The Guidebook

Nutritional Anemia
 The Guidebook
Nutritional
Anemia
Edited by
Jane Badham
JB Consultancy, Johannesburg, South Africa

Michael B. Zimmermann
Swiss Federal Institute of Technology, Zurich, Switzerland

Klaus Kraemer
SIGHT AND LIFE, Basel, Switzerland

SIGHT AND LIFE

Press
4

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 Preface 5

PREFACE TO THE NUTRITIONAL ANEMIA GUIDEBOOK

Two hundred million children under the age of five, women of childbearing age), food fortification, dietary
mostly living in sub-Saharan Africa and South Asia, fail diversification and education, as well as control of dis-
to reach their full cognitive, motor and social-emotional eases such as malaria, worm infections, and other chronic
potential because of micronutrient deficiencies and in- endemic infections. While each of these can help reduce
adequate stimulation. These children will probably fail at the burden of anemia, none is capable of doing the job on
school, fail to achieve their income potential, and remain its own.
trapped in the poverty cycle. A tragic reality.
The purpose of this Guidebook is to give you, the reader,
In May 2002, the General Assembly of the United a comprehensive summary of the critical issues from
Nations re-emphasized that control of nutritional anemia prevalence data and statistics, to economics, through to
should be one of the global development goals to be the diagnosis, functional consequences and background
achieved in the early years of this new millennium. information on each of the micronutrients believed to be
Sadly, there has been little documented progress in the directly or indirectly involved in anemia.
global fight against anemia and WHO data shows that
818 million children under the age of five and women are This Guidebook does not contain all the information or
affected by this public health problem, mainly in devel- give all the answers, but its intention is to give an over-
oping countries. About one million of them die every view of the latest scientific thinking and the challenges
year. This shows the magnitude of the problem and high- facing the world as we go forward in planning, imple-
lights the urgent need for action. menting and monitoring interventions to address what is
undoubtedly the biggest nutritional problem that the
SIGHT AND LIFE has always championed interventions world currently faces.
to address micronutrient malnutrition, including iron
deficiency and nutritional anemias, and, as a result, has We trust that the information, knowledge and insights
published a book, Nutritional Anemia. In a single vol- that you will gain from this Guidebook, will enable you
ume it highlights for the first time all the critical factors to become a part of the solution and actively engage in
in addressing nutritional anemia, with contributions from advocacy, programming or on-going research to make a
leading scientists in their respective fields. Each chapter difference.
addresses a specific issue in great detail. It has become
clear that the effective control of anemia requires inte-
grated solutions that are tailored to the particular needs
and opportunities in each country. Components of any Jane Badham
such an approach include micronutrient supplementation Michael B. Zimmermann
of the most vulnerable groups (particularly children and Klaus Kraemer
6 Editors

ABOUT THE EDITORS

JANE BADHAM KLAUS KRAEMER

Jane is a dietitian with an MSc in Nutrition from North Klaus obtained his doctorate in nutritional sciences
West University, Potchefstroom Campus, South Africa. from the University of Giessen, Germany. He is
She is currently the Managing Director of JB Con- currently Secretary General of SIGHT AND LIFE, a
sultancy, a health communication and strategy company humanitarian initiative of DSM, involved in a number
that advises the pharmaceutical industry, food industry, of activities to ensure a sustainable and significant
humanitarian organizations, and the media. Jane is also improvement in human nutrition, health, and wellbeing.
the CEO of the 5-a-Day for Better Health TRUST in Klaus has over 20 years of research experience in the
South Africa that promotes the increased consumption of field of health and safety of vitamins, minerals, carote-
vegetables and fruit. She serves on the Board of noids, and nutraceuticals. He serves on several profes-
Directors of the International Fruit and Vegetable sional societies dedicated to nutrition, vitamins, and anti-
Alliance (IFAVA) as well as being part of the organizing oxidants, has published many scientific articles, and
team of the African Nutrition Leadership Program coedited five books.
(ANLP).

MICHAEL ZIMMERMANN
Michael obtained his MD from Vanderbilt University
School of Medicine and his MSc in Nutritional Science
at the University of California in Berkeley, both in the
USA. He is currently Senior Scientist in the Laboratory
for Human Nutrition at the Swiss Federal Institute
of Technology in Zurich (ETH), visiting Professor at
Wageningen University in the Netherlands, and holds the
Unilever Endowed Chair in International Health and
Micronutrients. Michael’s research focus is nutrition and
metabolism, including the effects of micronutrient defi-
ciencies on thyroid function, and he has won many
awards for his work.
 Contributors 7

CONTRIBUTORS TO THE NUTRITIONAL ANEMIA BOOK

HAROLD ALDERMAN JÜRGEN ERHARDT

Africa Region of the World Bank, Washington, DC, University of Indonesia, SEAMEO-TROPMED,
USA; halderman@worldbank.org Jakarta, Indonesia; erhardtj@gmx.de

JANE BADHAM ALISON D. GERNAND

JB Consultancy, Health Communication and Strategy Bloomberg School of Public Health, Johns Hopkins
Consultants, Johannesburg, South Africa; University, Baltimore, USA; agernand@jhsph.edu
jbconsultancy@mweb.co.za
GARY R. GLEASON
HANS-KONRAD BIESALSKI Friedman School of Nutrition Science and Policy,
Institute for Biological Chemistry and Nutrition at the Tufts University, Boston, USA;
University of Hohenheim, Hohenheim, Germany; ggleason@inffoundation.org
biesal@uni-hohenheim.de
EVA HERTRAMPF DÍAZ
MARTIN BLOEM Institute of Nutrition and Food Technology (INTA),
World Food Programme (WFP), Rome, Italy; University of Chile, Santiago, Chile; ehertram@inta.cl
martin.bloem@wfp.org
SUSAN HORTON
TOMMASO CAVALLI-SFORZA Wilfrid Laurier University, Waterloo, Canada;
Nutrition and Food Safety, WHO Regional Office for shorton@wlu.ca
the Western Pacific, Manila, Philippines;
cavalli-sforzat@wpro.who.int RICHARD HURRELL
Institute of Food Science and Nutrition, Swiss Federal
MARY COGSWELL Institute of Technology (ETH), Zurich, Switzerland;
Division of Nutrition and Physical Activity, Centers for richard.hurrell@ilw.agrl.ethz.ch
Disease Control and Prevention, Atlanta; USA
ALAN JACKSON
IAN DARNTON-HILL Institute of Human Nutrition, University of Southamp-
Nutrition Section, UNICEF, New York, USA; ton, Southampton, UK; aaj@soton.ac.uk
idarntonhill@unicef.org
AFAF KAMAL-ELDIN
OMAR DARY Department of Food Science, Swedish University of
A2Z Project, Academy for Educational Development, Agricultural Sciences, Uppsala, Sweden;
Washington, DC, USA; odary@aed.org afaf.kamal-eldin@lmv.slu.se

BRUNO DE BENOIST KLAUS KRAEMER

World Health Organization (WHO), Geneva, Switzer- SIGHT AND LIFE, Basel, Switzerland;
land; debenoistb@who.int klaus.kraemer@sightandlife.org

SASKIA DE PEE SEAN LYNCH

World Food Programme (WFP), Rome, Italy; Eastern Virginia Medical School, Norfolk, USA;
sdepee@compuserve.com srlynch@visi.net

INES EGLI M.G. VENKATESH MANNAR

Institute of Food Science and Nutrition, Swiss Federal The Micronutrient Initiative, Ottawa, Canada; vman-
Institute of Technology (ETH), Zurich, Switzerland; nar@micronutrient.org
ines.egli@ilw.agrl.ethz.ch
8 Contributors

ERIN MCLEAN ELISABETH STOECKLIN

World Health Organization (WHO), Geneva, Switzer- R & D Human Nutrition and Health, DSM Nutritional
land; mcleane@who.int Products Ltd, Kaiseraugst, Switzerland;
elisabeth.stoeklin@dsm.com
REGINA MOENCH-PFANNER
Global Alliance for Improved Nutrition (GAIN), BRIAN THOMPSON
Geneva, Switzerland; rmoenchpfanner@gaingeneva.org Food and Agriculture Organization (FAO), Rome, Italy;
brian.thompson@fao.org
CHRISTINE A. NORTHROP-CLEWES
Northern Ireland Centre for Food and Health, University of DAVID THURNHAM
Ulster, Coleraine, UK; c.clewes@ulster.ac.uk Northern Ireland Centre for Food and Health,
University of Ulster, Coleraine, UK;
MANUEL OLIVARES di.thurnham@ulster.ac.uk
Institute of Nutrition and Food Technology (INTA),
University of Chile, Santiago, Chile; molivare@inta.cl MELODY C. TONDEUR
Division of Gastroenterology, Hepatology and Nutri-
NEAL PARAGAS tion, Hospital for Sick Children, Toronto, Canada,
Institute of Human Nutrition, Columbia University, melody.tondeur@sickkids.ca
New York, USA; np2014@columbia.edu
MARET G. TRABER
KLAUS SCHÜMANN Linus Pauling Institute & Department of Nutrition and
Technical University of Munich, Freising, Germany; Exercise Sciences, Oregon State University, Corvallis,
kschuemann@schuemann-muc.de USA; maret.traber@oregonstate.edu

JOHN M. SCOTT RICARDO UAUY

School of Biochemistry & Immunology, Trinity College Institute of Nutrition and Food Technology (INTA),
Dublin, Dublin, Ireland; jscott@tcd.ie University of Chile, Santiago, Chile;
ricardo.uauy@lshtm.ac.uk
NEVIN SCRIMSHAW
International Nutrition Foundation, Boston, USA; KEITH P. WEST
nevin@cyperportal.net Bloomberg School of Public Health, Johns Hopkins
University, Baltimore, USA; kwest@jhsph.edu
RICHARD SEMBA
School of Medicine, Johns Hopkins University, DANIEL WOJDYLA
Baltimore, USA; rdsemba@jhmi.edu Escuela de Estadistica, Universidad Nacional de
Rosario, Argentina
NOEL SOLOMONS
Center for Studies of Sensory Impairment, Aging and MICHAEL ZIMMERMANN
Metabolism (CeSSIAM), Guatemala City, Guatemala; Laboratory for Human Nutrition, Swiss Federal
cessiam@guate.net.gt Institute of Technology (ETH), Zurich, Switzerland;
michael.zimmermann@ilw.agrl.ethz.ch
ALFRED SOMMER
Bloomberg School of Public Health, Johns STANLEY ZLOTKIN
Hopkins University, Baltimore, USA; Departments of Paediatrics and Nutritional Sciences and
asommer@jhsph.edu Public Health Sciences, University of Toronto, Canada;
stanley.zlotkin@sickkids.ca
 Contents 9

CONTENTS

Preface 5

About the editors 6

Contributors 7

Contents 9

CHAPTER 1 Worldwide prevalence of anemia in preschool aged children,

pregnant women and non-pregnant women of reproductive age
Erin McLean, Ines Egli, Mary Cogswell, Bruno de Benoist
and Daniel Wojdyla 11

CHAPTER 2 The case for urgent action to address nutritional anemia

M.G. Venkatesh Mannar 12

CHAPTER 3 The economics of addressing nutritional anemia

Harold Alderman and Susan Horton 13

CHAPTER 4 Diagnosis of nutritional anemia – laboratory assessment of iron status

Hans-Konrad Biesalski and Jürgen G. Erhardt 15

CHAPTER 5 An overview of the functional significance of iron deficiency

Gary Gleason and Nevin S. Scrimshaw 16

CHAPTER 6 Iron metabolism

Sean Lynch 17

CHAPTER 7 Optimizing the bioavailability of iron compounds for food fortification

Richard Hurrell and Ines Egli 19

CHAPTER 8 Copper and zinc interactions in anemia: a public health perspective

Manuel Olivares and Eva Hertrampf and Ricardo Uauy 21

CHAPTER 9 Nutritional anemia: B-vitamins

John M. Scott 22

CHAPTER 10 Vitamin A in nutritional anemia

Keith P. West, Jr., Alison D. Gernand and Alfred Sommer 24

CHAPTER 11 Oxidative stress and vitamin E in anemia

Maret G. Traber and Afaf Kamal-Eldin 26

CHAPTER 12 Selenium
Richard D. Semba 27

CHAPTER 13 Interactions between iron and vitamin A, riboflavin, copper,

and zinc in the etiology of anemia
Michael B. Zimmermann 28
10 Contents

CHAPTER 14 Anemia in severe undernutrition (malnutrition)

Alan A. Jackson 29

CHAPTER 15 Infection and the etiology of anemia

David I. Thurnham and Christine A. Northrop-Clewes 31

CHAPTER 16 Making programs for controlling anemia more successful

Saskia de Pee, Martin W. Bloem, Regina Moench-Pfanner
and Richard D. Semba 33

CHAPTER 17 Successful approaches: Sprinkles

Stanley H. Zlotkin and Melody Tondeur 36

CHAPTER 18 Safety of interventions to reduce nutritional anemias

Klaus Schümann and Noel W. Solomons 37

CHAPTER 19 The importance and limitations of food fortification for the

management of nutritional anemias
Omar Dary 42

CHAPTER 20 Food-based approaches for combating iron deficiency

Brian Thompson 43

CHAPTER 21 Global perspectives: accelerating progress on preventing

and controlling nutritional anemia
Ian Darnton-Hill, Neal Paragas and Tommaso Cavalli-Sforza 45

CHAPTER 22 Conclusions and research agenda

Klaus Kraemer, Elisabeth Stoecklin and Jane Badham 48
 1 · Worldwide prevalence of anemia 11

