by the UN agency responsible. The apparent now been put on the access and use in households of trends of increasing the percentage of households appropriately iodized salt. that have iodized salt during the decade in so many In 1995, UNICEF reported that 58 out of 94 coun- countries illustrate that once the USI policy had tries had achieved or were progressing well toward USI been communicated and the salt industry engaged, [31]. From 1995 onward, Multiple Indicator Cluster progress in country after country toward universal Surveys (MICS) were undertaken in countries, with salt iodization accelerated. assistance of UNICEF and other support groups. Using Figure 2 shows the estimated number of newborns population proportional cluster sampling techniques, protected by iodized household salt and the proportion household surveys have been completed in more than not protected each year. It is estimated that at least 85 70 countries during the first round until 1997, and million newborns out of approximately 130 million verbal questions were included about the consump- annual births are protected every year from a loss in tion of iodized salt. At the end of the decade, the second learning ability that might otherwise have occurred. round of national surveys to determine the progress This endows some three-quarters of a billion additional toward reaching the World Summit on Children goals IQ points to the new generations of babies each year, included iodine testing of salt found in households by helping them come closer to achieving their genetic a rapid screening kit. Where a MICS shows evidence intellectual potential and allowing them to attain that 90% percent of households have iodized salt, a higher educational and social development ambitions. national survey is recommended, including urinary Validation of national impact, through improved levels iodine measurements, to verify that the national goal of urinary iodine, at this time has not yet been pub- of virtual elimination of iodine deficiency has been lished from many countries. Where such data have been achieved. Many countries have yet to act on this rec- collected there is good accord between the percentage ommendation, but in some countries (e.g., Panama, of availability of iodized salt in homes and the distri- Zimbabwe, Macedonia, and Bhutan) this success has bution of urinary iodine levels in the population, thus now been documented. showing protection from iodine deficiency. The Summit goal was not reached by 2000, how- ever. While the global progress has been impressive, The current situation and some of the world’s poorest nations have achieved high salt iodization levels, in 38 countries less than half Figure 1 provides a summary of household availability of the population had access to iodized salt by the end of iodized salt by global region by 2000, collated by of the decade. The list includes many countries of the UNICEF [32]. More than 70% of households in the Commonwealth of Independent States and East and world used iodized salt by 1999, compared with less Central Europe, where salt iodization practices once than 20% in 1990. By the end of the decade, iodized deemed adequate were abandoned in the transition salt was found in over 90% of the households of and iodine deficiency returned with all the serious 31 developing nations. In an additional 36 nations, consequences for the future development of these more than half of the population was protected from populations. iodine deficiency by consuming iodized salt. Large Newborns brain-protected and populous countries as well as poorer countries Newborns not brain-protected are on these lists. Bangladesh, Benin, Bolivia, China, E. Europe/Comm. of 1.308 4.467 Eritrea, Nigeria, and Peru are among the examples of Independent States/Baltic S. Asia 17.812 20.813

E./S. Africa E./S. Africa 6.749 5.628 W./C. Africa Middle East/N. Africa 5.283 4.271 Middle East/N. Africa S. Asia W./C. Africa 9.784 4.091 E. Asia/Pacific E. Asia/Pacific 23.371 8.214 C./S. America E. Europe/Comm. of Independent States/Baltic C./S. America 10.447 1.748 Other unknown 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 Percent Percent FIG. 2. Estimated number (millions) of newborns brain- FIG. 1. Estimated percentage of households with iodized salt protected each year, based on the percent of household by UNICEF regions in 2000 availability of iodized salt, by UNICEF regions S96 G. F. Maberly et al.

Lessons learned were held in several parts of the world. The concerns and interests of salt industry participants were the main A barrier that has largely been overcome is the accept- focus of discourse at these meetings, and governments ance of food-grade salt as the vehicle for delivering and other partners were invited to ask the producers additional iodine to populations. In some western how they could help them with their efforts. This was countries, a few in the scientific and lay circles continue a role reversal of what took place at the beginning of to discuss whether the customary salt intake is healthy the decade. The climax from this change of approach [33]. On the other hand, consumers almost everywhere occurred at the 8th World Salt Symposium, held on have accepted salt as a flavorful ingredient of common 7–11 May 2000 in The Hague, the Netherlands. The diets. Some expert advisors did not favor the USI strat- Symposium with the theme “Salt: Life Depends on It” egy, even if it only substituted non-iodized for iodized featured the consolidation of progress and the need for salt, out of fear that its promotion would cause an continued commitment to USI in plenary and forum increase in salt consumption. To date, there is no evi- sessions, and in social and cultural events. The meeting dence that the promotion of salt iodization has caused attracted more than 1,000 participants involved with consumption of more salt. Levels of iodization can be the salt industry and elimination of iodine deficiency easily adjusted for any level of salt consumption. from around the world [34]. An argument heard early in the decade that proc- At the symposium, a high-level roundtable meeting essed salt would not reach many people, especially was held among the leaders from public, private, civic, those of poor and distant communities, revealed lack and scientific organizations and steps were taken in of understanding how the salt trade works. USI was support of the goal to expand on the mutually sup- perceived as beneficial for mostly urban areas and resi- portive work of the alliance in the future. Among the dents near main roads and upscale markets. Bolivia, understandings reached was that the salt industry Bhutan, Eritrea, Laos, and Nepal offer examples to the would take a more dynamic leading role in working contrary. USI exerted its benefit also in the poorest to sustain the virtual elimination of iodine deficiency. and remotest rural areas, because almost all common Also, the collaboration of the key partnering organiza- grades of consumption salt can be iodized. tions would be formalized and strengthened. The successes of USI in country upon country are based on mutually supportive actions taken by con- cerned people from public-, private-, and civic-sector Future challenges origins. It is not likely that any of the individual sectors alone could have achieved so much and so rapidly. The Dr. Gro Harlem Brundtland, Director-General of the major lesson from the success of the decade was the World Health Organization, said at the 1999 World recognition that the public- and private-sector abili- Health Assembly: “When the elimination of iodine ties in overcoming iodine deficiency needed cohesive deficiency disorders is achieved, it will be a major and blending. A related lesson was that iodine deficiency total public health triumph, ranking even with small was a national problem, not a local one, and that the pox and poliomyelitis”[35]. Political decision makers approach should be universal, meaning addressing the are constantly changing, as are the issues that command entire population of the nation. After the demonstra- their attention. Experience over the years in Thailand, tion that iodized salt is safe and that the processing Guatemala, Colombia, Germany, and countries from technique is easy, the idea of “universal” salt iodization the former USSR illustrate that the iodine nutrition as the essential strategy became clear. The rapid, mas- status of populations can quickly deteriorate when salt sive gains in household access to iodized salt would is no longer iodized after a period of adequate iodine not have occurred through voluntary iodization of salt. nutrition. The need for sustained vigilance is illustrated With such an approach, the producer who decides to by recent developments in India, where the political bear the extra work and expense of supplying iodized commitment to universal salt iodization is being salt is unprotected in the market from his competitor tested. The salt situation, program status, and popula- who does not respond to the public health need of the tion iodine adequacy needs to be regularly assessed; nation. and political will, along with other critical program During the final years of the decade, key interna- elements, needs to be periodically renewed to assure tional organizations involved in the global elimination continued adequate iodine nutrition. of iodine deficiency strengthened their collaboration More and more nations of the world are in a transi- by forming a loose alliance. The shared goals of this tion from a campaign mode (to reach the goal of USI) alliance included the following: consolidating the gains to activities (which ensure that the national successes already made in USI; stating more explicitly the special are sustained). In simple terms, sustained elimination responsibility of salt producers; and jointly celebrating means that every family table and each processed success while expanding the alliance into the future. To food product containing salt always has salt with the pursue these goals, regional salt producers’ meetings appropriate quantity of iodine. The challenge of today Iodine deficiency: Progress toward elimination S97 is to proceed permanently while assuring that what is renewed commitments to protect women and children achieved will be permanent. The actions for sustaining in the new millennium [43]. It was agreed that each success may differ from the actions required to pursue country will report to the UN in 2003 on their progress it. Further research is needed to analyze the require- toward the sustained elimination of iodine deficiency; ments that will assure continued positive results from the new global elimination target has been moved the agreed upon USI policy. to 2005. Reports from Germany [36], Belgium [37], New Although iodine deficiency was not eliminated as Zealand [38], Australia [39], United States [40], France quickly as planned in the decade of the 1990s, the [41], and Italy [42] indicate the recent recognition that assembled leaders can be pleased with the progress the iodine intake in economically advanced parts of the made in most countries. A new Network for Sustained world has dramatically dropped or become deficient Elimination of Iodine Deficiency among the public- during the same period that most developing nations private-civic sectors was formally announced to have been tackling their iodine deficiency problems. advance this goal for the future and protect the gains Scientists in these countries are now calling for closer already made [44]. The Network’s establishment monitoring and, in some cases, renewed policy action resulted from a process initiated by the high-level to prevent iodine deficiency through salt iodization. political leaders at Salt2000, who expressed that the The time may have come to consider and accept the effect of joint action by the talents of public, private, full global application of “USI forever.” and civic sources in eliminating iodine deficiency is In May 2002 members of the UN met in a Special greater than the sum of its parts. This political wisdom Session on Children to review the score card of suc- will be needed when the issues of sustained iodine cess in achieving the goals set out in 1990 and to make nutrition are addressed.