1 • Globally 818 million women (both pregnant and

non-pregnant) and young children suffer from anemia
and over half of these, approximately 520 million,
live in Asia.
WORLDWIDE PREVALENCE OF ANEMIA IN • The highest prevalence for all 3 groups is in Africa,
PRESCHOOL AGED CHILDREN, PREGNANT but the greatest number of people affected are in Asia.
WOMEN AND NON-PREGNANT WOMEN OF • In Asia 58% of preschool aged children, 56.1% of
REPRODUCTIVE AGE pregnant women and 68% of non-pregnant women
Erin McLean, Mary Cogswell, Ines Egli, are anemic.
Daniel Wojdyla and Bruno de Benoist • More than half of the world’s population of preschool
aged children and pregnant women reside in countries
where anemia is a severe public health problem.
What is the problem and what do we know so far? • Countries with a severe public health problem were
Anemia is a widespread public health problem associated grouped in Africa, Asia and Latin America and the
with an increased risk of morbidity and mortality, espe- Caribbean.
cially in pregnant women and young children. It is a disease • Africa and Asia are the most affected and as these
with multiple causes, both nutritional (vitamin and mineral regions are also the poorest, it may reflect the link
deficiencies) and non-nutritional (infection) that frequently between anemia and development.
co-occur. It is assumed that one of the most common con- • Compared to North America, anemia is three times
tributing factors is iron deficiency, and anemia resulting more prevalent in Europe and this may be due to
from iron deficiency is considered to be one of the top ten the fact that Europe includes countries with a range of
contributors to the global burden of disease. social and economic profiles or as a result of low cover-
age of data in Europe compared to North America or
The World Health Organization (WHO) has as one of its that in north America foods are widely fortified with
mandates to inform its Member States about the global iron and a high proportion of iron intake comes from
health situation. It was decided to update the global esti- fortified foods.
mates of anemia and provide a current picture of the situ-
ation, especially in high-risk groups. This was done by It has to be noted that these estimates are not quantita-
generating global and United Nations Regional estimates tively comparable to previous estimates as the method-
of anemia prevalence in preschool aged children, preg- ologies used are different. They do have some limitations
nant women and non-pregnant women of childbearing but, based on the best available information, they are a
age. Data was gathered between 1993 and 2005, using good starting point to track progress in the elimination of
the most recent nationally representative survey for a anemia.
country or from at least two surveys representative of the
countries first administrative boundary. When data was Based on these estimates, the magnitude of nutritional
not available for a country, the anemia prevalence was anemia or of iron deficiency anemia is difficult to assess
predicted based on regression equations using the coun- since most of the surveys used do not address the causes
try’s United Nations Human Development Index and of anemia and are solely restricted to the measurement of
health indicators from the World Health Statistics data- hemoglobin.
base. Coverage varied by UN Regions and was highest in
northern America, Asia and Africa while it was lower in What is the way forward?
Europe and Oceania. The estimates are based on the 192 Globally, almost half of all preschool aged children and
Member States of WHO, so represent 99.8% of the pregnant women and close to one third of non-pregnant
global population. women, suffer from anemia. As the estimates represent a
large segment of the population, they are likely to reflect
What do we know about global prevalence of anemia? the actual global prevalence of anemia within these popu-
• Global prevalence of anemia in preschool aged children lation groups. However, UN Regional estimates may be
is 47.4%. more accurate for some populations and some areas since
• Global prevalence of anemia in pregnant women is the coverage varies significantly within regions.
41.8%.
• Global prevalence of anemia in non-pregnant women Anemia is of greatest concern in children less than
is 30.2%. 2years of age since their rapid growth requires a high
12 2 · The case for urgent action to address nutritional anemia

intake of iron, which frequently is not covered by the • Africa and Asia are the most affected and as these
diet, especially in low-income countries. regions are also the poorest, it may reflect the link
between anemia and development.
In order to make full use of these prevalence data, infor- • Compared to North America, anemia is three times
mation on the cause of anemia should be collected in any more prevalent in Europe.
survey on anemia so that interventions for anemia control
can be better adapted to the local situation and therefore
be more effective.
2
What is the key message?
Anemia remains a significant public health concern.
These new estimates are likely to reflect the current situ- THE CASE FOR URGENT ACTION TO ADDRESS
ation and are a good starting point for tracking global NUTRITIONAL ANEMIA
progress. Future surveys need to include data on the Venkatesh Mannar
causes of anemia, as lack of this data impairs our ability
to correct this significant public health problem.
What is the problem and what do we know so far?
FACTS: The United Nations goal of reducing by one third the
• Preschool children are aged between 0–4.99 years, prevalence of anemia by 2010 is unlikely to be met.
non-pregnant women between 15 and 49.99 years and Nutritional anemia remains common in many countries
no age defined for pregnant women. of the world and its eradication through effective inter-
• Hemoglobin concentration cut-offs to define anemia ventions must be a priority for attention and action. Iron
as set by the WHO are 110 g/L for pre-school aged deficiency in early childhood has a significant, negative
children and pregnant women, and 120 g/L for non- effect on a child’s physical and intellectual development.
pregnant women. There has been an intensification of efforts in several
• The prevalence of anemia as a public health problem countries and this gives encouragement that interven-
is categorized by the WHO as follows: tions can be successful and sustainable. It is recognized,
• <5% – no problem however, that there are no easy solutions and effective
• 5–19% – mild public health problem interventions have their drawbacks, but it would seem
• 20–39% – moderate public health problem that lack of priority of eradicating nutritional anemia by
• >40% – severe public health problem policy makers is the major concern. There is an urgency
• Global prevalence of anemia in preschool aged children to act.
is 47.4%
• Global prevalence of anemia in pregnant women is What has been achieved?
41.8% There are key developments that have occurred in the
• Global prevalence of anemia in non-pregnant women past 10 years:
is 30.2% • More technical consensus
• Globally 818 million women (both pregnant and non- • Better understanding of conditions needed for effec-
pregnant) and young children suffer from anemia and tive supplementation
over half of these, approximately 520 million, live in • Sufficient knowledge and experience (especially with
Asia. pregnant women) to design and implement effective
• The highest prevalence for all 3 groups is in Africa, programs
but the greatest number of people affected are in Asia. • Programmatic and technical guidelines for effective
• In Asia 58% of preschool aged children, 56.1% of programming
pregnant women and 68% of non-pregnant women • Better information on stable and bioavailable iron
are anemic. compounds
• More than half of the world’s population of preschool • Recognition by the food industry of the need for for-
aged children and pregnant women reside in countries tification
where anemia is a severe public health problem. • Feasibility of double salt fortification
• Countries with a severe public health problem were • Technology to fortify rice with iron and folic acid
grouped in Africa, Asia and Latin America and the • Increased successful work relating to improved varie-
Caribbean. ties of staple crops
 3 · The economics of addressing nutritional anemia 13

• Greater knowledge about the interface between iron • Interventions to address iron deficiency are one of the
status and infection. most cost effective public health interventions.
• The cost-benefits ratio for iron programs is estimated
What is the way forward? to be 200:1.
Concerns are that although iron supplementation has • Amongst a list of 17 possible development invest-
been shown to be effective in controlled experiments, ments, the returns of investing in micronutrient
supplementation in field settings does not seem to programs are second only to those of fighting
show a significant improvement in anemia prevalence. HIV/AIDS.
In addition, data to support large-scale food fortifica-
tion is still lacking and has not been systematically
documented.
It seems that progress will only be made if: 3
1. Key issues are addressed and consensus statements
developed
2. Bridges are built between science/technology and THE ECONOMICS OF ADDRESSING
those who deliver the services NUTRITIONAL ANEMIA
3. The field application of supplementation is strength- Harold Alderman and Susan Horton
ened
4. Universal fortification of staple foods with significant
levels of nutrients is globally recognized Why is economic assessment important?
5. Creative means of increasing the iron content of the The economic gains from addressing any micronutrient
diet are explored deficiency come from both cost reductions and from
6. Enhancing the iron absorption from diets is investigated enhanced productivity. They include lower mortality,
7. There is a better understanding of interactions be- reduced healthcare costs, reduced morbidity, improved
tween micronutrients and other dietary components productivity and intergenerational benefits through
and other causes of anemia improved health. In the case of iron deficiency anemia,
8. Social marketing and supporting behavioral change is economic assessment requires determining the costs of
encouraged iron deficiency in dollar terms in order to determine the
9. There is a combination of proper regulation and strong consequences in a unit of measurement that is common
and appropriate public education to other claims on public resources (both health interven-
10. A multi-intervention approach is accepted that in- tions and interventions outside the health arena). This
cludes adequate nutritional intake (supplementation, is in partial contrast to the calculation of a program’s
fortification, dietary modification, biofortification) effectiveness in terms of increases in life expectancy or
and reduction of concurrent infection disability-adjusted life years (DALYs).
11. There is more compelling advocacy at all levels,
forming of strategic alliances and commitment to It is also important to assess the economic impact of
action interventions in terms of cost and benefits. In making
12. There are global champions to push action forward. economic assessments, there are a number of important
issues that must be considered:
What is the key message? • There may be more than a single outcome for the
There is an urgent need for action but that action needs to intervention (e.g. an intervention in pregnant women
consider a number of factors if it is to be successful and may both reduce low birth weights and maternal
sustainable. mortality via changes in maternal hemoglobin);
• Some interventions affect not only anemia but also
FACTS: other health and economic outcomes (e.g. deworm-
• Iron deficiency could be preventing 40%-60% of ing can be effective in both improving hemoglobin
children in developing countries from growing to levels as well as absorption of vitamin A);
their full mental potential. • Measuring cost-effectiveness using the ultimate out-
• The WHO identifies iron deficiency as being come of interest (e.g. mortality) is usually too costly
amongst the ten most serious risks in countries with and time consuming and so often only proximate
a high infant mortality coupled with a high adult indicators (e.g. proportion anemic or hemoglobin)
mortality. are used;
14 3 · The economics of addressing nutritional anemia

• Cost-effectiveness varies with the scale of the pro- tions, estimated that the intervention could lead to an
gram (e.g. costs may decrease over time if there expected additional income of $29 for a cost of
are fixed costs that can be spread over larger pro- $1.70. Deworming has possibly been overlooked
grams); in importance and works synergistically with fortifi-
• There are distinctions between public and private costs cation and supplementation.
(e.g. the cost of a dollar of government revenues is • There are few studies that have shown the cost-effec-
generally more than a dollar to the economy). tiveness of home gardening and increased production
of small animals.
How are the economic benefits of addressing • Biofortification approaches are promising but
anemia assessed? involve extensive fixed costs for research, but with
There are two key approaches that are used: few, if any, incremental costs of operation over the
1. Calculation of the expected gains in economic terms general costs of producing a crop with increased iron
if a case of anemia were prevented. This approach is availability. Using a number of assumptions, the
useful for making comparisons of intervention costs. strategy could provide global total present value of
2. Estimation of the impact on GNP if anemia rates nutritional benefits of up to $694 million, giving a
could be reduced. This approach scales the individual cost-benefit ratio of 19 or an internal return of 29%.
gains and results in a stronger motivation for a
change in political will. What are the outcomes of economic assessments
that have been undertaken?
Results of economic benefits can either be reported in It is clear (see FACTS below) that anemia at all stages of
costs in terms of productivity; give sensitivity estimates; the lifecycle is associated with a significant health burden
or be reported in terms of DALYs, which are then con- and has a potentially large negative impact on productivity
verted into dollar terms. and hence also on income and GDP. The total loss per capi-
ta due to physical as well as cognitive losses, amounts to
Each approach has its advantages and limitations. It is billions annually and is considerable when compared to the
important to recognize that placing precise figures on modest costs of decreasing nutritional anemia.
economic value involves a range of assumptions and
requires the adaptation to a country’s specific context. What is the key message?
These approaches all measure different concepts and so Economic impact studies show that addressing nutritional
cannot be directly compared. anemia can have a significant impact on health burden,
productivity and income. Determining the overall eco-
What are the economic costs of reducing anemia? nomic impact (economic gain and cost-effectiveness) of
In terms of either the cost per DALY saved, or the cost- any intervention requires expert knowledge and must
benefit ratio calculated, iron fortification is one of the be based on the specifics of the program, the country and
most attractive public health interventions available. the desired outcome measurements.
• The cost of fortification per person per year is in the
range of $0.10 (US) to $1.00. FACTS:
• Home fortification is relatively new and holds con- • One study estimates that in developing countries one
siderable promise for some groups and the costs can fifth of perinatal mortality, and one tenth of maternal
be viewed as intermediate between fortification and mortality, is attributable to iron deficiency.
supplementation. • It is estimated that 1.5% of deaths worldwide are
• Supplementation costs per person are estimated in attributable to iron deficiency.
the range of $2.00–$5.00, noting, however, that • In terms of DALYs, anemia also accounts for 35 million
often reported costs do not fully cover personnel health life years lost (2.5% of global DALYs lost).
costs and that results of programs at scale have • Iron interventions in adults have shown increased
been disappointing. Operational research is needed productivity by around 5% in light manual labor and
to design programs which work cost-effectively in as high as 17% in heavy manual labor.
the field. • An Indonesian study shows effects on income of the
• Periodic deworming has been estimated in one study self employed of as much as 20% for men and 6% for
to cost US$3.50 to increase school participation by women.
one child year. A combined program of deworming • A range of studies indicate that a half standard deviation
and supplementation, using a number of assump- change in IQ impacts on earnings in the region of 5%.
 4 · Diagnosis of nutritional anemia 15

• It can be inferred that due to its effects on cognitive are also small portable hemoglobinometers for use in
development, anemia potentially reduces adult earn- the field. Unfortunately the Hb measurement is not
ings by 2.5%. very sensitive and specific for iron deficiency (only
• The cost of fortification per person per year is in the the third stage affects Hb synthesis). Thus, to deter-
range of $0.10 (US) to $1.00, with a cost-benefit ratio mine if iron deficiency is responsible for anemia, it is
of between 6:1 (physical benefits to adults) and 9:1 usually necessary to include other indicators.
(including estimated cognitive benefits to children). 2. Ferritin: It is currently considered the most important
• Supplementation costs per person are estimated in the indicator of the iron status as even in the first stage
range of $2.00 to $5.00, noting that often these costs of iron deficiency, its concentration decreases. There-
do not fully cover personnel costs. fore it is the most sensitive indicator and the cost of
• Supplementation programs are 5 times more costly ferritin ELISA kits or other methods for the measure-
than fortification in per DALY terms. ment of ferritin are relatively low. It is important to
• Deworming has been estimated in one study to cost note that ferritin is increased by many factors, includ-
$3.50 to increase school participation by one child year. ing infection and inflammation, thus a high value
• A combined programs of deworming and supplemen- does not necessarily indicate a good iron status. It is
tation is estimated to impact on earnings, with an therefore also valuable to measure parameters for
additional $29.00 expected for a cost of $1.70. acute [c-reactive protein (CRP)] and chronic infec-
tion [alpha-1-glycoprotein (AGP)].
3. Soluble Transferrin Receptor (sTfR). The measure-
ment of this indicator is increasingly being used to
4 determine iron deficiency in situations where infec-
tion is a factor, as it is much less influenced by this
condition. It is not as sensitive as ferritin, but more
LABORATORY ASSESSMENT OF IRON STATUS sensitive than Hb. Until now there is no internation-
Hans-Konrad Biesalski and Jürgen Erhardt ally certified standard available and each method/kit
has its own cut off values. sTfR measurements are
still much more expensive than ferritin measure-
What is the problem and what do we know so far? ments. The ratio of sTfR to ferritin is the most sensi-
Nutrition has a important role in anemia and of all the tive indicator for the iron status, since it allows the
nutrients involved, iron is the most crucial. Therefore calculation of the iron stores in mg/kg body weight.
the assessment of the iron status is very often essential in It is therefore similar to the gold standard of bone
the diagnosis of anemia. Iron deficiency generally occurs marrow staining in defining iron deficiency.
in three sequential stages: depleted iron stores, iron defi-
cient erythropoesis and iron deficiency anemia. All three Besides these indicators the following three are some-
stages can be analyzed biochemically with the measure- times also of interest:
ment of hemoglobin (Hb), ferritin and soluble transferrin 1. Iron saturation of plasma transferrin and mean cor-
receptor (sTfR). Although there are some clinical indica- puscular volume (MCV): They are well established
tors and the evaluation of iron intake might be helpful, indicators and relatively inexpensive to measure but
the diagnosis relies mainly on these biochemical indica- only useful in clinical settings where the equipment
tors. They are the only ones which give the necessary to measure them is available.
specificity and sensitivity. Unfortunately the procedures 2. Hematocrit: Is very easy to measure but since it is
to measure them are costly and mostly not easy to per- even less sensitive than Hb for iron deficiency it is
form. not very helpful in diagnosing nutritional anemia.
3. Zinc protoporphyrin (ZnPP): It is a simple and robust
How accurate and useful are the different measurement and useful in screening for iron deficien-
biochemical indicators? cy but requires a special machine. It must be noted
To measure the iron status there are three important indi- that lead even at normal environmental exposures can
cators: increase ZnPP. In most situations, though, it is not a
1. Hb: The measurement of Hb is essential for the diag- problem.
nosis of nutritional anemia and is one of the most
common, easiest and least expensive methods. Kits What is the way forward?
are available from several manufacturers and there It is generally agreed that a combination of Hb, ferritin,
16 5 · The functional significance of iron deficiency anemia

sTfR and parameters of infection (CRP, AGP) are the have been shown to absorb more iron from food, even in
best indicators to measure iron status, but four key ele- healthy women the iron requirement cannot be easily met
ments need to be improved through on-going research: by diet. Anemia in pregnancy is associated with increased
reduction of costs; improvement of throughput; increase maternal and child morbidity and mortality and lower birth
of sensitivity/specificity and increase of robustness. weight. Favorable pregnancy outcomes occur 30–45% less
often in anemic mothers, and infants of anemic mothers are
Another key challenge is to make the collection of blood less likely to have normal iron reserves – so they start life at
in the field as easy and reliable as possible. The collec- a disadvantage.
tion of blood samples on filter paper is an alternative to
venous blood samples, since it doesn’t require centri- What has been achieved?
fugation, freezing or transport of samples in a cold chain. Considerable emphasis is placed on reducing iron anemia
Unfortunately, dried blood spots (DBS) have some limi- in infancy and early childhood because of its association
tations and requiring strict procedures to be followed. with impaired psychomotor performance as well as
changes in behavior. Although some of the developmen-
What is the key message? tal deficits can be corrected with iron treatment, newer
The combination of Hb, ferritin, sTfR and parameters of studies suggest that difference in cognitive and social
infection (CRP, AGP) are the best indicators to measure adaptation remain, and are likely to be permanent. The
iron status, but to ensure implementation and accuracy of risk of iron deficiency is high during later infancy and
interventions, especially in developing countries, there young childhood, because the stores received at birth
needs to be more research in reducing the cost, improv- have been used to support normal functions and growth
ing the robustness of the measurements and finding easy and only about 50% of the iron requirement of a 6 month
field methods. old can be obtained from breast milk. Thus continued
breastfeeding will supply only half the infant’s iron
needs, and for many children the other half (+4 mg/day)
must come from fortified complementary foods or sup-
5 plementation if anemia is to be avoided. This is further
aggravated in infants who were of low birth weight,
which is common when the mother is malnourished dur-
AN OVERVIEW OF THE FUNCTIONAL ing pregnancy. Hence the WHO and UNICEF recom-
SIGNIFICANCE OF IRON DEFICIENCY ANEMIA mendation that low birth-weight infants in populations
Gary Gleason and Nevin Scrimshaw with high levels of anemia receive supplementary iron
beginning at 2 months and continuing up to 24 months.
As children grow older and start school, studies have
What is the problem and what do we know so far? shown that those who are anemic have poorer perform-
Iron deficiency anemia is the most widespread micronutri- ance. This has serious implications for the effectiveness
ent and overall nutritional deficiency in the world. Iron of education, especially in developing countries in which
deficiency occurs in three different stages. The first, deple- anemia is highly prevalent.
tion of iron stores, has no functional changes. When iron
stores are exhausted, however, and tissues begin to have Addressing iron deficiency and iron deficiency anemia
insufficient iron, the resulting condition is iron deficiency. from pregnancy through to infancy and childhood is critical,
Negative effects amongst those who are iron deficient, but and interventions need to start early in the lifecycle.
do not have outright anemia, include cognitive impairment,
decreased physical capacity, and reduced immunity. Thus Research also shows the impact of iron status on:
there are adverse consequences from iron deficiency even • Physical capacity – iron deficiency reduces physical
before iron deficiency anemia is present. The final stage is performance and has been especially noted in agri-
iron deficiency anemia which, when severe, can be fatal. cultural workers.
• Morbidity from infection due to iron’s role in several
Iron deficiency anemia during pregnancy is prevalent biological mechanisms involved in the immune
because additional iron is needed to supply the mother’s response to infections. There remains some debate
expanding blood volume (520% increase) and to support and unresolved issues, especially the relationship
the needs of the growing fetus and placenta. Thus, during between iron supplementation of young children who
the second half of pregnancy, although pregnant women are not iron deficient and malaria. More research is
 6 · Iron metabolism 17

necessary. New recommendations from the WHO are FACTS:

that iron deficiency anemia should be determined in • In many developing countries one out of two preg-
young children in areas where malaria is endemic nant women, and more than one out of every three
before they are given iron supplements. There is less preschool children, are estimated to be anemic.
controversy with regards to other infections but there • In countries where meat consumption is low, up to 90%
are still some cautions. The evidence supports a of women are, or become, anemic during pregnancy.
decreased resistance to infection in iron deficient • It is estimated that 800000 deaths worldwide are
individuals. However, if they are severely malnour- attributable to iron deficiency anemia, and it remains
ished and anemic, the body mechanisms that with- amongst the 15 leading contributors to the global bur-
hold iron from pathogens can be overwhelmed by too den of disease.
much iron (particularly administered parenterally). • When measured in DALYs, iron deficiency anemia
Under these circumstances the pathogen can grow accounts for 25 million or 2.4% of the total DALYs.
explosively before the immune system can recover • A normal male body has in total 54.0 g of iron and a
from the effects of the iron deficiency with disastrous normal woman an average of 2.5 g.
effects to the individual. • Approximately 73% of the body’s iron is in hemoglo-
• Temperature regulation – severe iron deficiency low- bin in circulating red cells and in the muscle protein
ers the body’s ability to maintain body temperature in myoglobin, 12% in iron storage proteins, and another
a cold environment. 15% is critically important in dozens of enzymes that
• Iron excess and chronic disease - concerns have been are essential for the functioning of all cells and tissues.
raised about the possible relationship between high Below normal hemoglobin levels, physical work capa-
iron stores and heart disease or cancer. Although the city is linearly related to hemoglobin levels. This is
studies that have been undertaken are inconclusive, particularly significant when hemoglobin concentra-
they indicate the need for more research in this field. tion falls below 100 g/L, which is 20–40 g/L below
the lower limit of normal adults.
What is the way forward? • Moderate anemia is defined as hemoglobin of 70–
In general, the negative effects of iron deficiency on 90 g/L, and severe anemia as hemoglobin of <70 g/L.
health, physical capacity, work performance, cognitive • Favorable pregnancy outcomes occur 30–45% less
performance and behavior can be corrected by providing often in anemic mothers, and infants of anemic mothers
adequate iron. Strategies to assure adequate iron nutrition are less likely to have normal iron reserves.
include a combination of promoting a diverse diet with • The global target is to reduce anemia prevalence
iron-rich foods, micronutrient fortification of staples and nationally, including iron deficiency, by 30% from
targeted fortification or iron supplementation for groups the year 2000 levels by 2010. Progress as of 2007 was
at high risk or with especially high needs. If moderate not on pace in most developing countries to meet this
to severe iron deficiency anemia occurs in infancy, the goal.
effects on cognition may not be reversible. Iron should
be viewed as a two edged sword in that either too little or
too much can have serious adverse consequence for the
individual. 6
What is the key message?
The functional consequences of iron deficiency, and the IRON METABOLISM
longer term economic and social impact, has led to a Sean Lynch
global target to reduce anemia prevalence by 30% from
the year 2000 levels by 2010. As of 2007, there has not
been substantial progress in most developing countries What do we know so far?
and iron deficiency anemia should be addressed as a pri- Iron plays a vital role in oxygen transport and storage,
ority, especially in the highest risk groups; pregnant oxidative metabolism, cellular proliferation and many
women, infants, and young children. However, there are other physiological processes. It has a key property that
some areas where caution is needed to avoid a potentially allows it to co-ordinate electron donors and to participate
negative impact of interventions. in redox processes. This property also accounts for its
potential to cause toxic effects through the generation of
free radicals. Furthermore, iron is an essential nutrient
18 6 · Iron metabolism

for all known pathogens. Freely available, iron may great- storage iron and by inflammation. It is suppressed when
ly increase their virulence. It is therefore not surprising iron stores are depleted, and by anemia, hypoxemia and
that the human body has tightly regulated processes for accelerated erythropoiesis. Hepcidin ensures that body
absorbing, transporting and storing iron. They ensure tissues receive the right amount of iron to meet their
that there is a ready supply for cellular growth and func- functional needs. However all cells also have the capacity
tion. At the same time they limit its participation in to regulate their own internal iron economy by increas-
potentially toxic free radical reactions. They also prevent ing or decreasing the expression of transferrin receptors
pathogens from getting ready access to the iron. which are required for the uptake of iron from the circu-
lating transferrin pool into cells.
Approximately 75% of the iron in the body is present in
metabolically active compounds. The remaining 25% It has been known that iron balance is maintained by
constitutes a dynamic store that is turned over constantly. the control of absorption for a long time. However sig-
This store ensures an adequate supply for normal organ nificant advances in our understanding of the processes
function despite short-term variations in absorption or regulating absorption have also taken place recently.
loss from the body. It also supplies the immediate needs Absorption occurs primarily in the proximal small intes-
when requirements are increased. The iron reserves that tine through mature enterocytes located at the tips of the
have then been utilized are then gradually replaced by duodenal villi. Two transporters, Heme Carrier Protein 1
increased absorption. The circulating transferrin pool (HCP1) and Divalent Metal Transporter 1 (DMT1) appear
supplies almost all functional requirements. It contains to mediate the entry of most if not all dietary iron into
only about 3 mg iron in adults, but ten times as much these mucosal cells. Heme iron is always readily
(535 mg) moves through the pool each day, roughly absorbed. Intact heme molecules are transported into the
80% destined for red blood cell production. Most of the enterocytes. However, heme constitutes only a small
iron that is transferred from the dynamic store to the cir- proportion of dietary iron even for people who eat a lot
culating transferrin pool comes from iron recovered from of meat or fish. Most of the iron is present in other forms
the processing of hemoglobin in red cells that have referred to collectively as nonheme iron. This iron is
reached the end of their approximately four month life transported into the enterocytes by DMT1, but it must
spans. Absorbed iron also enters this pool, but it amounts first be solubilized and reduced to the ferrous state.
to only about 1–1.5 mg a day. The release of iron into Moreover factors in food, particularly phytates and
the circulation is tightly regulated in concert with polyphenols, may prevent the binding of nonheme iron
requirements. It can be reduced or accelerated several to DMT1. As a consequence absorption is inhibited.
fold. However the saturation of transferrin with iron (the The possibility that specific receptors for other forms of
proportion of the protein that is carrying iron at any one dietary iron have a significant role in absorption awaits
time) is held at approximately 35% in normal individu- further clarification. As indicated above absorption is
als with adequate iron reserves. regulated by the control of iron export from duodenal
enterocytes to the circulating transferrin pool by ferro-
What recent achievements have improved our portin. These enterocytes have a short lifespan and iron
understanding of iron metabolism? that is not transferred to the circulation is lost when the
The recent discovery of a small cysteine-rich cationic cells exfoliate. Nonheme iron absorption is also regulated
peptide called hepcidin, which is produced in the liver, at the stage of entry into the enterocytes by modifications
circulates in the plasma and is excreted in the urine, has in the expression of DMT1.
revolutionized our understanding of the regulation of
iron absorption and storage. Hepcidin appears to have a What are the iron requirements throughout
primary role in ensuring the maintenance of an optimal the human lifecycle?
iron store, in regulating iron delivery to all body cells in Iron is found in almost all foods. Dietary iron intake is
concert with their functional requirements and blocking therefore related to energy intake. Iron requirements are
the absorption of unneeded iron through the intestine. It highest in the second and third trimesters of pregnancy.
acts as a negative regulator of release from stores and This need is met utilizing the maternal stores accumulated
intestinal absorption. High levels reduce the rate of prior to conception and during the first trimester owing
release from stores and absorption from the intestine by to the cessation of menstruation as well as markedly
binding to the only known cellular iron exporter, ferro- increased absorption during the second and third
portin, causing it to be degraded. The expression of hep- trimesters. Requirements are also high in young children
cidin is induced independently by the accumulation of particularly between 6 and 18 months of age. Once birth
 7 · Bioavailability of iron compounds for food fortification 19