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22. WHO/UNICEF/ICCIDD. Assessment of the iodine 33. WHO. Comparative analysis of progress on the elimina- deficiency disorders and their elimination. Geneva: tion of iodine deficiency disorders. Copenhagen: World WHO/UNICEF/ICCIDD, 2001 (in press). Health Organization Regional Office for Europe, 2000. 23. Houston R, Lotfi M, Nathan R, Pandav CS, eds. Assessing 34. van der Haar F, de Jong JM, Haxton DP, Mannar V. country progress in universal salt iodization programs. SALT2000: Marking and sustaining global progress in Iodized salt program assessment tool (ISPAT). Ottawa: universal salt iodization. IDD Newsletter 2000;16:33–7. MI/WHO/ICCIDD/USAID/PAMM/UNICEF, 1999. 35. WHO. WHO sets out to eliminate iodine deficiency dis- 24. WHO/UNICEF/ICCIDD. Recommended iodine levels orders [press release]. Geneva: World Health Organiza- in salt and guidelines for monitoring their adequacy and tion, May 25, 1999. effectiveness. Geneva: WHO/UNICEF/ICCIDD, 1996. 36. Hampel R, Kuhlberg T, Zollner H, Klinke D, Klein K, 25. FAO/WHO Expert Committee on Food Additives. Pichmann EG, Kramer A. [Current state of alimentary Evaluation of certain food additives and contaminants: iodine deficiency in Germany]. Z Ernährungswiss 1996; thirty-seventh report of a joint FAO/WHO Expert Com- 35:2–5. [German] mittee on Food Additives. WHO Technical Report Series 37. Delange F. [Iodine intake in the Belgian population is 1991;806:49. insufficient.] Bull Mem Acad R Med Belg 1998;153: 26. Todd CH, Allain T, Gomo ZAR, Hasler JA, Ndiweni M, 373–80. [French] Oken E. Increase in thyrotoxicosis associated with iodine 38. Thomson CD, Colls AJ, Conaglen JV, Macormack M, supplements in Zimbabwe. Lancet 1995;346:1563–4. Stiles M, Mann J. Iodine status of New Zealand residents 27. WHO/UNICEF/ICCIDD. Review of findings from as assessed by urinary iodide excretion and thyroid hor- 7-country study in Africa on levels of salt iodization mones. Brit J Nutr 1997;78:901–12. in relation to iodine deficiency disorders, including 39. Gunton JE, Hams G, Fiegert M, McElduff A. Iodine defi- iodine-induced hyperthyroidism. Geneva: WHO/ ciency in ambulatory participants at a Sydney teaching UNICEF/ICCIDD, 1997. hospital: Is Australia truly iodine replete? Med J Aust 28. Zhao J, Xu F, Zhang Q, Shang L, Xu A, Gao Y, Chen Z, 1999;171:467–70. Sullivan KM, Maberly GF. Randomized clinical trial 40. Hollowell JG, Staehling NW, Hannon WH, Flanders comparing different iodine interventions in school DW, Gunter EW, Maberly GF, Braverman LE, Pino S, children. Public Health Nutr 1999;2:173–8. Miller DT, Garbe PL, DeLozier DM, Jackson RJ. Iodine 29. Jooste PL, Weight MJ, Lombard CJ. Short-term effective- nutrition in the United States. Trends and public health ness of mandatory iodization of table salt, at an elevated implications: iodine excretion data from National iodine concentration, on the iodine and goiter status Health and Nutrition Examination Surveys I and III of schoolchildren with endemic goiter. Am J Clin Nutr (1971–1974 and 1988–1994). J Clin Endocrinol Metab 2000;71:75–80. 1998;83:3401–8. 30. Pardede LV, Hardjowasito W, Gross R, Dillon DH, 41. Valeix P, Zarebska M, Preziosi P, Galan P, Pelletier Totoprajogo OS, Yosoprawoto M, Waskito L, Untoro J. B, Hercberg S. Iodine deficiency in France. Lancet Urinary iodine excretion is the most appropriate out- 1999;353:1766–7. come indicator for iodine deficiency at field conditions 42. Rapa A, Marinello D, Chiorboli E, Sacco F, Bona G. at district level. J Nutr 1998;128:1122–6. Iodine deficiency in Italy. Lancet 1999;354:596–7. 31. Grant JP. The state of the world’s children 1995. New 43. UNICEF. A world fit for children. New York: United York: Oxford Press, 1995. Nations Children’s Fund, 2002. 32. UNICEF/WHO/World Bank. Ending iodine deficiency 44. Network for Sustained Elimination of Iodine Deficiency forever: a goal within our grasp. New York: United web site: http://www.IodinePartnership.net. Accessed on Nations Children’s Fund, 2000. January 17, 2003. Iron deficiency: Global prevalence and consequences

Rebecca J. Stoltzfus

Abstract Introduction

Iron deficiency is considered to be one of most prevalent Iron deficiency has long been considered a major form forms of malnutrition, yet there has been a lack of con- of malnutrition throughout the world, yet there has sensus about the nature and magnitude of the health been a lack of consensus about the nature of the public consequences of iron deficiency in populations. This paper health consequences of this widespread deficiency and presents new estimates of the public health importance of which population groups deserve primary attention in iron-deficiency anemia (IDA), which were made as part terms of intervention [1]. However, many experts agree of the Global Burden of Disease (GBD) 2000 project. Iron that in poverty-stricken populations, iron deficiency is deficiency is considered to contribute to death and dis- not being adequately controlled by public health and ability as a risk factor for maternal and perinatal mortal- nutrition interventions as they are currently imple- ity, and also through its direct contributions to cognitive mented [2]. impairment, decreased work productivity, and death This paper presents new estimates of the public from severe anemia. Based on meta-analysis of observa- health importance of iron deficiency [3], with some tional studies, mortality risk estimates for maternal and implications for where resources might best be focused, perinatal mortality are calculated as the decreased risk both in terms of research and interventions. These in mortality for each 1 g/dl increase in mean pregnancy estimates were made as part of the latest round of the hemoglobin concentration. On average, globally, 50% of World Health Organization’s (WHO) Global Burden the anemia is assumed to be attributable to iron defi- of Disease 2000 project (GBD 2000). Summary esti- ciency. Globally, iron deficiency ranks number 9 among mates have been published [4] and full reports are 26 risk factors included in the GBD 2000, and accounts forthcoming. for 841,000 deaths and 35,057,000 disability-adjusted life years lost. Africa and parts of Asia bear 71% of the global mortality burden and 65% of the disability-adjusted life Iron deficiency: results from GBD 2000 years lost, whereas North America bears 1.4% of the global burden. There is an urgent need to develop effective Within GBD 2000, iron deficiency was considered as and sustainable interventions to control iron-deficiency one of several forms of malnutrition. For a detailed anemia. This will likely not be achieved without substan- description of the methods and results, please see tial involvement of the private sector. Stoltzfus et al. [3]. What follows here is a brief summary. Conceptually, malnutrition—in this case iron defi- Key words: Anemia, iron deficiency, maternal mortal- ciency—may cause death or disability either directly ity, perinatal mortality (i.e., direct sequelae) or by increasing the risk of death or disability from other causes (i.e., as a risk factor). For example, IDA directly causes impaired muscle function Rebecca J. Stoltzfus is affiliated with the Division of and physical performance [5], but it acts as a risk factor Nutritional Sciences at Cornell University in Ithaca, New for maternal mortality. That is, women do not die in York. Please direct queries to Rebecca J. Stoltzfus, Division childbirth from IDA; rather, IDA increases a woman’s of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; email: [email protected]. risk of dying from cardiac failure in childbirth. Mention of the names of firms and commercial products Iron deficiency was considered to potentially con- does not imply endorsement by the United Nations University. tribute to death and disability through the following outcomes: child mortality, maternal mortality, peri-

Food and Nutrition Bulletin, vol. 24, no. 4 (supplement) © 2003, The United Nations University. S99 S100 R. J. Stoltzfus natal mortality, fitness and productivity, cognitive with and without endemic malaria. For perinatal impairment, and morbidity from infectious disease. Of mortality, there was evidence that the risk relationship these, infectious morbidity was subsequently dropped, was stronger in African studies than in studies from because the substantial epidemiologic evidence availa- other locations, and, therefore, an Africa-specific risk ble does not support a significant relationship between estimate was used. Data from two recent studies were iron deficiency and incidence or severity of infectious used to estimate the likely magnitude of bias in the disease [6]. For child mortality there was insufficient summary estimates due to unmeasured factors. Based epidemiologic data to provide sound estimates for IDA on this analysis, the risk estimates were attenuated by as a risk factor. This is a significant lack in the literature, 20%. The final risk estimates are shown in table 2. and it is important to realize that the evidence does not The GBD 2000 uses the disability-adjusted life year preclude an important relationship. (DALY) as the summary measure of death and dis- To derive the risk estimates for maternal and ability. The DALY measures years of life spent in less perinatal mortality, hemoglobin concentration was than full health. In the case of premature mortality, a used as the risk factor because there are insufficient full DALY is lost for each of year of expected life lost. studies (indeed, for maternal mortality, no studies) For other disease states, a fraction of a DALY (i.e., dis- that measure IDA specifically as the risk factor. It was ability weight) is assigned to each year lived with the then assumed that 50% of anemia was attributable to disease, with the weight corresponding to the severity iron deficiency. A further assumption was that the risk of the disease. In the case of IDA, premature mortality relationship between mortality and all anemia was the of mothers and children is one source of DALYs lost. same as the risk relationship between mortality and the Another is the disability weight assessed as a fraction of iron deficiency component of the anemia. a DALY for each year lived with anemia or its associated Population figures and anemia prevalence data were cognitive and physical impairment. provided by the WHO, and are shown for the world Globally, 841,000 deaths and 35,057,000 DALYs are and selected developing regions of the world in table 1. attributable to IDA (table 1). The relationship between Anemia prevalence is highest in young children, followed by women. Data for other population groups are not Table 2. Odds ratios and confidence limits used to generate shown here but are available in Stoltzfus et al. [3]. GBD 2000 mortality estimates Mortality-risk estimates associated with pregnancy Outcome Estimate 95% C.I. hemoglobin levels were derived from meta-analysis of 6 published studies of maternal mortality and 10 Maternal mortality 0.80 0.70 – 0.91 published studies of perinatal mortality. For both Perinatal mortality, Africa 0.72 0.65 – 0.80 outcomes, the studies included in the analysis varied Perinatal mortality, other regions 0.84 0.78 – 0.90 in their geographic location and included populations Source: Stoltzfus et al. [3]