iron reserves are exhausted, infants depend on weaning Increased hepcidin expression accounts for almost all
foods for iron because the iron content of human milk is the features of this condition which is generally con-
low. Unfortunately, traditional weaning foods in many sidered to be a host response that evolved to make
developing countries are poor sources of bioavailable iron. iron less available to pathogens.
Children aged 6 to 18 months are therefore frequently
iron deficient. Requirements are increased during the What is the key message?
adolescent growth spurt and by the onset of menstruation Major advances have been made in our understanding of
in girls. Finally women of childbearing age are at risk for the physiology of human iron metabolism and the patho-
iron deficiency because of their menstrual iron losses. physiology of related disorders, although many questions
Iron requirements are least in men and postmenopausal still remain unanswered. Ongoing research in this field
women. is required. The knowledge gained has nevertheless pro-
vided a sound scientific foundation for approaches to
What disorders of iron balance are found? combating nutritional iron deficiency.
The three common disorders of iron balance are iron
deficiency, iron overload and the anemia of inflamma- FACTS:
tion (also called the anemia of chronic disease). • Humans normally have 40–50 mg iron/kg body
1. Iron deficiency remains the most common micronu- weight.
trient deficiency disorder worldwide. It is virtually • Approximately 75% of the iron in the body is present
always an acquired condition resulting from a diet that in metabolically active compounds; the remaining
contains insufficient bioavailable iron. In developing 25% constitutes a dynamic store that is turned over
countries traditional foods usually contain large quanti- constantly.
ties of iron absorption inhibitors, particularly phytates • Iron delivery to the cells of the body is rigorously
and polyphenols. In addition recent observations sug- regulated by the control of absorption and release
gest that diseases that affect the duodenum especially from stores.
H. pylori infections and celiac disease may be more • Hepcidin has a central role in controlling iron balance.
prevalent than previously suspected and that they may • Iron deficiency, iron overload and the anemia of
have an important contributory role. More research is inflammation are the commonest disorders of iron
needed to confirm these observations and to establish metabolism. Nutritional iron deficiency results from
their possible relevance to the prevention of nutritional a diet that contains insufficient bioavailable iron to
iron deficiency. Finally, diseases that cause blood loss, meet requirements; primary iron overload is caused
particularly hookworm infections, have an important by inherited genetic mutations that lead to dysregula-
contributory role leading to the high prevalence of iron tion of hepcidin or abnormalities in its receptor ferro-
deficiency in many developing countries. portin; the anemia of inflammation is the result of
increased hepcidin expression induced by inflamma-
2. Iron overload is far less prevalent than iron deficiency. tory cytokines.
Primary systemic iron overload (hemochromatosis) is
almost always the result of an inherited abnormality of
the regulation of iron transport that affects hepcidin
or ferroportin. The common form of iron overload 7
in Caucasians, HFE hemochromatosis, results from a
relative hepcidin deficiency. Secondary iron overload
occurs in thalassemia and sideroblastic anemia OPTIMIZING THE BIOAVAILABILITY OF IRON
because the treatment of these conditions requires COMPOUNDS FOR FOOD FORTIFICATION
repeated blood transfusion and accelerated erythro- Richard Hurrell and Ines Egli
poiesis, which is characteristic of these disorders,
reduces hepcidin expression.
What is the problem and what do we know so far?
3. The anemia of inflammation is characterized by In any fortification intervention it is critical to ensure the
decreased iron release from stores, reduced absorp- efficacy of the fortificants used. Bioavailability is of key
tion, low plasma iron and transferrin concentrations, importance in establishing efficacy. The bioavailability
restriction of the available iron supply for red blood of iron compounds relative to ferrous sulphate (relative
cell production and mild or moderate anemia. bioavailability value, RBV) has been proved useful in
20 7 · Bioavailability of iron compounds for food fortification

ranking their potential for food fortification. However, • Category 1: Readily water-soluble and with an RBV
the efficacy of iron-fortified foods depends on the abso- of close to 100 in adults. Unfortunately these tend
lute absorption of the iron compound which is influenced to cause unacceptable color and flavor changes. This
by its RBV, but is also determined by the amount of category includes ferrous sulphate, ferrous gluconate,
fortificant added, the iron status of the consumer and ferrous lactate and ferric ammonium citrate.
the presence of either inhibitors (e.g. phytic acid) or • Category 2: Poorly water-soluble but dissolve readily
enhancers (e.g. ascorbic acid) of iron absorption in the in the dilute acid of the gastric juice and so have a
meal. RBV of 100. These cause fewer organoleptic changes
due to their low water solubility. This category
What has been achieved? includes ferrous fumarate and ferrous succinate.
The World Health Organization (WHO) has published • Category 3: Insoluble in water and poorly soluble in
guidelines on food fortification, which include recommen- dilute acid so cause few if any sensory changes, but
dations for preferred iron compounds and a procedure for have lower and more variable RBV. This category
defining iron fortification levels. includes ferric pyrophosphate, micronized dispersible
ferric pyrophosphate (MDFP), ferric orthophosphate
What iron compounds are recommended? and elemental iron compounds.
Although an order of preference for iron compounds is • Category 4: The advantage of these compounds is that
given by the WHO, it must be noted that preference also in the presence of phytic acid, they have an RBV 2–3
depends on the vehicle being used, and the guidelines fold of that of ferrous sulphate. They are however
list the most appropriate compounds to add to different more susceptible to adverse sensory changes than
vehicles: cereal flours, cereal-based foods, milk prod- category 2 or 3 compounds. This category includes
ucts, cocoa products, condiments. Each compound also amino acid chelates, and NaFeEDTA.
has specific advantages and disadvantages that must be
individually assessed. How can one enhance bioavailability
of fortification iron?
Electrolytic iron is the only elemental iron powder re- There are 5 key ways of enhancing the bioavailability of
commended. Atomized iron and carbon dioxide reduced iron added to foods:
iron powders are specifically not recommended due to 1. Ascorbic acid is the most commonly added com-
their low RBV. Hydrogen-reduced iron and carbonyl iron pound for the enhancement of iron absorption but is
powders may be recommended once there is more infor- sensitive to processing and storage losses. Ascorbic
mation on these compounds. In addition NaFeEDTA is acid acts in a dose dependent way and the general
not recommended for complementary food fortification recommendation is a 2:1 molar ratio of ascorbic acid
as there are too few studies in young children and the to iron for low phytate products, and 4:1 for high
Joint FAO/WHO Expert Committee on Food Additives phytate products.
has set limits in their recommendations. 2. Erythorbic acid is a stereoisomer of ascorbic acid and
appears to have a better enhancing effect but is more
How important is relative bioavailability (RBV)? sensitive to oxidation, which may limit its usefulness.
RBV is important for ranking different iron compounds 3. Organic acids, although they enhance iron absorption,
relative to ferrous sulphate whose RBV is set at 100. The are not an option (with the possible exception of fruit
ranking is made either on the ability of the iron com- juices) as the large quantities required for the effect
pound to replete hemoglobin in anemic rats or, more cause unacceptable flavor changes in most vehicles.
recently, to fractional iron absorption in humans using 4. The EDTA complexes of Na2EDTA and CaNa2EDTA
isotope techniques. As a result, four categories of iron are accepted food additives and could be used to
compounds have been developed. Each category and enhance iron absorption of water-soluble iron com-
each compound within the category has advantages and pounds.
disadvantages that must be considered on an individual 5. Degradation of phytic acid (a potent inhibitor
basis, based specifically on the selected fortification of iron absorption) by the addition of exogenous
vehicle. Compounds’ characteristics can also vary phytases or by the activation of native phytases in
depending on the method of manufacture, and their RBV cereal grains in an aqueous environment under con-
may also be influenced by the food vehicle and the iron trolled conditions of pH and temperature, might be
status of the subject, which can sometimes result in appropriate in low cost cereal and legume based com-
unexpectedly low RBV values. plementary foods.
 8 · Copper and zinc interactions in anemia 21

What levels of fortification are recommended? it has been proposed that they compete for a shared
Key when defining fortification levels is knowledge of absorptive pathway, but the exact mechanisms involved
the composition of the usual diet in order to estimate in the interaction at the absorption level are not fully
dietary iron bioavailability at 5%, 10% and 15%, and to understood. It has also been demonstrated that large
have detailed information on the dietary intake of iron doses of zinc inhibit copper absorption and may produce
within the target population. The ultimate goal is to cal- copper deficit, which indirectly could affect iron status
culate the amount of extra daily nutrient required so that leading to anemia. Zinc and copper have an antagonistic
only 2.5% of the target population has an intake of below interaction within the erythrocyte. The public health
the Estimated Average Requirement (EAR). Care must relevance of these interactions has been considered lim-
also be taken when high levels of fortification are ited in the past, but recent studies show that combined
required to meet the goal, to ensure that other population iron and zinc supplementation was less efficacious than
groups do not exceed the upper limits. single supplementation with iron in reducing the preva-
lence of anemia and in improving iron status. It should be
It is noted that the EAR cut point method should not be noted that some studies have not confirmed this poten-
used to estimate prevalence of inadequate iron intakes tially detrimental effect but three studies in subjects pre-
as iron intakes of some population subgroups (e.g. men- sumably deficient in iron and zinc, demonstrated a larger
struating women and children) are not normally distrib- increase in hemoglobin after combined iron and zinc sup-
uted. In these population groups it is recommended to plementation than with iron or zinc supplementation
use the full probability approach to define the fortifica- alone.
tion level. The WHO provides probability tables for this.
In the developing world iron deficiency coexists with
What is the key message? micronutrient deficiencies and infection, and recent
Technically we now know how to design an efficacious research shows that copper and zinc deficiencies could
iron fortified food. This information is provided in the be a contributing factor in the increased frequency of
WHO Guidelines. When designing an iron-fortified infections. In addition, acute infections are a well-recog-
food, the food manufacturer must choose the iron com- nized cause of mild to moderate anemia. Resistance to
pound with the highest RBV which causes no/limited infections depends on a healthy immune function and
sensory changes in the food and which is cost effective. copper and zinc are both necessary for the normal func-
At the same time, the level of fortification should be tion of the immune system. In addition to alterations to
based on the needs and eating habits of the consumer. the immune system, zinc deficiency may also contribute
Widespread infections and concurrent deficiencies in to an increased susceptibility to pathogens and several
other micronutrients may blunt its efficacy. In addition, it studies have shown an increased incidence of diarrhea
must not be forgotten that an efficient manufacturing and and acute lower respiratory infection in zinc deficiency.
distribution system, quality control, monitoring proce- It has also been found that zinc supplementation may
dures, synergistic health measures and good social mar- reduce the incidence of malaria. However, an immuno-
keting must also be in place for any intervention to be suppressive effect has been observed at very high doses
successful. of supplemental zinc, but this might be explained in part
by secondary copper deficiency induced by excessive
zinc. Neutropenia is a frequent clinical manifestation of
copper deficiency and this may be the link between an
8 increased frequency of severe lower respiratory infec-
tions that have been described in copper deficient infants.

COPPER AND ZINC INTERACTIONS IN The modification of laboratory indices of iron status are
ANEMIA: A PUBLIC HEALTH PERSPECTIVE related to the severity of the infectious process. This know-
Manuel Olivares, Eva Hertrampf and Ricardo Uauy ledge has led to the use of serum transferring receptor as
an aid in the interpretation of iron status in populations
with a high frequency of infections.
What is the problem and what do we know so far?
Both copper and zinc are essential nutrients and deficien- What are the basics of copper metabolism?
cies of both result in anemia. Experimental studies have Copper is an essential nutrient which is absorbed primarily
shown an inhibitory effect of zinc on iron absorption and in the duodenum by a mechanism not yet fully understood,
22 9 · Nutritional anemia: B-vitamins

but the chemical form of the copper in the lumen markedly ence of inhibitors or enhancers and adapts to physiolog-
affects its absorption. Apparent absorption varies from ical need. The total body zinc content is 1.5–2.5g and
15–80% (usual range 40–60%) and is determined by host is determined by diet content, zinc nutritional status and
and dietary related factors (intake and nutritional status), zinc bioavailability from food. The main causes of zinc
some of which have yet to be defined. As solubility of the deficiency are low intake, increased requirements, mal-
compound increases, copper is absorbed more effectively absorption, increased losses and impaired utilization. The
and it seems that animal protein, human milk and histidine first descriptions of severely zinc deficient subjects
enhance absorption whereas cows milk, zinc, ascorbic acid included anemia, but this could possibly be due to com-
and phytates diminish absorption. bined iron deficiency or the special effect of zinc on red
cell maturation. The mechanism of altering erythro-
Copper deficiency is usually the consequence of low poiesis is not fully understood.
copper stores at birth; inadequate dietary copper intake;
poor absorption and increased requirements induced by Zinc deficit may contribute to the burden of anemia by
rapid growth or increased copper losses and is often as altering erythropoiesis and decreasing red cell resistance
a result of multiple factors. Acquired copper deficiency to oxidative stress, impairing host defense. In addition,
is a clinical syndrome occurring mainly in infants, and is high doses of zinc supplementation interfere with copper
more frequent in preterm infants (especially of a very low and iron absorption and may also interfere with iron
birth weight) and infants fed exclusively cow’s milk mobilization and impaired immune responses.
based diets and should be suspected in infants with pro-
longed or recurrent diarrheal episodes. It would seem What is the key message?
that the most common cause of overt, clinical copper Although the potential public health relevance of zinc
deficiency is insufficient copper supply during the nutri- and copper interactions with iron remains undefined,
tional recovery of malnourished children. High oral they both potentially impact on the burden of anemia,
intakes of zinc and iron decrease copper absorption and directly and indirectly through infection, and must not be
could predispose to deficiency. Common clinical mani- ignored in nutritional anemia interventions.
festations are anemia (92%), neutropenia (84%) and bone
abnormalities. The hematological changes are attributed
to a number of mechanisms and are fully reversed by
copper supplementation but are unresponsive to iron 9
therapy alone.