Table 1. Population, anemia prevalence in risk groups, and death and disability attributable to iron-deficiency anemia in the world and in selected developing regions of the world Burden attributable to iron Anemia prevalence deficiency (thousands) Population Region (thousands) Women Men Children Deaths DALYsa Africab 639,593 41% 28% 60% 271 10,140 Latin Americac 502,162 23% 11% 46% 33 1,249 Eastern Mediterraneand 481,635 44% 17% 63% 80 3,195 Southeast Asia-Ie 293,819 49% 32% 49% 34 1,528 Southeast Asia-IIf 1,241,806 60% 36% 66% 324 12,497 North Americag 325,183 8% 5%h 7% 5 478 World 6,045,017 — — 841 35,057 Source: Stoltzfus et al. [3] a. DALY = disability-adjusted life year b. Excluding Egypt, Morocco, Somalia, Sudan and Tunisia. c. Excluding Cuba d. Afghanistan, Djibouti, Egypt, Iraq, Morocco, Pakistan, Somalia, Sudan, Yemen e. Indonesia, Sri Lanka, Thailand (I) f. Bangladesh, Bhutan, Democratic People’s Republic of Korea, India, Maldives, Myanmar, Nepal (II) g. Including Cuba h. Because anemia cutoffs are defined as the 5th percentile of a normative distribution, this represents the theoretical minimum population prevalence of anemia Iron deficiency: Prevalence and consequences S101 maternal pregnancy anemia and perinatal mortality is associated with pregnancy anemia. This fraction is also responsible for the largest contribution to both deaths high in Latin America (61%), Eastern Mediterranean- and DALYs, representing 56% of the total [3, 4]. D (72%), and Southeast Asia-D (68%) (see table 1 for The global distribution of the disease burden of IDA regional definitions). By contrast, in North America is heavily concentrated in Africa and WHO region and Cuba, only 10% of total DALYs derives from Southeast Asia-D (table 1). These regions bear 71% of pregnancy anemia, with the remaining 90% coming the global mortality burden and 65% of the DALYs lost. from the direct disabling sequelae of IDA. The same By contrast, the DALYs lost to IDA in North America is true for European countries with very low mortality and Cuba amount to 1.4% of the global total. It is an rates (data not shown). The resulting message is that as important (but not surprising) message that there is overall mortality rates decline, the relative importance enormous inequity in the burden of iron deficiency of the direct sequelae (i.e., cognitive impairment and in the world. There is an equally enormous need for decreased work productivity) increases, while that interventions that will work in the less-developed of pregnancy anemia and its associated mortality regions of the world. decreases. Another interesting comparison between world It is an important caveat that the GBD 2000 project regions is the relative importance of maternal and peri- likely underestimates the consequences of IDA in natal mortality, which derives entirely from pregnancy childhood for two important reasons. First, as stated anemia, compared with the “direct consequences” of above, data are lacking to estimate the risk relationship iron deficiency, which derive primarily from child- between IDA and childhood mortality, even though a hood IDA. This is shown graphically in figure 1. It is true relationship might exist. Second, the DALY, being a important to remember that the relative sizes of these measure of disease and disability, does not capture fully regional “pies” are vastly different. In fact, if these pies the developmental consequences of IDA in childhood, were truly proportional in size, the pie representing which mainly involve changes in function within the North America and Cuba would be barely visible, at range of “normality.” That is, IDA is associated with about 5% of the total pie for Africa. (Exact ratios can be shifts in intelligence that mainly fall within the range calculated from table 1.) Nonetheless, these pie graphs of normal function, rather than clinical retardation. demonstrate that the relative importance of the differ- Economic measures of the consequences of IDA ent consequences of IDA varies by context. In regions would tend to weight the effects of IDA on cognition where mortality rates are high, pregnancy anemia rates and work productivity much more heavily than its are also almost invariably high, and these two combine effects on maternal and perinatal mortality [7]. Thus, to create very large burdens of perinatal and maternal it is extremely important to understand the measuring mortality attributable to IDA during pregnancy. In stick used in the GBD 2000. It is a measure of health Africa, 81% of the total DALYs derives from mortality consequences and only health consequences.

Africa North America and Cuba Maternal mortality Perinatal Maternal mortality mortality

Direct disability

Perinatal mortality Direct disability FIG 1. Proportions of DALY’s attributable to mortality and disability in Africa and North America and Cuba. The relative contributions of perinatal mortality, maternal mortality, and direct disability (i.e., cognitive impairment and decreased work productivity) to the total disability-adjusted life years (DALYs) lost to iron-deficiency anemia in two regions of the world, Africa vs North America and Cuba. In Africa, maternal mortality contributes 15% of DALYs lost, perinatal mortality contributes 66%, and direct disability contributes 19%. In North America and Cuba, maternal mortality contributes < 1% of DALYs lost, perinatal mortality contributes almost 10%, and direct disability contributes almost 90%. Source of data: Stoltzfus et al. [3] S102 R. J. Stoltzfus

Implications and conclusions both shown benefits to children’s development [10, 11]. There is a need for longitudinal studies of cohorts of GBD 2000 estimates provide a new basis for advocating children whose iron status in early childhood is well the control of iron deficiency. Compared with other described, so that the long-term consequences of early forms of malnutrition included among the 26 risk deficits can be described in social, economic, and edu- factors in GBD 2000 (table 3), iron deficiency ranks cational terms [12]. #9 overall in terms of DALYs lost, falling lower than There is also a need for further research that describes underweight (#1), and slightly higher than zinc defi- the effects of IDA on people’s well-being and activities ciency (#11) and vitamin A deficiency (#13). There is in social terms. Iron deficiency adversely affects work no excuse for the scientific and public health commu- productivity of adults, and likely also affects voluntary nity to be complacent about iron deficiency. activities[13]. A particularly salient area for future At the same time, GBD 2000 further illuminates research is the effect of maternal IDA on well-being important gaps in our knowledge about the and care-giving capacities and behaviors in the post- consequences of iron deficiency. Evidence for the partum period. These effects are difficult to character- relationships between IDA and maternal and perinatal ize because of the numerous methods of coping that mortality needs to be strengthened by well-controlled humans use to adapt to compromised health. Yet the prospective observational studies. Randomized trials implications for the lives of women and infants may be are conceivable and would add greatly to the evidence significant, and these studies are certainly within the base, but will likely not be placebo-controlled for ethical reach of innovative social scientists. reasons. As previously mentioned, there is an urgent These gaps in the evidence should not preclude need for more evidence on the relationship between advocacy and action. It is striking that while iron IDA and mortality in young children. Fortunately, deficiency in developed countries is being controlled research is in process to address this question. mostly through private sector actions—namely avail- Regarding the relationship of iron deficiency to ability of iron-rich foods and iron-fortified weaning child development, cognition, and work productivity, foods—the public sector is shouldering the burden as described by Dr. Tomas Walter in the colloquium of iron interventions in less-developed countries, and [8], evidence is mounting that early iron deficiency frankly is failing. During the colloquium, Nita Dalmiya significantly affects children’s neural physiology and informed us that UNICEF is the largest distributor of behavior [5]. Well-controlled observational studies iron supplements in the world [14]. This is an unten- show that IDA is associated with behavioral differences, able solution to the problem. The question is not only developmental delays, and lower IQ and poorer school one of sustainability, because at this point there is little performance [9]. Two published randomized controlled or no success to be sustained. A recent WHO progress trials of iron supplementation in early childhood have report on malnutrition [15] stated:

Table 3. Relative rank and attributable DALYs for 13 risk fac- “Unfortunately, there has been little appreciable tors considered in GBD 2000 a,b change over the last two decades in the high world- wide prevalence of IDA. Few active programmes in both Attributable developed and developing countries have succeeded in Rank Risk factor DALY reducing iron deficiency and anaemia. Important factors 1 Underweight 137,801 contributing to the lack of progress include failure to 2 Unsafe sex 91,869 recognize the causes of iron deficiency and anaemia, lack of political commitment to control it, inadequate plan- 3 High blood pressure 64,270 ning of control programmes, insufficient mobilization 4 Tobacco 59,081 and training of health staff, and insufficient community 5 Alcohol 58,323 involvement in solving the problem.” (p. 17) 6 Unsafe water, sanitation, and hygiene 54,158 In the context of the industry-sponsored colloquium, 7 High cholesterol 40,437 two critical needs to address the burden of IDA were 8 Indoor smoke from solid fuels 38,539 emphasized. First is the need for affordable, appealing 9 Iron deficiency 35,057 products. Despite the high prevalence and large dis- 10 High body mass index 33,415 ability burden associated with early childhood anemia, 11 Zinc deficiency 28,034 affordable, high-quality, and appealing supplemental 12 Low fruit and vegetable intake 26,662 forms of iron designed for young children are gener- 13 Vitamin A deficiency 26,638 ally not available in less-developed countries. Even Source: Ezzati et al., 2002 [4]. UNICEF currently does not stock an iron supplement a. Shown here are the top 13 risk factors; those ranked 14–20 are for young children. This has been a challenge because (in order): physical inactivity, occupational risk factors for injury, young children cannot safely swallow hard pills, and lead exposure, illicit drugs, unsafe health-care injections, lack of contraception, childhood sexual abuse. liquid supplements are bulky to ship and store and are b. Global total: 1.46 billion relatively unstable chemically. Preparations designed to Iron deficiency: Prevalence and consequences S103 appeal to children also introduce the risk of toxic over- Recent ethnographic work on women’s perceptions dose, so issues of dose and packaging are critical from of anemia and anemia treatments in Pemba Island, a safety standpoint. Innovations such as home fortifi- Zanzibar supports this argument. Young [19] con- cants [16] (“sprinkles”), spreads, “foodlets” [17], and cluded that over-the-counter pharmacies are among powdered beverages like the one developed by Procter the most empowering places for Zanzibari women to & Gamble Co. [18] are potential solutions, if they can receive health care. In the context of a poorly function- be made widely available at affordable prices. ing public health care system, small private pharma- Second, the public sector working through clini- cies provide an alternative to irregular supplies from a cal distribution channels can only achieve targeted government perceived as oppressive, because customers periods of supplementation of short duration (e.g., have immediate access to iron pills and are “no longer prenatal care). While these approaches are needed patients without any real bargaining power, at the to create a safety net during high-risk periods, they mercy of potentially hostile or indifferent staff” [19, cannot control the problem completely. As has been p. 110]. Furthermore, private pharmacies are gener- the case with North America, there needs to be private ally convenient, require less waiting, are not dependent sector involvement; i.e., the opportunity for people to on uncertain donor aid, and provide a living for the purchase dietary iron supplements or iron-fortified owners. They appear to be a win-win situation for both foods for consumption in high-risk periods (e.g., early the small business owner and women seeking care. childhood and pregnancy) and as needed throughout There is an important role to be played by companies the life cycle. The need for private sector provision of that manufacture pharmaceutical and food products dietary iron supplements is perhaps even more acute to develop high-quality, appealing, safe products that where governments are in financial and political crisis, can be distributed through local markets. Such work or where the public sector functions poorly. Unfortu- is urgently needed to reduce the burden of disability nately, this is true for many of the least developed and death associated with the present high prevalence regions where the burden of IDA is greatest. of IDA.

References

1. Stoltzfus R. Defining iron-deficiency anemia in public iron supplementation and anthelmintic treatment on health terms: a time for reflection. J Nutr 2001;131: motor and language development of preschool children 565S–7S. in Zanzibar. BMJ 2001;323:1389–93. 2. UNICEF/UNU/WHO/MI. Preventing iron deficiency in 12. Horton S, Levin C. Commentary on “Evidence that iron women and children. Technical consensus on key issues. deficiency anemia causes reduced work capacity.” J Nutr Boston: International Nutrition Foundation, 1999. 2001;131:691S–6S. 3. Stoltzfus RJ, Mullany L, Black RE. Iron deficiency anae- 13. Haas JD, Brownlie T. Iron deficiency and reduced work mia. Comparative quantification of health risks: the capacity: a critical review of the research to determine a global and regional burden of disease due to 25 selected causal relationship. J Nutr 2001;131:676S–90S. major risk factors. Cambridge: Harvard University Press, 14. Dalmiya N, Schultink W. Combating hidden hunger: (in press). the role of international agencies. Food Nutr Bull 4. Ezzati M, Lopez AD, Rodgers A, Vander HS, Murray 2003(Suppl);24:S69–77. CJ. Selected major risk factors and global and regional 15. WHO. Nutrition for health and development: a global burden of disease. Lancet 2002;360:1347–60. agenda for combating malnutrition: a progress report. 5. Beard JL. Iron biology in immune function, muscle Geneva: World Health Organization, 2000; (WHO/ metabolism and neuronal functioning. J Nutr 2001;131: NHD/00.6). 568S–80S. 16. Zlotkin S, Arthur P, Antwi KY, Yeung G. Treatment of 6. Gera T, Sachdev HP. Effect of iron supplementation on anemia with microencapsulated ferrous fumarate plus incidence of infectious illness in children: systematic ascorbic acid supplied as sprinkles to complementary review. Brit Med J 2002;325:1142. (weaning) foods. Am J Clin Nutr 2001;74:791–5. 7. Ross J, Horton S. Economic consequences of iron 17. Briend A. Possible use of spreads as a foodlet for improv- deficiency. Ottawa: Micronutrient Initiative, 1998. ing the diets of infants and young children. Food Nutr 8. Walter T. Effect of iron-deficiency anemia on cognitive Bull 2002;23:239–43. skills and neuromaturation in infancy and childhood. 18. Mehansho H, Mellican RI, Hughes DL, Compton Food Nutr Bull 2003(Suppl);24:S104–10. DB, Walter T. Multiple-micronutrient fortification 9. Grantham-McGregor S, Ani C. A review of studies on technology development and evaluation: from lab to the effect of iron deficiency on cognitive development market. Food Nutr Bull 2003(Suppl);24:S111–9. in children. J Nutr 2001;131:649S–66S. 19. Young SL. Listen, without blood there is no life: an 10. Idjradinata P, Pollitt E. Reversal of developmental delays ethnography of anemia during pregnancy. Master of in iron-deficient anaemic infants treated with iron [see Science Thesis, University of Amsterdam, Amsterdam, comments]. Lancet 1993;341:1–4. The Netherlands, 2002. 11. Stoltzfus RJ, Kvalsvig JD, Chwaya HM, et al. Effects of Effect of iron-deficiency anemia on cognitive skills and neuromaturation in infancy and childhood

Tomas Walter

Abstract are altered auditory-nerve and vagal-nerve myelina- tion, respectively, as iron is required for normal myelin Iron-deficiency anemia in infancy has been consistently synthesis. shown to negatively influence performance in tests of psychomotor development. In most studies of short-term follow-up, lower scores did not improve with iron therapy, Key words: Iron deficiency, anemia, behavior, despite complete hematologic replenishment. developmental neurology The negative impact on psychomotor development of iron-deficiency anemia (IDA) in infancy has been well documented in more than a dozen studies during Behavioral studies the last two decades. Two studies will be presented here to further support this assertion. Additionally, we will When IDA ensues during the first 2 years of life, it is present some data referring to longer follow-up at 5 and associated with delayed psychomotor development 10 years as well as data concerning recent descriptions and changes in behavior. These effects have been of the neurologic derangements that may underlie these shown to persist after several months of iron therapy, behavioral effects. despite complete correction of iron nutrition meas- To evaluate whether these deficits may revert after ures. Moreover, it is still uncertain after an extended long-term observation, a cohort of infants was re-evalu- period of observation whether or to what extent these ated at 5 and 10 years of age. Two studies have examined derangements are reversible. It is worrisome that the children aged 5 years who had anemia as infants using long-term prospective follow-up studies reported to comparable tools of cognitive development showing per- date, to be discussed below, show the persistence of sisting and consistent important disadvantages in those cognitive deficits at 5 to 6 and at 10 years of age in those who were formerly anemic. These tests were better predic- who experienced IDA during infancy. tors of future achievement than psychomotor scores. These The inherent difficulties of identifying intervening children were again examined at 10 years and showed variables in the complex field of mental development, lower school achievement and poorer fine-hand move- coupled in some cases with suboptimal design, have ments. Studies of neurologic maturation in a new cohort prevented significant progress in the investigation of of infants aged 6 months included auditory brain stem iron deficiency. However, two studies—one conducted responses and naptime 18-lead sleep studies. The central in Costa Rica in 1982 [1], and the other in Santiago, conduction time of the auditory brain stem responses was Chile, in 1986 [2]—confirm conclusions arising from slower at 6, 12, and 18 months and at 4 years, despite iron previous work. therapy beginning at 6 months. During the sleep-wake- The study in Santiago was performed in association fulness cycle, heart-rate variability—a developmental with a field trial of fortified infant foods. A total of expression of the autonomic nervous system—was less 196 healthy, full-term infants were assessed with the mature in anemic infants. The proposed mechanisms Bayley Scales of Infant Development (BSID) [3] at 12 (see Box 1), 121⁄2, and 15 months of age. This well-known and accepted tool is used to determine psychomotor development from ages 3–42 months. It Tomas Walter is affiliated with the Institute of Nutrition consists of a mental scale to evaluate cognitive skills, and Food Technology at the University of Chile in Santiago, Chile. Please direct queries to [email protected]. such as language acquisition and abstract thinking, Mention of names of firms and commercial products does and a motor or psychomotor scale to evaluate gross not imply endorsement by the United Nations University. motor abilities, such as coordination, body balance, and

S104 Food and Nutrition Bulletin, vol. 24, no. 4 (supplement) © 2003, The United Nations University. Effect of iron deficiency anemia in infancy and childhood S105

Why is severe iron deficiency—enough to lead to anemia— Box 1. Bayley Scales of Infant Development necessary to affect behavior? » Psychomotor development of the infant This is an unanswered question. Animal experimentation » Mental development index (MDI) shows that brain iron is acquired early in postnatal life; » Psychomotor development index (PDI) has a very slow turnover and when an iron deficient diet » Adjustment for the age 100 ± 16 (like the IQ) is provided, the decrease in hemoglobin production » Behavior scale: psychologic evaluation coincides with the depletion of tissues [9–11]. Therefore, anemia may be a reflection of tissue iron depletion walking. These scales are expressed as an index adjusted severe enough to somehow affect behavior. On the for age as the Mental Development Index (MDI) and other hand, the behavior measures available for this the Psychomotor Development Index (PDI). In age group might be insensitive to subtle changes that addition, it includes an Infant Behavior Record, which may be present before the progression to anemia. is based on clinical evaluation by a psychologist. The Costa Rican study [1] enrolled 191 otherwise Effect of iron treatment healthy 12- to 23-month-old infants with heterogene- Consistent results have been obtained in studies that ous iron status. The infants were divided into groups have included a placebo treatment group. Together, ranging from most to least iron deficient. The Bayley’s these studies indicate that short-term increases in test scales of infant development were administered before, scores observed among iron-treated anemic infants after 1 week, and after 3 months of iron treatment with are not significantly greater than those among pla- appropriate placebo controls. These infants were tested cebo-treated anemic infants, but are thus likely related further after 6 months with unchanged results [4]. to a practice effect. Although separating the effects of iron deficiency Results of psychomotor studies in infancy without anemia from those of IDA is important, a more pertinent question from a clinical perspective is Four major questions related to iron deficiency were whether iron therapy completely corrects behavioral answered with these studies and are discussed below. abnormalities regardless of how soon the changes are detectable. Studies in Costa Rica [1], Chile [2], the At what stage of iron deficiency is infant behavior adversely United Kingdom [12], and Indonesia [6] included an affected? iron treatment period of 2 to 4 months after which It was clear in both studies that a decrease in psychomotor development tests were repeated. Despite hemoglobin below the conventional cutoff limit for improved iron status, most of the formerly anemic anemia was necessary to significantly affect mental infants were unable to improve their psychomotor and psychomotor development scores. This has also performances. The only study to date that showed been the case for most similar studies. The performance a convincing reversal of lower BSID scores is the of the iron-deficient infants without anemia as a whole Indonesian study [6]. was indistinguishable from that of the iron-replete Notwithstanding, in most of the studies iron therapy, controls. even complete iron repletion was ineffective in improv- In the Chilean study [2] among anemic infants, ing the psychomotor scores of anemic infants to the hemoglobin (Hb) concentration was correlated with level of nonanemic controls. The protocol in Indonesia performance. The lower the Hb, the lower the devel- [6] shows that studies in this field may give conflicting opmental scores. Similarly, in the Costa Rican study, results and that newer and more imaginative techniques infants with moderate iron deficiency anemia (Hb < must be used to elucidate current controversies. 100 g/L) had lower mental and motor test scores than appropriate controls. The Santiago study [2] also evalu- Specific patterns of failure ated the effect of chronic anemia. Infants whose anemia The Chilean study [2] found that with regard to the had duration of 3 or more months had significantly mental scale, fewer anemic infants than control infants lower mental and motor development indices than did successfully completed tasks that required comprehen- those with anemia of shorter duration. The results of sion of language without visual demonstration. In the other research published to date support the conclusion psychomotor scale balance in the standing position (sits of these two studies: iron deficiency severe and chronic from standing, stands alone, and stands up) and walk- enough to cause anemia is associated with impaired ing were accomplished by significantly fewer anemic achievement in developmental tests in infancy, and infants than controls (see tables 1 and 2). Similar find- as anemia becomes more severe [5], deficits are more ings were reported in the Costa Rican study [1]. profound [5–8]. Information about other behavioral differences has been limited. Previous work relied primarily on rating scales during developmental testing, and most studies used the Bayley Scale’s Infant Behavior S106 T. Walter