Dietary copper deficit and genetic defects of copper NUTRITIONAL ANEMIA – B VITAMINS
metabolism have significant effects on iron metabolism John Scott
and red cell resistance to oxidative stress, and thus may
contribute to the burden of anemia. In addition, copper is
also associated with impaired host defenses and could What is the problem and what do we know so far?
increase the burden of anemia secondary to infection. Although most anemia in developing countries is due to
Copper deficit should be included in the differential diag- iron deficiency, a proportion may be due to deficiency of
nosis of anemia unresponsive to iron supplementation. vitamins of B complex, principally folate and vitamin B12.
Copper excess may also contribute to anemia by induc- This anemia is macrocytic but with the presence of
ing hemolysis. abnormal red cell precursors in the bone marrow called
megaloblasts. Concurrent presence of iron deficiency results
What are the basics of zinc metabolism? in an anemia that is often normocytic. This can result in
Zinc is widely found within cells, which makes the study diagnostic difficulties and as a result, what is often attrib-
of zinc dependent mechanisms to determine physiolog- uted to pure iron deficiency may frequently be due in part
ical function difficult, but zinc plays a central role in to folate or vitamin B12 deficiency, and the true prevalence
cellular growth, differentiation and metabolism. Some of of folate of vitamin B12 deficiency is difficult to establish.
the critical functions affected by zinc status include preg-
nancy outcome, fetal growth and development, linear Some nutrients are not at risk of being deficient because of
growth, susceptibility to infection and neurobehavioral their adequate level in most diets. Others are of particular
development. Zinc is absorbed through the small intes- risk in certain individuals and under certain conditions.
tines and is affected by its chemical form and the pres- For the B complex vitamins, there is a wide spectrum
 9 · Nutritional anemia: B-vitamins 23

of risk with biotin and pantothenic acid seldom being a large part of most diets. The best source of folate is
deficient, whereas vitamin B12 and folate deficiency is a vegetables, but in developing countries insufficient food
cause for great concern. Folate and B12 have an impact on intake is common, resulting in a high prevalence of
a number of key health outcomes, both for the mother folate deficiency. In addition, there is a large increased
herself and adverse pregnancy outcomes. The develop- requirement for folate during pregnancy and lactation.
ment of the embryo and fetus may be stunted. Impaired Compounding the problem even further is the fact that
cognitive development and increased mortality and mor- recently a polymorphism, that has a high prevalence in
bidity in adult life are a cause for concern, in addition to some communities, has been found in one of the folate
the well proven case of increased risk for spina bifida, dependent enzymes that increases folate requirement by
neural tube defects (NTD) and other birth defects. as much as 30%. This means that folate deficiency in
both developed and developing countries is common and
What has been achieved? is of particular concern leading up to and during preg-
Towards the end of the nineteenth century it was recog- nancy. As a result, folic acid supplementation before,
nized that a macrocytic anemia, with larger than normal during and after pregnancy is now accepted as being
circulating red blood cells accompanied by abnormal red critical regardless of the nutritional status of the woman.
cell precursors in the bone marrow, was the result of There is some concern that high levels of folic acid
folate or vitamin B12 deficiency and that the two defi- supplementation might accelerate the growth of existing
ciencies are interrelated as a result of their biochemical tumors, most commonly cited with respect to colorectal
interdependence. Treatment of folate deficiency, either cancer but possibly true of other cancers. The recommen-
with food folate or more commonly with the synthetic dation from the experts is that more research is needed
form folic acid, and treatment of vitamin B12 deficiency but that there is currently insufficient evidence to halt
with vitamin B12, usually produces complete remission folic acid fortification. Folic acid fortification is manda-
of the anemia. However, in the case of vitamin B12 defi- tory in over 40 countries and is being considered by
ciency, where advanced neuropathy has already resulted, many others, mainly driven by public health policies, in
there may be some residual damage. Generally vitamin order to prevent neural tube defects (NTDs).
B12 deficiency is the result of either a direct nutritional
deficiency (common in vegans) or malabsorption due to What do we know about vitamin B12?
the absence of either gastric acid or intrinsic factor need- Vitamin B12 enters the human food chain exclusively
ed for absorption. Nutritional deficiency can be treated through animal sources either as meat, milk, milk prod-
either by fortification or supplementation, as can gastric ucts and eggs. Its synthesis is completely absent in plants
atrophy. Malabsorption due to lack of intrinsic factor of all kinds, only being present in such foods by way of
requires parenteral treatment. bacterial contamination or fermentation. This is because
the enzymes necessary to assemble vitamin B12 are only
There is a major concern that vitamin B12 deficiency can present in bacteria and some algae. For this reason vege-
be incorrectly presumed to be a folate deficiency and tarians and more particularly vegans, are at high risk of
thus be treated with folic acid. This will result in normal- insufficient dietary intake. Individuals in many develop-
ized DNA biosynthesis giving the impression that the ing countries, who have low intakes of animal based
anemia has been successfully treated. However, it does foods due to lack of accessibility and high cost, are also
not treat the neuropathy that requires vitamin B12, so the at risk of vitamin B12 deficiency.
neuropathy will then progress to a more advanced and
irreversible stage. Masking of vitamin B12 deficiency by Most diets, in contrast to folate, have levels of vitamin B12
folic acid supplementation is dose dependant and is con- that exceed the recommended daily allowance (RDA) and
sidered not to happen at intakes of <1000 µg (or 1.0 mg) it is therefore surprising that there is a relatively wide-
of folic acid per day. spread prevalence of vitamin B12 deficiency. This has been
ascribed to the presence of hypochlorhydria, due to gastric
In developing countries, the prevalence of megaloblastic atrophy and the absence of acid preventing the liberation
anemia may be significantly under-detected as a result of the of vitamin B12 from food. Such hypochlorhydria is
very common concomitant prevalence of iron deficiency. thought to occur in significant proportions of all popula-
tions, being especially common in the elderly, where the
What do we know about folate? prevalence might be as high as 30%. It is also suggested
Folate is unstable, not fully bioavailable and is not found that gastric atrophy might be higher in some ethnic
in great density in most foods except liver, which is not groups. Vitamin B12, as a result of impaired absorption,
24 10 · Vitamin A in nutritional anemia

can also be the result of true pernicious anemia, which • Detection of vitamin B12 deficiency can be undertak-
is a specific autoimmune disease that reduces or eventu- en using serum vitamin B12 or more recently recom-
ally eliminates the active absorption of vitamin B12 from mended holtotranscobalamin, but levels need to be
the diet. Its prevalence seems to range from a fraction of very low to be diagnostic.
a percent to as high as 4.3%, but overall its prevalence is • Status biomarkers such as serum homocysteine or
low compared to gastric atrophy. The negative effect of methylmalonic acid are helpful but are not capable of
vitamin B12 malabsorption is on the absorption of food a definite conclusion and are usually not available.
bound vitamin B12 and not on free vitamin B12, contained • Vitamin B12 deficiency is a severe problem on the
in supplements or in fortified foods. Those with perni- Indian Subcontinent, in Mexico, Central and South
cious anemia must get vitamin B12 by injection. America and certain areas of Africa.
• The prevalence of pernicious anemia is reported as
What about the other B vitamins? being from a fraction of a percent to as high as 4.3%,
Extremes of poor intake of riboflavin (vitamin B2), pyri- but gastric atrophy is far more prevalent and in the
doxal (vitamin B6), niacin (vitamin B1), thiamine and pan- elderly is considered common (as high as 30%).
tothenic acid can cause deficiencies and are classified as
essential nutrients, however, the prevention and the conse-
quence of deficiency or under-provision of folate and vita-
min B12 are by far the most important public health issues. 10
What is the key message?
It would appear when addressing anemia that more atten- VITAMIN A IN NUTRITIONAL ANEMIA
tion needs to be given to folate status and perhaps even Keith P. West, Jr., Alison D. Gernand
more so to the vitamin B12 status of individuals, especially and Alfred Sommer
pregnant and lactating women, when addressing anemia.

Results from intervention trials seem to indicate that What is the problem and what do we know so far?
daily iron together with multiple micronutrients is most Beyond iron, anemia can be caused or made worse by a
effective in improving anemia. By their very nature one number of nutritional deficiencies. In particular, vitamin A
cannot unravel which component in a multivitamin deficiency may mediate iron metabolism at several points
preparation may be the one to elicit a response, however along the internal iron and reticuloendothelial circuitry to
fortification with low dose folic acid and vitamin B12 increase the risk of iron deficient-erythropoiesis and ane-
offers an attractive, cost-effective way of reducing NTDs mia. Although controversial, there are four plausible mech-
and eliminating megablastic anemia in developing coun- anisms by which vitamin A nutriture may affect risk of
tries. anemia: influencing tissue storage and release of iron into
circulation; having a direct regulatory effect on erythro-
FACTS: poiesis; modifying the sequestration and release of tissue
• Folic acid supplementation before, during and after iron, associated with responses to infection; and exerting
contraception can reduce the prevalence of spina bifi- an effect on iron absorption. The greatest body of evidence
da and other neural tube defects by more than half supports the first two mechanisms. The control of
and possibly by as much as three-quarters vitamin A deficiency, which often coexists with iron defi-
• Masking of vitamin B12 deficiency by folic acid sup- ciency in undernourished populations, can therefore be
plementation is dose-dependant and considered not important for preventing anemia due to either malnutrition
to happen at intakes of <1000 µg (or 1.0 mg) of folic or inflammation associated with infection.
acid per day.
• The Upper Tolerable Intake Level (UL) for folic acid Vitamin A is known to have two basic functions. The first
is set at 1000 µg. is that of a cofactor which maintains proper function of
• Research in Canada shows that folate fortification rod photoreceptor cells in the back of the eye and enables
of 100 µg/day has resulted in between 50% and 70% vision under conditions of low light. A deficiency in
reductions in the prevalence of NTDs. vitamin A can, thus, lead to night blindness. The second,
• Detection of folate deficiency can be undertaken which is likely to explain the various effects of vitamin A
using serum folate or preferably red cell folate but on hematopoiesis, involves regulating nuclear transcrip-
levels need to be very low to be diagnostic. tion and synthesis of proteins that affect cell growth,
 10 · Vitamin A in nutritional anemia 25

differentiation, metabolism and longevity. Its role is improve red cell production or survival. Vitamin A supple-
most evident in epithelial linings of the eye that become mentation appears most able to exert its positive effects on
dry (keratinized) from vitamin A deficiency, which in its hemoglobin level and reduce risk of anemia in vitamin A-
most severe form can lead to blinding xerophthalmia. deficient populations. Vitamin A may be less effective in
However, vitamin A also helps to regulate functions of controlling anemia in the presence of infections such as
many other cell types, including those involved in immu- hookworm, malaria, tuberculosis or HIV, each of which
nity, bone growth and red blood cell production. These may affect vitamin A and iron metabolism and, in doing so,
many functions lead to diverse health consequences of obscure hematologic effects of vitamin A. Also, little effect
vitamin A deficiency (VAD) that have been grouped as a of vitamin A on hematopoiesis may be discernable in nutri-
class of disorders (VADD) that include xerophthalmia tionally adequate populations.
and its resulting blindness, increased severity of infec-
tion, anemia, poorer growth and mortality itself. Because What is the way forward?
of its extent and severity, vitamin A deficiency remains Vitamin A deficiency continues to be a major nutritional
the leading cause of pediatric blindness and a major problem in the developing world, affecting vision, resist-
nutritional determinant of severe infection and mortality ance to infection, growth and survival. It is increasingly
among children in the developing world. In addition, recognized as a contributory cause of anemia. Interven-
maternal vitamin A deficiency is rising as a major public tions to reduce nutritional anemia in women and children
health concern. Less well appreciated are the degrees and should consider preventing other nutritional deficiencies
conditions under which vitamin A deficiency may also that may enhance effects of iron prophylaxis, such as that
contribute to anemia, which adds further importance to of vitamin A. Recognizing this linkage may stimulate
its prevention. co-assessment of iron and vitamin A status when investi-
gating anemia in high-risk populations. Researchers
Vitamin A deficiency results from a diet that is chronically should continue to elucidate vitamin A interactions with
low in foods rich in preformed vitamin A or its precursor iron. While vitamin A can be expected to reduce risk of
carotenoids (especially b-carotene). Food sources of pre- severe infection, its effect on reducing the anemia of
formed vitamin A include liver, cod liver oil, milk, cheese infection still requires research since its influence on iron
and fortified foods, while common food sources of provita- metabolism may be obscured by the types and severity
min A carotenoids include soft yellow fruits, orange and of infections in patients or a population. As research con-
yellow tubers, and dark green leafy vegetables. tinues, practitioners can expect to achieve, on average,
gains in the hematologic status of deficient and anemic
What has been achieved? populations through vitamin A interventions. While likely
On a global scale, enormous strides have been made to to be helpful, it should also be kept in mind that vitamin
reduce the burden of vitamin A deficiency, and resulting A can not be expected to have a major effect on anemia
risks of blindness and mortality, among children. A due to frank iron deficiency, hookworm and malaria
concurrent reduction in the risk of anemia has typically infections, and other causes of chronic, moderate-to-
been less recognized as a public health benefit of control, severe inflammation.
despite substantial evidence linking these two conditions.
Clinical studies early in the last century, and numerous What is the key message?
population surveys in developing countries in the mid-20th Vitamin A supplementation alone, or in combination with
century, noted a consistent, positive correlation, ranging iron, is likely to reduce the burden of anemia in areas where
from 0.2 to 0.9, between serum retinol and the concentra- vitamin A deficiency is a public health problem. Supple-
tion of blood hemoglobin. During a study in the seventies, mentation has proven effective as large, infrequent doses,
eight men deprived of vitamin A over a period of months daily or weekly doses, and via diet by consuming vitamin A
developed anemia that failed to respond to iron but did so fortified food. The effects are clearest in the absence of
with vitamin A repletion, suggesting that vitamin A is infectious disease and in nutritionally deficient popula-
required to mount an adequate hematological response to tions.
iron. Subsequent studies in anemic children and women
have revealed blunted hemoglobin responses to iron in the FACTS:
presence of marginal or deficient vitamin A status, and • Vitamin A deficiency is the leading cause of pediatric
markedly improved hemoglobin responses to vitamin A blindness and a major nutritional determinant of
alone or when provided with iron. Vitamin A supplementa- severe infection and mortality among children in the
tion appears to stimulate iron metabolism in ways that can developing world.
26 11 · Oxidative stress and vitamin E in anemia