TABLE 1. Mental scale items (12 months) TABLE 2. Motor scale items (12 months) Infants passing (%) Infants passing (%) Description (item no.) Anemic Control p value Description (item no.) Anemic Control p value Pushes car along (99) 56 77 NS Walks with help (42) 85 97 NS Turns book pages (103) 69 83 NS Sits from standing (43) 67 97 0.01 Imitates words (mama, Pat-a-cake (44) 82 97 NS dada) (106) Stands alone (45) 64 93 0.02 At 12 months 13 47 0.01 At 15 months 75 100 0.07 Walks alone (46) 38 67 0.05 Says two words with Stands up from sitting (47) meaning (113) At 12 months 3 7 NS At 12 months 0 7 NS At 15 months 42 80 0.05 At 15 months 42 93 0.005 Stands on left foot with Points own toys, shoes or help (52) clothing (117) At 12 months 0 10 NS At 12 months 0 18 NS At 15 months 8 40 0.05 At 15 months 25 60 0.07 of age. Infants who were already receiving more than Record. Nonetheless, observations have suggested a 250 ml/day of unmodified cow’s milk or formula pattern of alterations. Infants with IDA were rated as were randomly assigned to iron-fortified formula or unusually fearful, tense, restless, hesitant, withdrawn, no-added-iron milk. Breast-fed babies consuming or unhappy during testing [13]. In addition, infants < 250 ml/day of cow’s milk or formula were randomly with iron deficiency without anemia have been rated as assigned to receive vitamins with or without iron and more “solemn” than infants with better iron status. The once cow’s milk was introduced, the formerly assigned only study to examine behavior in a context other than type of milk. Prior to randomization, a venipuncture developmental testing of infants with documented IDA excluded the few who were anemic (Hb < 110 g/L plus was conducted by Lozoff and colleagues in Guatemala two or more abnormal biochemical measures) from the [14]. During a short free-play period, quantitative preventive trial. Hematologic assessments at 12 months coding of behavior showed that iron-deficient were performed on all participants. The main outcome anemic infants and their mothers maintained closer variable to assess developmental status of all infants was proximity to each other than did comparison group the Bayley Scales of Infant Development at 12 months, dyads. The authors postulated that the pattern of closer in addition to a visual attention measure at 6 and 12 proximity reflected heightened attachment behavior, a months, a temperament measure, and determination counterpart of the fearfulness and hesitance noted on of the timing of motor milestones. Study II, consisting behavioral ratings during developmental testing and of neuromaturational evaluations, was done with the evidence of altered affect, activity, or energy. anemic infants at 6 or 12 months of age as below. Because several studies have shown that the The preventive trial in Chile association between IDA in infancy and lower developmental test scores is confounded by The children in this protocol participated in two studies environmental disadvantages, Study I of this project that comprised a recent project [15]—a preventive trial. was a double-blind, placebo-controlled preventive Study I, a clinical trial of the developmental effects of trial in which healthy Chilean 6-month-old infants preventing IDA, involved 1700 healthy Chilean infants were randomly assigned to supplemental-iron or and their parents living in suburban areas near the no-added-iron treatments until 12 months of age. At capital city of Santiago. The infants, who were 4 to 12 months, the supplemented group had less anemia 5 months old and receiving well-child care in the (Hb < 110 g/L) and less iron deficiency without anemia designated community clinics, were screened for the (two or three abnormal measures: free erythrocyte following entrance criteria: residence in the targeted protoporphyrin (FEP), mean corpuscular volume area, birth weight ≥ 3.0 kg, no major birth or neonatal (MCV), or serum ferritin (SF); however, in contrast complications, no jaundice requiring phototherapy, to a recent smaller preventive trial in Canada [16], no hospitalization at any age, no iron-containing we could not show higher Bayley mental (MDI) or preparations at any age other than those given by the psychomotor (PDI) development index scores related study, and no major acute or chronic illness. to absence of anemia. Qualifying infants were randomly assigned to a For Study I, healthy full-term Chilean infants who high-iron or no-added-iron condition at 6 months were free of iron-deficiency anemia at 6 months were Effect of iron deficiency anemia in infancy and childhood S107

5.0 development. These children were the subjects of Iron therapy respective reports during their infancy described above [1, 2]. At 5 years of age, an evaluation with a 4.6 comprehensive set of psychometric tests showed that those who as infants had presented with IDA had Anemic lower scores on many of these tests when compared with children with higher hemoglobin in infancy. 4.2 Milliseconds These disadvantages persisted after statistical control of many potentially confounding variables. At this Controls age (5 years), measures of cognitive development are 3.8 better predictors of future achievement, so they are 0 1 2 3 4 even more reason for concern. For example, a 5-point Age (yrs) drop in intellectual quotient (IQ) was consistent in both studies, as well as in other tests concerned with FIG. 1. Evoked auditory brain stem potentials (ABS) of the intellectual function. Five points of IQ are a significant anemic and control children at 6 months and up to 4 years. The differences in speed of central conduction time in mil- handicap affecting millions of infants that have or have liseconds are significant at all points (p < 0.001). had anemia worldwide. This is worrisome because this is a preventable deficit. assigned to high- or low-iron groups or to high- or Neuromaturation studies no-added-iron groups. Behavioral/developmental outcomes at 12 months of age included overall mental IDA has long been thought to have central nervous and motor test scores and specific measures of motor system effects. However, finding direct evidence of such functioning, cognitive processing, and behavior. impact in the human infant has presented many meth- There were no differences between high- and low-iron odological challenges. Auditory brainstem responses groups in the prevalence of iron-deficiency anemia (ABR), which represent the progressive activation of the or behavioral/developmental outcome, and they auditory pathway from acoustic nerve (wave I) to the were combined to form an iron-supplemented group lateral lemniscus in the brain stem (wave V), provide (n = 1123) for comparison with the no-added-iron a non-invasive means of examining an aspect of the group (n = 534) At 12 months iron-deficiency anemia central nervous system that is rapidly maturing during was present in 3.1% and 22.6% of the supplemented the age period when iron deficiency is most common. and unsupplemented groups, respectively. The groups Another rapidly maturing process in infancy is the bal- differed in specific behavioral/developmental outcomes ance of the autonomic nervous system. Experimental but not global test scores. Infants who did not receive animals have also aided in orienting human studies. supplemental iron processed information slower. They were less likely to show positive affect, interact socially, Studies of ABR responses in infants with IDA or check their caregivers’ reactions. A smaller propor- As part of Study II we studied auditory brain stem tion of them resisted giving up toys and test materials, responses (ABR) during spontaneous naps in 55 and more could not be soothed by words or objects healthy 6-month-old Chilean infants with IDA and 26 when upset. They crawled somewhat later and were nonanemic controls [21, 22]. Central Conduction Time more likely to be tremulous. The results suggest that (CCT), the Wave I-IV interpeak latency, was longer in unsupplemented infants responded less positively to the iron-deficient anemic group, with differences the physical and social environment. The observed dif- becoming more pronounced at follow-up at 12 and 18 ferences appear congruent with current understanding months, despite effective iron therapy, and continuing of the effects of iron deficiency on the developing brain. to be slower at a 4 years of age follow-up (fig. 1) The study shows that healthy full-term infants may [23–26]. The CCT is considered an index of central receive developmental and behavioral benefits from nervous system development, because myelination of iron supplementation in the first year of life. nerve fibers and maturation of synaptic relays lead to an exponential reduction in CCT from birth reaching Long term effects of iron-deficiency anemia on adult levels at 24 months. The pattern of resulting cognitive performance differences in latencies but not amplitudes, in longer CCT (as an overall measure of nerve conduction The long-term effects of IDA have been addressed by velocity) indicates that altered myelination is an two recently described follow-up studies in 5-year-old appealing explanation, especially in view of recent Costa Rican [17] and Chilean [18–20] children who laboratory work documenting iron’s essential role in had been well characterized as infants in both iron myelin formation and maintenance [27–31]. This study status environmental variables and psychomotor shows that IDA adversely affects at least one aspect of S108 T. Walter central nervous system development in 6-month-old of similar effects in the human infant has posed many infants that lasts at least to 4 years of age and suggests methodologic challenges. During the last 20 years, the benefits of studying other processes that are rapidly research on the effects of IDA and iron therapy on myelinating during the first 2 years of life. infant development has depended heavily on stand- ardized tests of infant development, which have serious Sleep studies and autonomic nervous system limitations and bear unknown relations to central nerv- development ous system functions. By measuring auditory-evoked potentials, we provide more direct evidence of central Maturational patterns of heart rate variability (HRV) nervous system alterations in infants with IDA. Such provide noninvasive tools for the investigation neurophysiologic measurements had not been previ- of central nervous integrity during early human ously conducted in the iron-deficient infant. development and are likely to reflect brain function Changes in auditory brainstem-evoked potentials alterations earlier and more closely than tests of or responses (ABRS) are particularly relevant to study behavior and psychomotor development. Patterns of in infants with IDA. ABRS consist of a succession of heart rate and HRV were measured in 18 anemic 6- five to seven waves recorded at the scalp within the month-old infants and corresponding control infants first 10 milliseconds after stimulation. Development from polygraphic recordings during quiet and active changes in ABRS have been carefully studied. There sleep and wakefulness [32, 33]. Iron-deficient anemic are well-established developmental progressions from infants presented lower amplitude in all sleep-wake birth until stable values are reached at 18 to 24 months, states. It was proposed that delayed myelination of with decreases in the absolute and interpeak latencies, the vagal nerve results in decreased parasympathetic decrease in duration, and increase in amplitude [21–23]. influences that may underlie behavioral effects in iron Latency changes have been related to increases in deficiency in infancy. conduction velocity during axonal myelination. Other changes, such as increase in amplitude and reduction Reliance on animal studies in duration, are probably due to improvements in synchronization at the axonal or synaptic levels. Thus, The many challenges of studying the central nervous these developmental progressions are occurring during system in human infants has meant that direct evidence the age period when iron deficiency is most common. of central nervous system effects has had to come from animal studies. That evidence is increasingly compelling. In addition to earlier research on iron’s role Conclusions in central nervous system neurotransmitter function [34–38], recent work shows that brain iron is essential Behavioral studies have consistently shown that for normal myelination [27–31, 39, 40]. In rats, there IDA has adverse effects. Perhaps the most important is an influx of transferrin and iron into the brain in the implication of our findings, however, is that they may immediate postnatal period. As iron and its transport further generate plausible and testable hypotheses and storage compounds are redistributed in the brain, about the effects of iron deficiency on the developing myelinogenesis and iron uptake are at their peak. Iron central nervous system. Many parts of the brain are and its related proteins concentrate in oligodendrocytes becoming myelinated in the first 2 years of life, when and become more concentrated in white than in gray iron deficiency is most prevalent. We are obtaining matter (the majority of brain iron is found in this more direct and indirect non-invasive measures myelin fraction). Oligodendrocytes synthesize fatty of myelination in the human. With the hypothesis acids and cholesterol for myelin production, a process of impaired myelination in early IDA, it should be that requires iron. Furthermore, animal studies have possible to design studies with specific measures, using consistently found a lasting deficit in brain iron when techniques such as positron emission tomography IDA occurs early in development [9–11]. Although (PET) scan imaging, evoked and spontaneous only two studies of iron deficiency in animal models potentials, and, eventually, behavioral progressions examined myelination directly, both found iron- known to depend on myelination. Such hypothesis- deficient rats to be hypomyelinated [29, 40]. driven research would be a substantial advance over previous studies of iron-deficient infants, which has Challenges in designing clinical studies largely depended on global tests of development. Thus, these studies suggest new, promising directions The results of these and other animal studies indicate for understanding more specific central nervous system that IDA during brain growth has long-lasting effects mechanisms by which IDA could alter infant behavior on the central nervous system. Yet obtaining evidence and development. Effect of iron deficiency anemia in infancy and childhood S109