• It is estimated that 125–130 million preschool aged with other molecules, and thus cause free radical dam-
children are vitamin A deficient and 20 million age. Free radicals can damage virtually all molecules
pregnant women have marginal to deficient vitamin A including protein, DNA, carbohydrates and lipids. Lipid
status. peroxidation is especially dangerous because it is a chain
• Vitamin A deficiency disorders include xerophthal- reaction that generates radicals.
mia, increased severity of infection, poor growth,
anemia and increased risk of mortality. What is vitamin E and how does it work?
• Vitamin A affects hemoglobin levels because it is The term vitamin E refers to the group of eight phyto-
involved in iron metabolism and red blood cell pro- chemicals exhibiting the antioxidant activity of alpha-
duction. tocopherol, but only alpha-tocopherol meets human vita-
• Vitamin A deficiency contributes to nutritional ane- min E requirements. Vitamin E, particularly alpha-toco-
mia, probably by restricting iron use for hemoglobin. pherol functions as a lipid soluble, chain-breaking
• Supplementation with vitamin A can reduce risk of antioxidant and is a potent peroxyl radical scavenger. It
mild to moderate anemia in vitamin A deficient and halts lipid peroxidantion. In humans, vitamin E deficien-
anemic populations. cy occurs as a result of fat malabsorption because vita-
• Hematopoietic benefits of vitamin A are more likely min E absorption is dependent not only on the fat content
to be seen when anemia is not due to severe infectious of the food, but also the mechanisms for fat absorption.
diseases such as hookworm, malaria, HIV/AIDS and Unlike other fat-soluble vitamins, which have specific
tuberculosis. plasma transport proteins, the various forms of vitamin E
are transported non-specifically in lipoproteins in the
plasma. There are a number of routes by which tissues
can acquire vitamin E; however the mechanisms for the
11 release of alpha-tocopherol from the tissues are
unknown. In addition, no organ is known to function
as a storage organ for alpha-tocopherol. Unlike other
OXIDATIVE STRESS AND VITAMIN E IN ANEMIA fat-soluble vitamins, vitamin E is not accumulated in
Maret Traber and Afaf Kamal-Eldin the liver to toxic levels, which suggests that excretion
and metabolism are important in preventing adverse
effects. Vitamin E deficiency does occur as a result of
What is the problem and what do we know so far? genetic abnormalities in alpha-tocopherol (leading to a
Anemia can result from a range of nutritional deficiencies, syndrome called AVED or Ataxia with isolated vitamin E)
inherited disorders and/or from infections or exposure and as a result of various fat malabsorption syndromes.
to certain toxins and medications. Anemia can lead to a The major deficiency symptom is a peripheral neuro-
variety of health problems since the oxygen required by the pathy, but anemia is also a consequence of inadequate
body is carried by red blood cells and because oxidative vitamin E levels. Both anemia and the peripheral neu-
stress, the overproduction of reactive oxygen species and ropathy appear to occur as a result of free radical damage
impaired antioxidant potential, can be generated by the iron due to the lack of sufficient alpha-tocopherol.
released from damaged red blood cells. Oxidative stress is
associated with anemia. Moreover, a major site of antioxi- What is the role of vitamin E in the malnourished?
dant defense in blood is the erythrocyte because it contains Vitamin E status can be compromised during anemia
intracellular enzymatic antioxidants. Low molecular as a result of the increased oxidative stress caused by
weight antioxidants, especially vitamin E and vitamin C erythrocyte hemolysis. Despite the wide range of types
provide additional significant protection. of anemia, oxidative stress is the common denominator.

What is oxidative stress? A hepatic protein is required to maintain normal plasma

Oxidative stress represents an imbalance between the alpha-tocopherol concentrations and so it is not surpris-
generation of free radicals and reactive oxygen species ing that vitamin E deficiency symptoms have been
and protection by antioxidant enzymes and low molecu- reported in children with severely restricted food intake,
lar weight antioxidants. A free radical is any chemical which not only limits vitamin E intake but also the pro-
species that contains one or more unpaired electrons tein necessary to synthesize the required hepatic protein.
capable of independent existence. A species with an The degree to which vitamin E deficiency is associated
unpaired electron has the tendency to react very rapidly with kwashiorkor and/or marasmus is not clear because
 12 · Selenium 27

the evaluation of vitamin E status in malnourished children vitamin E and vitamin C supplementation would be of
is difficult and so it is not certain that vitamin E supple- benefit to support immune function during various infec-
mentation would be beneficial until the underlying tious diseases.
metabolic problem is resolved.
What is the key message?
In the case of iron deficiency anemia not only is there Many anemia types are accompanied by a low vitamin E
decreased production of hemoglobin and other iron-con- status. While the deficiency may be caused by inadequate
taining proteins but the erythrocyte membranes are also food intakes, they could also be caused by impaired vita-
more susceptible to oxidative damage. Research showed min E transport to tissues or increased oxidative stress.
that iron supplementation to deficient individuals was This emphasizes the critical need not only for vitamin E
found to increase oxidative stress but treatment with a supplementation but also adequate dietary support with
combination of iron and vitamins A, C and E proved respect to all nutrients.
effective in normalizing the oxidative stress.
FACTS:
What about vitamin E in thalassemia and • The term vitamin E refers to the group of eight phy-
sickle cell diseases? tochemicals, exhibiting the antioxidant activity of
These are both inherited blood hemoglobin disorders that alpha-tocopherol, which come from the diet, but with
cause anemia. About 90 million people worldwide carry only alpha-tocopherol meeting human requirements.
the defective genes leading to thalassemia. The mild to • The United States Food and Nutrition Board have
severe anemia associated with thalassemia results from defined the lower limit of plasma alpha-tocopherol at
oxidative stress and some recommend supplementation 12 µmol/L for normal, healthy adults.
of these individuals with vitamin E and vitamin C. • Children with plasma alpha-tocopherol at 8 µmol/L
Oxidative stress is also manifested in sickle cell disease, resulting from malnutrition have been observed to
which is a chronic inflammatory disease, thus there may have vitamin E-responsive neurologic abnormalities.
be a benefit for vitamin E supplementation. • About 90 million people worldwide carry the defective
genes leading to thalassemia.
What about vitamin E in malaria? • Malaria accounts for about 2.7 million deaths a year
Malaria is endemic in many parts of the world and and there are about 500 million episodes reported
research shows elevated biomarkers of oxidative stress each year.
in malaria infected erythrocytes and that this decreases
as the individual recovers. The findings from a number
of studies suggest that improved antioxidant defenses
will be beneficial in mounting appropriate immune 12
responses. Interestingly however, the research also
shows that a level of oxidative stress might be important
during the treatment of malaria although it contributes SELENIUM
negatively to the general health, possibly inducing Richard Semba
anemia as a result of the destruction of the red cells. Thus
the individual may benefit from post-treatment vitamin E
supplementation. What is the problem and what do we know so far?
Anemia is common in older adults and the prevalence of
Does vitamin E have a role to play in anemia increases with advancing age and is associated
HIV and AIDS? with numerous adverse outcomes. About one third of the
Anemia is common in HIV/AIDS and severe anemia is anemia that occurs in some high-risk populations is unex-
associated with an increased risk of mortality. A recent plained, and selenium deficiency may potentially explain
review of clinical trials has suggested that currently there a portion of this unexplained anemia. The relationship
are no useful therapeutic strategies to decrease anemia in between selenium status and anemia has not been well
HIV/AIDS and despite positive reports there are few characterized in humans. Selenium deficiency should be
antioxidant intervention trials, suggesting that there has considered a possible cause of anemia that requires further
been limited success since the first trials were reported. investigation and confirmation.
Vitamin E has been shown to improve host immune
response and so it is reasonable to consider whether Selenium is an essential trace element and a normal con-
28 13 · Micronutrient interactions in the etiology of anemia

stituent of the diet. Dietary intake varies widely world-

wide as the natural selenium levels in foods reflect the
13
concentrations in the soil. The richest dietary sources are
organ meat and seafood. Selenium is present mostly in
human tissue in the form of two selenium containing INTERACTIONS BETWEEN IRON AND
amino acids. Its biochemical functions are related to its VITAMIN A, RIBOFLAVIN, COPPER AND ZINC
role in selenoproteins, and several of these are antioxi- IN THE ETIOLOGY OF ANEMIA
dant enzymes. Selenium absorption is not regulated and Michael Zimmermann
only 50–100% of dietary selenium is absorbed. Insuffi-
cient intake usually does not have obvious clinical mani-
festations, although low levels have been linked to What is the problem and what do we know so far?
increased susceptibility to oxidative stress and increased It is estimated that about half of all cases of anemia are
risk of cancer and even heart disease. The selenium due to iron deficiency and the remainder is due to other
requirement for prevention of chronic disease has not yet causes such as other nutritional deficiencies, infectious
been definitively determined. disorders, hemoglobinopathies and ethnic differences in
normal Hb. The prevalence of anemia is particularly high
What has been achieved? in developing countries where micronutrient deficiencies
Research has showed that low serum selenium levels often coexist. A deficiency of one micronutrient may
appear to be independently associated with anemia among influence the absorption, metabolism and/or excretion of
older adults (>65 years). In addition, a strong correlation another micronutrient. Of specific interest in anemia
between low plasma selenium concentrations and low are the interactions between iron deficiency and four
hemoglobin has also been observed in studies in older indi- other micronutrients – vitamin A, riboflavin (vitamin B2),
viduals. However, the direction of the association is not copper and zinc.
clear but could potentially be through selenium’s role in the
maintenance of an optimal concentration of glutathione The link between vitamin A deficiency and anemia has
peroxidase, a key antioxidant in erythrocytes, or through been recognized for many years and although improving
increased inflammation and oxidative stress. vitamin A status often increases hemoglobin and reduces
anemia, the exact mechanism is unclear. Although data
What is the way forward? from human studies are equivocal, riboflavin deficiency
The observations of an association between low selenium may also impair erythropoiesis and contribute to anemia.
levels and anemia in older men and women raises a In addition, copper deficiency is also known to impair
potentially important public health question – Has sele- dietary iron absorption but as copper deficiency is rare in
nium deficiency been overlooked as a cause of anemia? the general population, the interaction may not be of
Further research is required in order to gain insight into public health importance. Finally, although the data do
selenium’s potential role in the pathogenesis of anemia. not suggest zinc deficiency as playing a role in anemia,
deficiencies of iron and zinc often coexist and supple-
What is the key message? ments containing both iron and zinc could be of value in
Research shows that selenium may be associated with vulnerable populations. It is noted however that several
anemia but to gain insight, more focused research is studies have suggested that zinc supplementation may
required in this field. reduce iron efficacy.

What is known about the link between

iron deficiency and vitamin A?
Vitamin A deficiency affects more than 30% of the glob-
al population and the most vulnerable are women of
reproductive age, infants and children. This is the same
group most vulnerable to anemia. Surveys in developing
countries have generally reported positive correlations
between serum retinol and hemoglobin concentrations,
with stronger associations in populations with poorer
vitamin A status. However, data from human studies
investigating the influence of vitamin A on absorption is
 14 · Anemia in severe undernutrition 29

equivocal and suggest that further research is needed to that when zinc supplements are given with iron supple-
clarify the actual effect of vitamin A on iron absorption. ments, iron status does not improve as much as when
In addition, the mechanism by which vitamin A exerts its iron is given alone. Further research is definitely needed
effect on erythropoiesis remains unclear, although sever- to clarify the effect of joint zinc and iron supplementa-
al mechanisms have been proposed. Intervention studies tion.
suggest that in areas where vitamin A and iron intakes are
poor, dual fortification or supplementation is likely to be What is the key message?
more effective in controlling anemia than providing vita- The prevalence of anemia is particularly high in develop-
min A or iron alone. ing countries where micronutrient deficiencies often co-
exist and a deficiency of one micronutrient may influence
What is known about the link between the status of another. Although more research is needed,
iron deficiency and riboflavin? vitamin A, riboflavin, copper and zinc may be important in
Riboflavin is required for many metabolic pathways. addition to iron in addressing nutritional anemia.
Riboflavin deficiency is common in areas where intakes
of dairy products and meat are low and school children
are a group at high risk for riboflavin deficiency. It
appears that riboflavin deficiency, in addition to its other 14
symptoms, may impair erythropoiesis and contribute to
anemia as a result of a number of suggested mechanisms.
Although these mechanisms have been investigated in ANEMIA IN SEVERE UNDERNUTRITION
animals, there is little human data. The data from the (MALNUTRITION)
studies that have been undertaken suggest that the effect Alan Jackson
of riboflavin status on hemoglobin is variable and may
be confounded by the multifactorial etiology of anemia.
It must be noted that the data from a number of studies, What is the problem and what do we know so far?
in contrast to earlier studies, do not support a detrimen- Anemia is found commonly as an associated feature of
tal effect of riboflavin deficiency on anemia. many pathological conditions. In most cases, severe mal-
nutrition is also accompanied by anemia, as an integral
What is known about the link between part of the process of reductive adaptation associated
iron deficiency and copper? with weight loss, reduced lean body mass and the pres-
Copper deficiency is a rare cause of anemia and how the ence of edema. However, the specific cause of anemia is
deficiency causes anemia is uncertain. It is, however, also complicated by associated deficiencies of specific
known that the resultant anemia is responsive to dietary micronutrients, increased red cell destruction and the
supplementation with copper but not with iron. It is ongoing suppression of red cell formation as a result of
noted that although copper deficiency impairs dietary the inflammatory response to multiple infections. As a
iron absorption and results in iron deficiency anemia, result, the anemia associated with established severe
copper deficiency is rare in the general population and so undernutrition, or malnutrition with edema during child-
is unlikely to be of public health importance. hood or adulthood is not specific but is usually associat-
ed with an inability to effectively utilize iron, leading to
What is known about the link between an increase in the iron present in the body in both the
iron deficiency and zinc? stored and free form. Therapy with iron at this stage
Iron deficiency anemia is frequently the result of low increases mortality. Given the complexity of the possible
dietary iron absorption due to low intakes of meat and interactions in the established condition, it can be very
high intakes of inhibitors (e.g. phytate, polyphenols). difficult to determine the sequence with which one factor
Interestingly, these same dietary factors decrease bio- might have acted as a primary exposure, subsequently
availability of zinc. Although the data does not suggest interacting with other factors, which later contribute and
zinc deficiency as playing a role in anemia, deficiencies play a secondary role.
of iron and zinc often coexist and supplements contain-
ing both could be of value in vulnerable population What has been achieved?
groups. It must be noted, however, that several studies The terms marasmus, kwashiorkor, marasmic-kwashiorkor,
have suggested that concurrent zinc supplementation protein deficiency, energy deficiency and protein-energy
may reduce the efficacy of iron and some studies suggest deficiency have all been used at different times to
30 14 · Anemia in severe undernutrition