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neurotransmission. In: Lagoth A, ed. Handbook of 39. Lin HH, Connor JR. The development of the neurochemistry. New York: Plenum Press, 1985; 731– transferrin-transferrin receptor system in relation to 55. astrocytes, MBP and galactocerebroside in normal and 37. Youdim MBH, Ben-Shachar D, Yehuda S. Putative myelin-deficient rat optic nerves. Brain Res Dev Brain biological mechanisms of the effect of iron deficiency Res 1989;49:281–93. on brain biochemistry and behavior. Am J Clin Nutr 40. Roskams AJ, Connor JR. Iron, transferrin, and ferritin 1989;50:607–17. in the rat brain during development and aging. J 38. Youdim MBH, Yehuda S. Iron deficiency induces reversal Neurochem 1994;63:709–16. of dopamine dependent circadian cycles: Differential response to d-Amphetamine and TRH. Peptides 1985; 6:851–5. Multiple-micronutrient fortification technology development and evaluation: from lab to market

Haile Mehansho, Renee I. Mellican, Don L. Hughes, Don B. Compton, and Tomas Walter

Abstract adequate levels of bioavailable iron, vitamin A, iodine, zinc, vitamin C, and B vitamins, without compromising At the World Summit for Children (New York, 1990), a taste, appearance, and bioavailability. The critical resolution was passed to eliminate vitamin A and iodine limiting step in the micronutrient fortification program deficiencies and significantly reduce iron-deficiency is the production and distribution of the multiple- anemia by the year 2000. In responding to this urgent micronutrient-fortified product. The fortified powder call, we developed a unique multiple-micronutrient drink was marketed in Venezuela under the brand name fortification delivery system called “GrowthPlus/ NutriStar®. CreciPlus®.” Using this technology, a fortified powder fruit drink has been formulated and extensively evaluated. One serving of the product delivers the following US Key words: Fortification, iron bioavailability, micro- recommended dietary allowances: 20–30% of iron; nutrients, powder fruit drink, vitamin stability 10–35% of vitamin A; 25–35% of iodine; 100–120% of vitamin C; 25–35% of zinc; 15–35% of folate; and 10– 50% of vitamins E, B2, B6, and B12. This was accomplished Introduction through (a) identifying and selecting the right fortificants, and (b) understanding their chemical and physical More than 2 billion people worldwide suffer from properties that contribute to multiple problems (product iron, iodine, and vitamin A malnutrition [1–3]. acceptability, stability, and bioavailability). Data from a When they are not prevented or remain untreated, home-use test showed fortification with the “Multiple- such deficiencies have been shown to cause serious Fortification Technology” has no effect on the appearance health and economic problems. These include stunted and taste of the eventually consumed powder fruit drink. growth, impaired mental development, fatigue, One-year stability studies demonstrated that iodine and poor school performance, increased morbidity and the vitamins have adequate stability. Bioavailability mortality, reduced work output, and low self-esteem. evaluation by using double-isotope labeling technique In all, micronutrient malnutrition is among the showed that the iron from the fortified powder drink has leading cause of poor public health and economic excellent bioavailability (23.4% ± 6.7). In conclusion, development [1–3]. That is why the phrase “hidden a powder fruit drink has been clinically demonstrated hunger” is used to describe the nature and seriousness to deliver multiple micronutrients, which include of the deficiencies of these three micronutrients and why it is emerging as a top priority on the global public health agenda [1]. At the World Summit for Children Haile Mehansho, Don L. Hughes, and Don B. Compton are (New York, 1990) and the International Conference affiliated with The Procter & Gamble Co. in Cincinnati, Ohio, on Nutrition (Rome, 1992) most of the members of USA; Renee I. Mellican is affiliated with Tropicana Products, the United Nations signed a declaration to eliminate Inc. in Bradenton, Florida, USA; and Tomas Walter is affiliated with the Institute of Nutrition and Food Technology vitamin A and iodine deficiencies and reduce rates at the University of Chile in Santiago, Chile. Please direct of iron-deficiency anemia by one-third by the year queries to the corresponding author: Haile Mehansho, The 2000. Progress has been made in raising awareness Procter & Gamble Co., Miami Valley Laboratories, 11810 and developing strategies [1, 3]. But except for the E. Miami River Road, Cincinnati, OH 45252, USA; email: improvement made with regard to iodine, hidden [email protected]. Mention of the names of firms and commercial products hunger remains a persistent problem. It is important does not imply endorsement by the United Nations to recognize that single micronutrient deficiencies University. don’t occur in isolation. Millions of people worldwide

Food and Nutrition Bulletin, vol. 24, no. 4 (supplement) © 2003, The United Nations University. S111 S112 H. Mehansho et al. suffer from deficiencies of multiple micronutrients at the adverse effects of micronutrient malnutrition. All the same time. In addition, iron, vitamin A, and iodine of these elements are potential barriers to the success have an overlapping impact on growth, development, of a micronutrient-fortification program. They should performance, and health (table 1 [4, 5]). not be only identified but also addressed during the We, in the private sector, have recognized that different stages of the fortification program. We have eradication of micronutrient malnutrition is an unmet used the “Sustainable Food Fortification Program” consumer need. Thus, producing and marketing multi- in developing a multiple-micronutrient fortification ple-micronutrient-fortified (iron, iodine, and vitamin technology called GrowthPlus®. The GrowthPlus/ A) products will play an important role in improving CreciPlus® technology has been used to formulate a people’s health, self-esteem, and, ultimately, perform- powder fruit drink, which was marketed in Venezuela as ance. However, there are several challenges in manufac- NutriStar®, and earlier test marketed in the Philippines turing and marketing products with meaningful levels as NutriDelight.® of bioavailable and stable iron, iodine, and vitamin A without altering the accepted appearance and taste of the finally consumed product [6–8]. How do we Establishing strategic alliance with the successfully produce and market multiple-micronu- public sector trient-fortified products that will have a meaningful impact on the target population? How do we develop We recognized that in the private sector we don’t and implement an affordable and sustainable fortifica- have adequate capability to deliver a sustainable tion program? multiple-micronutrient fortification program by ourselves. Thus, it is critical that a strategic alliance is established among the major stakeholders [1, 7, 8]. Micronutrient fortification of foods As shown in figure 2, the major stakeholders include the scientific community, government, international During the last 15 years, The Procter & Gamble Co. agencies, non-government organizations (NGOs) and (P&G) has been working on developing micronutrient industry [8]. When it comes to improving the lives fortification technology and products that meet the of children and women through the eradication of need of a large segment of the population in developing micronutrient malnutrition, these stakeholders have countries. During these years, we have learned that a common mission and goal, which is the elimination fortifying foods with micronutrients is more than of micronutrient malnutrition. It is important to adding fortificants, putting them in a package, and recognize that each stakeholder brings unique and marketing them. Based on our experiences as well as complementary skills. Forging alliances between the learning from others, we have developed a model called public and the private sectors will not only benefit the “Sustainable Food Fortification Program,” the success parties involved, but more importantly will deliver a of which is dependent on the integration of multiple sustainable micronutrient-fortification program by key elements (fig. 1). Thus, for food fortification to leveraging each party’s strength. succeed, the model must include the following: (a) Our micronutrient fortification technology and the identification of deficiency among the target groups, development of fortified powder fruit drink is, in fact, (b) development of fortification technology/products to meet the need, (c) evaluation of the product’s impact on alleviating the deficiencies, (d) manufacturing and distribution of the products, and (e) education of Education, so consumers about the benefits of fortified products and marketing

marketing cial, Strategy/approach TABLE 1. Consequences of iron, vitamin A, and iodine deficiencies Production, distribution, Iron Vitamin A Iodine Efficacy evaluation of fortified products deficiency deficiency deficiency

Growth ↓ ↓ ↔ Development of fortification Mental ability ↓ ↔ ↓ Strategy/approach technology/product Strength ↓ ↔ ↓ Mortality/morbidity ↑ ↑ ↔ Identification of deficiencies Economic develop- ↓ ↓ ↓ ment Sources: Scrimshaw [4], Underwood [5]. FIG. 1. Sustainable micronutrient fortification program Legend: ↓ decrease, ↑ increase, ↔ no change model Multiple-micronutrient fortification technology development S113

composition in the fortified powder drink and the clinical studies conducted in Tanzania [9, 10] are all Universities Nonprofit and research international an outcome of this public-private partnership. centers organizations Micronutrient fortification technology Target development population It has been more than four decades since food fortification has been recommended as one of the preferred long-term approaches in eradicating Government Industry nutrition deficiencies. However, its success, particularly agencies in developing countries, has been very limited. One of the major challenges has been lack of affordable and easy-to-use fortification technology [6–8]. During fortification, we are bringing a vehicle (food or FIG 2. Micronutrient fortification strategy: Public-private beverage) and the fortificants (vitamin or mineral partnership [8] sources) together. Because these are chemical moieties with functional groups, there is an interaction. It is this an outcome of public-private partnership that has interaction that causes the development of undesirable been ongoing for the last 10 years (fig. 3). It began taste (e.g., metallic aftertaste, rancidity), unacceptable with Dr. Michael Latham’s visit to P&G’s Miami Valley appearance, poor stability, and significantly reduced Laboratories Technical Center in Cincinnati to give a bioavailability [6–15]. seminar on micronutrient malnutrition. This initial To find solutions, we have evaluated the chemical partnership between Cornell University (Ithaca, New properties of different micronutrients (particularly York) and P&G (Cincinnati, Ohio) further grew with iron, iodine, and vitamin A) that are used commonly in the addition of the United Nations Children’s Fund food fortification. With iron fortification the challenges (UNICEF, New York), Micronutrient Initiative (MI, include metallic aftertaste, off-color, off-flavor, vitamin/ Ottawa, Canada), Tanzania Food & Nutrition Center flavor degradation, and poor bioavailability [6–8, (TFNC; Dar es Salaam, Tanzania), The University of 11–18]. These undesirable attributes are reflections Chile (Santiago, Chile), and the Nutrition Center of the of the chemical properties of iron. As a member of Philippines (NCP, Manila, Philippines). The nutrient the transition elements, iron is known to undergo

Univ. UNICEF Chile Nutri Gov’t Cornell Star agencies UNICEF NCP P&G Pediatric assoc. Cornell MI • Production UNICEF Univ. • Distribution P&G Chile • Education Cornell MI • Philippines Clinical studies (1999–2000) P&G (1995–present) Cornell UNICEF

(GrowthPlus) P&G technology Dr. Michael (1993–1995) Latham Beginning of partnership Seminar (1993) (1993) Clinical Product & Idea Technology study education

FIG. 3. Public-private partnership: “The fortified powder story” S114 H. Mehansho et al. an oxidation-reduction reaction. The challenge with “unlock” stage, the iron delivered via the GrowthPlus® delivering both vitamin A and iodine is linked mainly technology is released (becoming bioavailable) follow- to stability. Both nutrients have poor stability during ing the ingestion of the product. This has been demon- processing, storage, and cooking. Because of its multiple strated through repeated clinical studies (8–10, 15). double bonds, vitamin A is sensitive to light and oxygen [12]. On the other hand, iodine undergoes oxidation- reduction; thus, it is easily lost (escapes as iodine gas) Technology evaluation when exposed to excess moisture and temperature [13]. Further complicating the matter is that the degradation The effectiveness of the GrowthPlus® technology in of vitamin A and iodine is accelerated by the presence keeping the iron sources (ferrous bis-glycinate and of bioavailable iron as a fortificant [13]. ferrous fumarate) stable has been tested by formulating The challenges in overcoming these multiple difficul- various prototypes. They include water, chocolate milk, ties of delivering bioavailable/stable multiple micronu- and baby cereal. Fortification with iron that contains trients via a single vehicle were addressed by developing multiple micronutrients was done with and without a fortification technology called “GrowthPlus.®” This the GrowthPlus® technology. The results (not shown unique technology delivers better-absorbed and uti- here because the color changes cannot depicted in black lized iron, vitamin A, and iodine (plus other vitamins and white) demonstrated that in the absence of iron and minerals) without compromising taste, color, and fortification, the water, chocolate milk, and baby cereal product and vitamin stability. This was accomplished containing banana were clear, brown, and off-white, by understanding and analyzing the factors that influ- respectively; however, addition of iron (without using ence the reactivity, stability, and bioavailability of the the GrowthPlus® technology) caused the water to be micronutrients in a food/beverage-based delivery rusty, the chocolate milk to become brownish-gray, system. Based on the chemical properties of the three and the baby cereal to turn green. In contrast, when micronutrients (iron, vitamin A, and iodine), a deliv- the fortification of those same prototypes with the ery-system model called “Lock-Unlock” was developed. same iron source was delivered via the GrowthPlus® Thus, during the “lock” stage the nutrients remain technology, the development of off-color was stable (unreactive) during manufacturing/process, completely prevented. storage, and consumption of the fortified product by delivering them via chelation/reduction and/or encap- sulation approaches. The stabilization of iron via the Product formulation GrowthPlus® technology is shown in figure 4. Chela- tion was used to prevent the metallic aftertaste usually The success of any fortification program is dependent associated with mineral fortification. The iron-medi- on identifying the right vehicle(s) and using a fortifica- ated off-color development, which is the result of either tion technology that delivers the critical micronutrients iron oxidation from ferrous to ferric or its interaction without compromising bioavailability, stability, taste, with the vehicle components (e.g., polyphenols), was and appearance of the finally consumed product prevented by creating an environment that keeps iron [6–8]. Thus, the multiple micronutrients delivered in the ferrous form. This is accomplished by optimizing via the GrowthPlus® technology must be formulated both the pH and level of reducing agents by which the into products that are commonly consumed by target iron remains to stay in the ferrous form. During the groups. Data obtained from market research surveys

H H O H H O O O N N H C H C H H C Fe2+ C Fe3+ C C H H C N H C N H O O H H H H O O

• Poor solubility • Off-color development • Poor bioavailability • Degradation of vitamins

FIG. 4. Stabilization of iron by the GrowthPlus® Technology Multiple-micronutrient fortification technology development S115 showed that fruit-flavored drinks are not only well liked households. The overall acceptance of the fortified by the target groups but also commonly consumed glo- powder drink with the GrowthPlus® was compared with bally (Compton DB, personal communication, 1998). a placebo (product with the same appearance and taste P&G developed the fortified powder fruit drink but without multiple-micronutrient fortification). The called NutriStar® by combining the GrowthPlus® subjects were asked questions about the overall product fortification technology and a unique fruit juice flavor acceptance, flavor, and color during the 5-day use test. system (fig. 5). Thus, the fortified powder fruit drink The findings showed the multiple-micronutrients consisted primarily of sweeteners, thickeners, clouds, (including iron, iodine, vitamin A) delivered via acidulent, natural fruit flavors, and GrowthPlus® GrowthPlus® fortification technology had no significant (iron containing multiple-micronutrients). It is effect on the flavor, color, and overall acceptance of the important to recognize that the nutrition formula finally consumed fruit drink (table 2). of the fortified powder fruit drink was developed to fill the nutrition gap in developing countries [19, 20]. The amount delivered (per single serving) through a Nutrient stability evaluation fortified product is dependent on the regulatory laws of the country and the prevalence of the micronutrient The fortified powder drink contains three minerals deficiency. Hence, a single serving of the fortified (iron, zinc, and iodine) and eight vitamins (vitamin A, powder fruit drink is usually formulated to deliver (in vitamin E, vitamin C, niacin, B6, B2, folic acid, and B12). percentage of US recommended dietary allowance) 20– How stable are these multiple micronutrients during 30% of iron, 15–35% of vitamin A, 25–30% of iodine, the shelf life of the product? With iron and zinc, stabil- 25% of zinc, 100% of vitamin C, and 15–25% of B ity is not an issue; what is added will be there. However, vitamins (folic acid, B12, B6, B2, and niacin). During the with iodine and vitamins (such as vitamin A), poor last 6 years, the product attributes (taste, appearance, stability, and bioavailability) of the fortified powder TABLE 2. Effect of GrowthPlus® on the acceptance of forti- fruit drink/NutriStar® have been evaluated prior to its fied powder fruit drink introduction into the market place. Fortified Nonfortified powder fruit powder fruit Parameters drink drink Product acceptance evaluation Overall ratinga 44 45 Attribute ratinga For the fortified product to have an impact in combating Orange flavor 43 46 micronutrient malnutrition, it first has to be consumed Aftertaste 40 44 by the target groups. To be consumed, however, the Color 44 48 addition of the fortificants (premix) should not change the appearance and taste of the product that is finally a. Ratings used a five-point scale (excellent, very good, good, fair, poor). Average ratings are calculated using weights as follows: consumed [11]. Thus, the first evaluation work was on (((Nex×100)+(Nvg×75)+(Ngd×50)+(Nfr×25))/Ntotal ) × 100 the sensory attributes of the finally consumed beverage, There is no significant difference between the fortified and the non- conducted via a 5-day home-use test among Filipino fortified powder beverage at p < .05