describe what is now termed severe undernutrition with exposed reflects that experienced by all the other cells
or without edema. There is emerging consensus that in the body. For the red cell, enhanced susceptibility to
there are two key features that capture the essence of pro-oxidant damage will predispose to a shortened life
the underlying processes which lead to the state of being span, which increases the extent to which iron has to be
malnourished, without necessarily being specific about held in an innocuous form. An increase in stored and/or
the detailed aspects of multiple complex underlying free intracellular iron can act as the focus for ongoing
causes: pro-oxidant stress and ensuing cellular pathology. An
1. An inadequate intake of food, due either to a poor increased loss of red cells in the face of any limitation
appetite or limited availability of food, leads to a on red cell production inevitably leads to a reduction in
wasting syndrome with a relative loss of weight and red cell mass, and increased iron in storage.
associated with a range of complex adaptive changes
in all tissues and organs Anemia, as a reduction is circulating red cell mass, must
2. The presence of an underlying specific pathology, be the result of a change in the balance between the rates
such as an infection or a poor quality diet, separately of red cell synthesis and red cell degradation, assuming
and together might predispose to a reduced food no external blood loss. The reduction in red cell synthe-
intake and in addition challenge metabolic integrity sis may be part of the general adaptive response, or a
that predisposes to the formation of edema. constraint on the availability of energy or a specific
nutrient. Alterations in the rate of degradation would
There are four key processes which separately and result from the production of cells of poor quality being
together contribute to anemia: more vulnerable and thus more likely to have a shortened
1. Reductive adaptation life span because they exist in the challenging environ-
The anemia is in part an aspect of the body’s adapta- ment produced by infection, nutritional or metabolic
tion to reduced food intake and decreased metabolic derangement.
activity. It should be differentiated from the anemia
associated with chronic disorders. At an early stage In the case of red cell synthesis, there may be severe
erythropoiesis may be normal or increased with a changes in the bone marrow, but potentially these appear
lower hemoglobin resulting from a reduction in the to be completely reversible with successful treatment
life span of the red cells. In the later, more advanced and recovery. However even after recovery of weight,
stage, as tissue metabolism falls, erythropoiesis is no there seems to be a delay in the time needed for complete
longer stimulated with a decrease in red cell mass. recovery of the red cell formation, implying an ongoing
2. Specific nutrient deficiencies constraint on erythropoiesis. During acute illness, there
The multiplication and differentiation of red cell appears to be an ongoing drive to red cell formation but
precursors with the formation of mature erythrocytes with an associated constraint on the effective utilization
which eventually appear in the circulation is a com- of the available iron. An important feature of this stage
plex process which requires the full complement of that needs to be emphasized is the notable presence or
nutrients and metabolic intermediates. A limitation in iron deposits in the reticulo-endothelium, including
any of these nutrients will limit the formation of red marrow, liver and spleen. This may be visible as hemo-
cells, their structural integrity and their functional siderin, or using appropriate techniques, identifiable as
capability. Over and above the needs of other cells, free iron. This makes the identification and characteriza-
red cells have a special need for those nutrients which tion of ‘iron deficiency’ problematic and has important
are directly involved in the formation of hemoglobin. implications for therapy.
3. Infection
There is a complex interaction between infection and What is the required treatment?
poor nutrition with each predisposing to, and making The likelihood of an individual dying from a period of
the other worse. In severe malnutrition, the effects of severe undernutrition, or surviving with a reasonable
infection on anemia might be directly related to a spe- chance of recovery, not only depends on what is done in
cific infection or indirectly to a more general inflam- terms of immediate care, but critically the order in which
matory and immune response. Separately and together, different interventions are carried out. The identification
these will limit the availability of nutrients for red cell and classification of severe malnutrition places emphasis
formation and increase the likelihood of anemia. on two characteristics, loss of relative weight, and the
4. Hemolysis, pro-oxidant damage presence of edema. An inappropriate approach to treat-
The hostile environment to which the red cell is ment might focus on correcting the edema through the
 15 · Infection and the etiology of anemia 31

use of diuretics, correcting the wasting through the pro-

vision of food, or treating abnormal blood biochemistry
15
by direct provision of single nutrients. It is now known
that each runs the risk of contributing to increased mor-
tality unless specific attention is given to the correction INFECTION AND THE ETIOLOGY
of the cellular damage associated with complex nutrient OF ANEMIA
deficiencies and imbalances. Although anemia might be David Thurnham and Christine Northrop-Clewes
a common presenting feature, and have many of the
characteristics of an iron-deficient picture, the problem in
the short term is one of an inability to effectively utilize What is the problem and what do we know so far?
the iron that is in the body, rather than an immediate Anemia and disease are both highly prevalent in develop-
shortage. Therapy with iron at this point increases mor- ing countries. It is known that the inflammatory response
tality. With appropriate treatment, as infections are to disease stimulates a series of changes in iron meta-
addressed and specific nutrient deficiencies corrected, bolism that results in anemia if the inflammation is pro-
cellular competence returns. Lean body mass can be pro- tracted. It must be noted that the hypoferremia of inflam-
gressively restored and the red blood cell mass expanded mation does not represent a genuine iron deficiency, but
to draw on the iron held as hemosiderin and ferritin. At rather a redistribution of iron that can prevail in the face
some stage during the recovery process the iron in stor- of normal iron stores.
age is likely to be insufficient to meet the demand and as
a more classical picture of iron deficiency emerges, iron Typically, infants are exposed to infection and inflam-
supplementation becomes needed and is appropriate. mation and this is in fact necessary to develop the
immune system. However, too frequent exposure will
What is the key message? increase the risk of anemia. Parasitic infections also
Accumulated evidence shows that the anemia of severe contribute to inflammation and anemia. Thus, in the
malnutrition is the consequence of multiple factors and developing world where there is a high prevalence
represents an interaction between adaptation to inade- of diarrhoea, vomiting, fever, malaria, and helminth
quate food intake and the impact of other stresses asso- infections, anemia is common. Attempts to reduce the
ciated with infection or dietary imbalance. Constraints prevalence of anemia have been ongoing for over two
on the effective utilization of iron lead to an increase decades, but the condition is still common. One of the
in unutilized iron, despite no increase in the total body reasons for the apparent failure could be that the
burden of iron. Iron supplementation is hazardous in this assumption has been that ‘iron deficiency’ was the only
situation. It is thus essential, in order to avoid causing cause. It is now more widely recognized that anemia is
more harm than good, to understand the broader context a consequence of both inflammation and insufficient
of the anemia of severe malnutrition and to ensure the bioavailable dietary iron.
use of appropriate interventions at the appropriate times.
What has been achieved?
FACTS: There is now wider recognition that infection is respon-
• The terms marasmus, kwashiorkor, marasmic-kwa- sible for a large part of the anemia in developing coun-
shiorkor, protein deficiency, energy deficiency and tries and, as a result, there is an acceptance that infection
protein-energy deficiency have all been used at dif- and the inflammatory response may also play an impor-
ferent times to describe what is now termed severe tant role in the initial cause. Frequent exposure to endemic
undernutrition with or without edema. diseases will promote the inflammatory response and
• Infants and children suffering from severe malnutrition hypoferremia and increase the risk of anemia by impair-
frequently have moderately reduced hemoglobin – 80 ing erythrocyte synthesis and/or a shortening red cell life
to 100 g/L, or reduced hematocrit – 30% to 35%. span. Whether this is accompanied by a metabolic iron
• The normal life span of a red blood cell is on average, deficiency will depend on the ability to maintain iron
120 days but may be shorter in severely malnour- stores through iron absorption, iron loss and dietary iron
ished children. bioavailability, in order to maintain normal hemoglobin.
• Despite low hemoglobin there is an increase in both It must also be remembered that disease reduces appetite
stored and free cellular iron, and supplementation – the more frequently an individual is sick, the more
with iron increases mortality. likely they are to be malnourished.
32 15 · Infection and the etiology of anemia

What is the relationship between What is the way forward?

infection and anemia? • Infection and inflammation play an important role in
Infants are rarely anemic at birth. The relative hypoxic the etiology of anemia and it is recommended that
conditions in utero result in high hemoglobin concentra- the acute phase proteins CRP and AGP should be
tions at birth but as the oxygenation of infant blood monitored before and after supplementation and
improves, erythropoiesis ceases and hemoglobin concen- should be measured together with ferritin.
trations drop over the first two months of life. By the age of • Research has shown that in many cases, iron supple-
4–6 months, iron stores are marginal or become depleted ments give little benefit and might in fact increase the
and the supply and bioavailability of dietary iron becomes prevalence of infection. This can now be explained
critical. Up to 4 months, breast milk is the main source of by our knowledge of inflammation. If anemia in
dietary iron and protective immune factors for growing apparently healthy persons is mainly due to subclini-
infants, but as complimentary foods increase, so does cal inflammation, it explains why supplementation
exposure to environmental pathogens and the frequency with iron is so poorly effective in lowering the preva-
of bouts of illness. Such infants are dependent on good lence of anemia, as iron does not cure infections.
sources of dietary iron to maintain hematological status, Also, additional dietary iron given to infants exposed
since iron absorption will be minimal during periods of to frequent infections may upset the delicate balance
anorexia and is blocked by fever and inflammation. of pro- and anti-inflammatory cytokines.
Although the frequency of infectious episodes declines as • Research shows that vitamin A supplements reduce
humoral immunity develops and food intake in older some of the inflammation and enable iron mobiliza-
children is less influenced by infectious diseases, mainte- tion to restore hemopoiesis, and so vitamin A supple-
nance of iron stores can be jeopardized by iron losses. Iron mentation should precede iron supplementation.
in the body is tightly conserved but the risk of schistosomal • Research needs to determine whether worms such as
or hookworm infections increases with age and these para- Ascaris contribute to anemia through inflammation
sites can cause chronic bleeding and iron loss. Thus infec- and it needs to be determined whether the recently
tious diseases, gut parasites and poor diet combine to discovered hepcidin, which is increased by inflam-
deprive children of iron from early infancy. The research mation and blocks absorption and mobilization of
shows that even mild anemia impairs cognitive capacity, iron, is produced locally in the gut.
increases the risk of preterm delivery in pregnancy and
reduces work output. It is thus clear that there is the possi- What is the key message?
bility that inflammation may be a key etiological factor Infection and inflammation play an important role in the
responsible for the initiation and for the continuing pres- etiology of anemia and must not be neglected in any inter-
ence of anemia in developing countries. vention. Iron supplements must be given with caution but
the risk of adverse consequences may be modified by
Raised acute phase proteins (APP) serve as markers for vitamin A status. It would, therefore, seem prudent that
subclinical inflammation. Three of these proteins are par- iron interventions should be preceded by vitamin A supple-
ticularly useful. C-reactive protein (CRP) and Alpha1- ments with or without anti-helmitic treatment according
antichymotrypsin (ACT) are the more acute markers of to local conditions. The area of infection and inflammation
inflammation; they increase within the first 6 hours of is relatively new and its effect on anemia requires more
infection, reach their maximum concentrations within research.
24–48 hours and usually fall as clinical signs start to
appear. Alpha1-acidglycoprotein (AGP, also known as FACTS:
orosomucoid) concentrations are much slower to rise and • 2 billion people across the globe are estimated to be
only achieve maximum concentration 2–5 days after anemic.
infection and thus are more of a chronic marker of • 40%–50% of children under 14 years and women of
inflammation. Where these proteins are increased, they childbearing age in developing countries suffer from
indicate that iron metabolism is disturbed and that the anemia.
alterations in iron metabolism caused by inflammation • Children aged 5–14 and pregnant women are at high-
may be contributing to the prevalence of anemia in the est risk of anemia with estimated prevalence of 48%
population. Using these proteins, it is possible to identify and 52% respectively.
persons in an apparently healthy population who may be • An estimated 200 million people globally are infected
incubating a disease, have recently recovered from a dis- with schistosomiasis and another 600 million live in
ease or are in later convalescence. endemic areas.
 16 · Making programs for controlling anemia more successful 33

• It is estimated that 1.3 billion people globally are encompasses generating political support and funding
affected by hookworm. as well as motivating acceptance of better nutrition
• It is estimated that 900 million people in the world practices by families and communities through health
are infected with Trichuriasis. education and promotion. A balanced program with inter-
• Approximately 1500 million people globally are connected components is required to support effective
infected with Ascaris. reduction of iron deficiency anemia.

Why is communication regarding controlling

iron deficiency anemia difficult?
16 In the case of the control of VADD and IDD, the approach
is ‘bullet orientated’ in that one simply emphasizes the
use of vitamin A capsules and iodized salt respectively. In
MAKING PROGRAMS FOR CONTROLLING the case of iron deficiency anemia, the design of the
ANEMIA MORE SUCCESSFUL intervention and implementation strategy is not the same
Saskia de Pee, Martin Bloem, Regina Moench-Pfanner for every situation and needs to involve various sectors.
and Richard Semba
What are the problems addressing nutritional
anemia and what are the possible solutions?
What is the problem and what do we know so far?
The 1990 World Summit for Children set goals for elim- Anemia versus iron deficiency
inating micronutrient deficiencies because of their wide- Problem: Anemia is not only due to iron deficiency and
spread prevalence, and in particular their severe conse- iron deficiency does not always lead to anemia.
quences in developing countries, some of which are still
emerging. Substantial progress has been made in com- Background: As a result of this problem, there has been
bating vitamin A deficiency (VADD) and similar or even an ongoing debate as to what the intervention goal should
more progress has been made in combating iodine defi- be – just reducing iron deficiency and iron deficiency ane-
ciency disorders (IDD). However, in the case of iron mia or also reducing anemia due to other causes, such as
deficiency anemia, the knowledge of the impact on men- malaria, helminth infestation, deficiencies of other micro-
tal development is relatively recent and therefore com- nutrients etc. Because an effective approach requires
bating iron deficiency anemia among young children was knowledge of the primary causes of anemia, gathering
not a World Summit goal and progress in eradicating iron knowledge on this is prioritized and often no action is
deficiency anemia has lagged behind. taken until this is clear.