Fe, I, Zn 25 Vitamin A, niacin 20

Folic acid, B2 30

B6, B12, E 25 Vitamin C 100

FIG. 5. Fortified powder fruit drink/NutriStar®: (Nutrient composition/serving in %Venezuelan RDA) S116 H. Mehansho et al. stability is a serious problem. The stability of the vita- Bioavailability evaluation mins and minerals in the fortified powder fruit drink and the finally consumed reconstituted beverage was Most of the vitamins and iodine have adequate evaluated as a function of storage time. bioavailability as long as they are stable [21, 22]. The fortified powder fruit drink was packaged in a However, for minerals such as iron, their bioavailability sachet and stored in temperature-controlled rooms for is dependent on the source vehicle and the diet up to 1 year. As shown in table 3, all nutrients (added as consumed with it [6–8, 11, 16, 17]. Thus, once good- GrowthPlus®) including vitamin C, iodine, folic acid, tasting multiple-micronutrient-fortified products and B12 were stable after 1 year of storage at ambient are developed, it is critical that the bioavailability of temperature. The percent recovery ranged from 91.5% the iron is evaluated. The bioavailability of the iron for vitamin A to 113.9% for vitamin B6. It is important from the fortified powder fruit drink was determined to note also all values after 1 year of storage are above by using a double isotope labeling technique [16]. the targeted value (claimed values in the product). The study was done in collaboration with Dr. Tomas The fortified powder fruit drink is consumed Walter at the University of Chile. The treatments after being reconstituted with added water. What included the following: (a) fortified powder beverage is the stability of the nutrients in the reconstituted alone and (b) fortified powder beverage with rice. fortified powder fruit drink? The stability of the As shown in figure 6, the absorption values were major micronutrients (namely, vitamin A, vitamin C, normalized to that of a standard ferrous ascorbate riboflavin, and iodine) that are known to be sensitive (40% absorption). Furthermore, comparison was made to degradation in aqueous delivery systems was further with the other common dietary iron sources [16–18]. evaluated after the fortified powder fruit drink was When the reconstituted fortified powder fruit drink reconstituted. The results obtained after 1-hr and 24- was consumed alone, 23.4% of the iron was absorbed. hr storage at ambient temperature are shown in table This is comparable to that absorbed from meat, and 4. As expected, there was no change in the iron level. about five times that of milk fortified with ferrous Riboflavin, vitamin C, and vitamin A showed little or sulfate [16–18]. However, when consumed with rice, no degradation. However, the level of iodine in the the percent of iron absorbed was reduced by about reconstituted beverage was decreased by 21% and half (23.4% vs 10.7%). Although there is a significant 16% after 1 hour and 24 hours, respectively. Taking the target value into consideration, the reconstituted Table 4. Nutrient stability from a reconstituted fortified fortified powder drink delivers the iodine level claimed powder fruit drinka on the package. Results in the literature have shown Time 0 1 h 24 h that vitamins and iodine are sensitive to degradation, particularly in aqueous delivery systems [12–14]. Vitamin A (IU) 499.5 494.5 (99%) 479.5 (96%) Furthermore, such degradation is further accelerated Vitamin C (mg) 91.8 86.5 (94%) 76.9 (84%) by the presence of divalent ions, particularly iron and Iron (mg) 4.5 4.5 (100%) 4.6 (102%) copper. The stability observed in both the powder and Riboflavin (mg) 0.3 0.32 (107%) 0.38 (127%) beverage forms is due to the ability of the GrowthPlus® Iodine (µg) 47.2 37.3 (79%) 39.8 (84%) technology to keep the multiple micronutrients in a a. Analysis was done on fortified powder drink beverage prepared by stable and/or non-reactive form. dissolving 25 g powder fruit drink in 180 ml water.

Table 3. Nutrient stability in fortified powder fruit drink (in 100 g)a % recovery after % target value Nutrients Initial 12 months 12 months after 12 months Iron (mg) 54.3 54.8 100.9 140.9 Vitamin A (IU) 10963 10030 91.5 139.3 Iodine (µg) 590 582 98.6 143.1 Vitamin C (mg) 899 988 110.0 148.2 Zinc (mg) 49.6 49.6 100.0 118.9 Folic acid (µg) 797 873 109.5 132.1

Vitamin B12 (µg) 8.6 8.8 102.3 157.1 Vitamin B6 (mg) 6.5 7.4 113.9 132.1 Vitamin B2 (mg) 6.2 5.9 95.2 115.7 Niacin (mg) 33.2 32.0 96.4 115.1 Vitamin E (mg) 31.3 31.9 101.9 102.9 a. The samples were stored in a temperature-controlled room at 70ºF. Multiple-micronutrient fortification technology development S117

25 evaluated by randomized, double-blind, placebo- controlled clinical studies in schoolchildren and 20 pregnant and lactating women [8–10, 23, 24].

15 Production and distribution of fortified 10 products

Iron absorption (%) 5 Currently, many of the multiple micronutrient for- tification programs and research focus mainly on 0 surveys, development of fortified product prototypes, ® Rice Corn Fish and evaluation (stability, bioavailability, and efficacy). + rice Meat ® Wheat Spinach NutriStar However, the impact of any fortified product in alle- Chocolate milk NutriStar viating micronutrient malnutrition will occur only Ferrous sulfate in milk when the fortified product is produced, distributed in the marketplace, and consumed by the target groups. We believe this step is the least recognized bottleneck FIG. 6. Iron absorption from fortified powder fruit drink in the success of any fortification program. This final (NutriStar®) and other iron sources stage of the sustainable fortification program model includes production/scaling up, packaging, quality reduction of iron absorption by rice, the bioavailability control, and distribution. Here, the private sector is value is still comparable to that of iron from fish, which the major player. is accepted as a good source of bioavailable iron. Our GrowthPlus® technology-based multiple-micro- nutrient-fortification program has already reached a milestone. The fortification technology developed, Product efficacy evaluation the clinical data generated, and the public-private partnership resources invested have been taken to a Conducting an effectiveness trial among the target higher level, which includes scaling up, manufactur- groups, particularly when it is done before the ing, distribution, and marketing. The outcome, which product is nationally distributed is important for the is a fortified powder fruit drink named NutriStar,® has success and sustainability of a fortification program. been in production and distribution for more than a It has practical implications, because it measures the year in Venezuela. impact after repeated consumption of the fortified NutriStar® is manufactured by following a written product on improving nutrition status. The multiple- procedure and good manufacturing practices (GMP). micronutrient-fortified powder fruit drink has been A quality assurance & control (QA&C) program, which

TABLE 5. Key elements in quality assurance program » Finished product specification and description: Quality has to be built into the fortified product. Thus, before the prod- uct is manufactured, both the specification and description of the finished product must be established. Subsequently, products are manufactured by following written procedures known as standard operating procedures (SOP). Based on the claim to be made, the type and level of the minerals and the form and source of fortificants are specified. » Starting materials: The quality of the starting materials for both the product and packaging play an important role in the quality of the final mineral-fortified product. The fortificants should meet established specifications. In addition, purchases are made from approved suppliers that follow good manufacturing practices (GMPs). Once received, the fortificants are recorded and stored as specified under appropriate conditions. » Production and packaging: The quality of manufacturing and packaging determines the quality of the final product. The product is made by following GMPs. The fortificants are added into the product formulation by using specified procedures and equipment. The amount of each fortificant added is recorded. Finally, the amount in the finished product is verified by using a validated analytical method. » Release of finished product: The product released for distribution should meet all finished product specifications. This includes the safety of the product and the level of the nutrients claimed. There should be a system for (a) monitoring and correcting deviations from specification and (b) identifying the product in case there is a complaint from the consumer. » Documentation: Accurate recording is essential for (a) identifying and correcting deviations, (b) recalling a product with serious problems, and (c) making an improvement on the quality of the product. » Training: All personnel involved in the development, manufacturing, packaging, and storing of the fortified product should be trained in quality assurance. Source: Mehansho and Mannar [7]. S118 H. Mehansho et al. includes the major key elements, has been already built symposium, and an interactive/integrated educational into the production of the fortified powder drink program called BIDA. Currently, the micronutrient (table 5). The objective of the QA&C program is to educational program (BIDA) is widely distributed and deliver a safe fortified product with nutrient levels utilized in the Philippines (Florentino Solon, personal as claimed on the package during the shelf life of the communication, 2002). product. Note that the packaged NutriStar® is released for distribution only after meeting the finished prod- uct specification (i.e., safety and nutrient levels). The Conclusion acceptance and consumption of NutriStar® by the Venezuelan population is meeting P&G’s expectations. Eradication of micronutrient malnutrition, even Consumption data for 12 months show that about 120 though it seems formidable, can be accomplished. million servings of NutriStar® have been sold. This Based on our and others’ experience, an effective and translates to a production and consumption of 1,080 sustainable micronutrient-fortification program will metric tons of NutriStar® in 1 year. require a holistic and integrated program. The program should address the multiple barriers identified in the “Sustainable Food Fortification Model” and leverage Education and social marketing the untapped expertise and strength of the public- private partnership based on a win-win situation. The Both education and raised awareness are key to the development of GrowthPlus® fortification technology success of a sustainable micronutrient-fortification and the fortified powder fruit drink known as NutriStar® program. The objective of such a program is to provide in Venezuela has been accomplished by following the simple, friendly, and effective messages to profession- “Sustainable Food Fortification Model” and utilizing als (e.g., doctors, nutritionists, health workers), poli- the resources and expertise of the public-private cymakers, and the target population on the prevalence partnership. The highlights include the following: and consequences of micronutrient malnutrition and (a) fortification with meaningful levels of the most the benefits of the micronutrient-fortified products. deficient micronutrients without altering the taste of the Public-private partnership is critical for the education finally consumed beverage by using the GrowthPlus® program to be successful. This can only be accom- technology; (b) proving that repeated consumption of plished by leveraging the expertise and resources of the the product improves the micronutrient status of the stakeholders from both the private and public sectors. target population; (c) manufacturing by following In the Philippines during the test market of GMP and QA&C program, and (d) distributing and NutriDelight, a strategic alliance between the public marketing the product. Finally, after several years of sector (UNICEF, Nutrition Center of the Philippines, fruitful, collaborative work, we believe that we have National Nutrition Council, Ministry of Health and reached the stage where this innovative approach to Ministry of Education) and P&G was established. controlling prevalent micronutrient deficiencies can The outcomes of this particular alliance include be successfully used in the marketplace. micronutrient education via television, a micronutrient

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