Why is control of iron deficiency anemia Solution: Focusing on the following facts should
lagging behind? facilitate taking decisions as to which programs to
There have been a number of suggested reasons why iron implement:
deficiency and anemia control are not being implemented • Over 2 billion people are anemic and estimates of the
at a larger scale. These include focusing on what would number of people affected by iron deficiency are even
be needed to implement the preferred approach in a higher. Therefore, it is unlikely that any population is
better way so as to increase compliance and coverage; affected by anemia that is not to some extent due to
evaluation of alternative supplements and dosing fre- iron deficiency nor that only iron deficiency underlies
quencies to improve compliance and hence impact; and the anemia observed.
assessing what should be communicated to whom in • The iron needs during infancy and pregnancy are so
order to gain momentum for control of iron deficiency high that it is virtually impossible to meet these
anemia. It would seem, however, that at the core is the through the diet alone. Only when the diet of infants
fact that there is a lack of mechanisms at country and and pregnant women contains a considerable amount
global levels to ensure that effective measures are imple- of fortified foods and heme iron, from animal foods,
mented. The situation might, therefore, largely be due to might their needs be met by the diet alone. Thus, iron
the fact that operational components of controlling iron deficiency in these age groups is almost guaranteed
deficiency anemia are less well developed in comparison and the question is not whether intervening with iron,
to research and development (R&D), and that neither of multi-micronutrients and/or infection control will
these are well linked to communication. Communication have an impact on iron deficiency and anemia, but
34 16 · Making programs for controlling anemia more successful

rather which strategy is most effective. Instead of level because most people who suffer from anemia or
determining the precise extent to which each factor iron deficiency are not aware of it and they are less likely
plays a role, action should be taken to address the to take supplements for a long time, as their perception
causes that are assumed most important, while con- is that these should noticeably improve their condition.
currently monitoring the impact of these measures on
iron deficiency and anemia in the population, in order Solution: Because one third of the world population suffers
to adjust and fine tune the program. The rationale for from iron deficiency and anemia, primarily because their
this is that doing nothing does more damage than not diet does not meet their needs, a food-based approach,
treating all cases just because some causes are not yet which aims at increasing the intake of iron and other
recognized. micronutrients of the whole population and focuses
particularly on the most at-risk groups makes the most
Nutrition, health, development or economic sense. Such an increased intake should be sustained for a
consequences long period of time and should be perceived as a way to
Problem: For a long time, iron supplementation was pro- promote good health and protect cognitive development.
moted as a means to prevent and treat anemia, a largely In addition, by increasing everyone’s intake of iron,
medical term that did not speak to the minds of policy using a food-based approach, women will enter preg-
makers and governments concerned with stimulating nancy with higher stores, which will reduce the gap
economic growth etc. between needs and intake during pregnancy. The biggest
challenge of a food-based approach is to find a way to
Background: Anemia was described as a state where not increase intake sufficiently among the most at-risk
enough oxygen was transported through the body and groups, young children and pregnant women. The best
people suffering from anemia were described to be more way to assure consumption of an adequately high amount
easily tired (lethargic), have lower work productivity, of micronutrients is by adding fortificants to an individ-
lower achievement in school, and severe anemia increased ual’s bowl of food, a strategy known as home fortifica-
the risk of maternal mortality. This description was mainly tion.
tailored to the understanding of nutritionists and medical
professionals. However, the consequences on a child’s Few successful experiences have been described
current and future mental capacity, a nation’s development, Problem: The experiences with iron & folic acid supple-
as well as the economic consequences, were not suffi- mentation during pregnancy are mixed and decision
ciently advocated among various appropriate sectors such makers seem to think twice before embarking on further
as the economic child welfare, and education sector etc. iron deficiency anemia control program for pregnant
women and/or young children. Because of this, there
Solution: The fact that damage done by iron deficiency are few successful program experiences described, espe-
to a young child’s mental capacity cannot be reversed cially for young children.
later in life, and quantifying the loss of GDP when iron
deficiency and anemia are left untreated, should be the Background: Most research on iron deficiency and ane-
key messages to mobilize action in combating iron defi- mia has been conducted by academic institutions and is
ciency and anemia across a wide range of sectors. thus focused on gaining new knowledge on the technical
feasibility of interventions, rather than on operational
Medical versus food-based, public-health approach feasibility. The consequence seems to be that program
Problem: When anemia is regarded a medical problem, personnel wait for the scientists to conclude what is best,
solutions sought will focus on a medical approach for whereas the scientists go on to improve possible inter-
addressing the problem. This implies identifying the ventions and test new preparations, dosing schemes,
precise cause for each population before taking action, combinations of micronutrients etc. At the same time,
giving a high dosage of nutrients that is sufficient to treat programs that are conducted on a regular basis often do
rather than to prevent anemia, and giving messages not place enough emphasis on monitoring and evaluation
focused on treating a perceived or assumed problem. and are hence not doing a good job in communicating
successes and lessons learned.
Background: As iron deficiency and anemia are so wide-
spread, existence of the problem can be assumed and Solution: There should be a greater link between the
action should therefore be taken accordingly. However, R&D community and those implementing programs to
at the same time it is difficult to do so at an individual ensure that greater investment is made in defining the
 16 · Making programs for controlling anemia more successful 35

operational feasibility of promising interventions and to reports on complications arising from routine iron
thoroughly monitor and evaluate their implementation. supplementation during pregnancy that are related to
These experiences should be implemented on a suffi- thalassemia and hemoglobinopathies in the popula-
ciently large scale. Too often relatively small projects are tion.
implemented, and conclusions made which are not suit- • The idea that screening is required before supplemen-
able for scaling up to an entire province or country. tation because of the prevalence of hemochromatosis.
Homozygotes for hemochromatosis have a very low
Communicating and interpreting new research prevalence (<0.5%) and the gene for the common
findings and exceptions form of hemochromatosis is only prevalent in popu-
Problem: New research findings and reports on cases lations whose ancestral origins were in Northern
which experienced no benefit or even negative effects of Europe. With regard to the risk of iron overload in
iron or multi-micronutrient supplementation, often lead people suffering from hemochromatosis, the experts
to conclusions that these supplements should be withheld do not believe this is a reason to withhold iron from
from everyone because of the possibility that they could people at risk of iron deficiency living in developing
also be at risk of these negative consequences. countries.
• The finding that iron fortification and supplemen-
Background: Scrimshaw has suggested the following tation could increase the risk of heart disease and
misconceptions that could impede implementation of cancer. A possible relationship between iron status
programs: and risk of cardiovascular disease and cancer has
• The myth that iron deficiency is more difficult to been the subject of a number of recent observational
prevent than IDD and VADD. This is largely based studies. As yet, there is no good evidence that such a
on the fact that few successful programs have yet relationship exists nor that it would be a causal rela-
been implemented for iron deficiency control as com- tionship.
pared to the control of vitamin A and iodine defi-
ciency. Solution: It is most important not to lose sight of the very
• The myth that iron supplementation can increase the widespread prevalence of iron deficiency and anemia, or
severity of infections. Three papers have reviewed of the severe consequences and the underlying cause of a
the evidence in this regard and concluded that only deficient diet. Whereas research findings should be thor-
very young children (<2 mo), severely malnourished oughly examined and their applicability to the situation
children with clinical complications, and children in among different populations evaluated, they should lead
areas where malaria is highly endemic and no good to fine-tuning and better implementation of iron defi-
malaria control programs have been implemented ciency and anemia control programs rather than to a
should not receive high doses of iron (>10 mg/d) as halt of programs when that means that the majority of the
supplements. Fortified foods can be provided to chil- population is left untreated because of a small increased
dren in areas with high malaria endemicity. There is risk among a minority of the population. This situation
not enough evidence at present to know whether home has recently occurred in response to the finding of a
fortificants, most of which provide 10 mg–12.5 mg of higher mortality among children in a highly malaria
iron mixed with one meal, are safe in areas with high endemic area when supplemented with iron in the
malaria endemicity and it has therefore been recom- absence of malaria control measures. That the increased
mended that these are only provided under carefully risk was small, that those findings were not observed in a
controlled circumstances. The increase of diarrhea different area where malaria transmission was controlled
that was found among children who received iron was using treated bed nets and treatment of suspected cases,
too small to be of clinical significance. and that malaria was very highly endemic in the area,
• The assumption that thalassemias and other hemoglo- did not receive much emphasis in the discussions that
binopathies are contra-indications to iron supplemen- followed on the publication of the findings.
tation. In some regions of the world, anemia is com-
plicated by thalassemia and hemoglobinopathies. In What is the way forward?
severe cases of thalassemia, there may be iron over- As the prevalence of iron deficiency and anemia is so
load. Routine iron supplementation during pregnancy widespread and the consequences for individuals and
in areas with a high prevalence of thalassemia and populations so severe, the focus should be on implement-
hemoglobinopathies results in widely varying hema- ing control programs. Advocacy should focus on the
tologic responses. However, there do not seem to be benefits for early child development and hence success
36 17 · Micronutrient Sprinkles to control anemia

later in life and increased productivity which ultimately of interventions. The concept of ‘home fortification’
benefit the economy of the nation. came about some 10 years ago, when addressing iron
deficiency anemia was made a priority, and yet available
Programs should promote a food-based approach, interventions seemed not to be effective in reaching
including fortification of staple foods and condiments the most vulnerable populations. This resulted in the devel-
for the general population as well as home fortificants opment of ‘Sprinkles’ which are single-dose sachets con-
for specific target groups, as these are: taining a blend of micronutrient powder, which is mixed
• are more sustainable directly into food. Studies show Sprinkles to be effective,
• are less perceived as treatment of a condition well tolerated and easy to administer. Currently there are
• applicable for use in malaria-endemic areas. two readily available formulations – ‘nutritional anemia
formulation’ and ‘complete micronutrient formulation’, but
When any large-scale program is implemented, it is other micronutrients can be added depending on local con-
essential that the coverage, compliance and effectiveness ditions. Sprinkles use is been investigated to contribute to
are assessed. healthy infant complementary feeding through the concur-
rent promotion of appropriate weaning practices of preg-
What is the key message? nant and lactating women and the area of humanitarian aid
The control of iron deficiency and anemia is lacking and emergency settings.
behind that of VADD and IDD. Its control should be
accelerated by focusing on the fact that many people lack What has been achieved?
an adequate amount of iron in their diet, which needs to The problem of iron deficiency anemia in children
be addressed through a food-based approach including largely disappeared in North America following the forti-
(home) fortification, and concurrent, with but not fication of commercial foods with iron and other essen-
dependent on, methods of tackling the other causes of tial micronutrients. Unfortunately, commercially fortified
anemia. The consequences of anemia and iron deficiency foods have had limited success in developing countries as
on cognitive development, productivity and economic store-bought foods are not widely available or affordable,
development need to be emphasized. And to move for- especially for young children. Single-dose sachets of
ward most effectively, programs and policies should be micronutrient powder (Sprinkles) were developed to
thoroughly monitored, evaluated and communicated. address the problems and limitations of traditional forti-
fication interventions. The iron (ferrous fumarate) is
encapsulated within a thin lipid layer that prevents it
from interacting with the food, thereby limiting changes
17 to the taste, color and texture of the food. Other micro-
nutrients can be added to the iron, based on local
requirements and deficiencies. Caregivers can also be
SUCCESSFUL APPROACHES – SPRINKLES easily instructed in their use and they can be added to
Stanley Zlotkin and Mélody Tondeur any semisolid food, after cooking and before serving. In
addition the concept is programmatically feasible and
no cultural barriers have been identified.
What is the problem and what do we know so far?
Current INACG/WHO/UNICEF recommendations are Staple isotope studies have been carried out to demonstrate
to provide daily iron supplementation to all infants of the encapsulated iron and zinc’s bioavailability. Commu-
normal birth weight in the first year of life, starting at 6 nity based studies in several countries, involving both
months, where the prevalence of anemia is below 40%, non-anemic and anemic infants and children, have eval-
and to continue supplementation until 24 months where uated the efficacy, bioavailability, dose, acceptability and
prevalence is 40% or above. The concern is that few safety of Sprinkles. Results show:
options exist for supplementing iron to infants and young • Single dose packaging and distribution of a limited
children. Syrups (ferrous sulphate) have been the primary supply are deterrents to overdosing and a child would
strategy, but the unpleasant, metallic after taste, dark stain- need to consume many sachets (>20/day) before
ing of teeth and abdominal discomfort, negatively impact there would be any toxicity concerns. Risk of over-
on adherence. In addition, technical problems of short dose is lower than with liquid preparations
shelf life, expensive transportation costs and difficulty in • Infants with iron deficiency anemia (IDA) absorb
accurately dispensing drops have hampered the success iron from Sprinkles about twice as efficiently as iron-
 18 · Safety of interventions to reduce nutritional anemias 37

deficient and non-anemic infants FACTS:

• The 12.5 mg iron dose, as recommended by the • WHO/UNICEF estimates that more than 750 million
WHO, is efficacious and sufficient children around the world have iron deficiency and
• Sprinkles with 12.5 mg of iron given for 2 months anemia.
is adequate for anemia reduction but should be re- • Symptoms of iron toxicity occur when intake is
peated more than once a year (i.e. 2 months in every between 20–60 mg iron per kg of body weight.
6 month period) • A study has shown Sprinkles to be cost-effective with
• The only reported side effect is darkening of the stool, an estimated DALY saved of $12.20 (US), and cost
which is expected as most of the iron is excreted in per death averted $406.
the stool • Cognitive benefits associated with the prevention
• An average of 70% of required sachets were consumed, of iron deficiency anemia which, when translated
indicating a high level of acceptance into academic achievement and ultimate adult employ-
• Sprinkles are effective in preventing and treating ment, are estimated to be $37 gained for each $1
anemia spent.

What is the way forward?

The impact of iron on enhancing the severity of infec-
tions, both parasitic (malaria) and bacterial, remains an 18
important but unresolved issue. It is considered that if
rapid absorption of iron exceeds the transferrin binding
capacity, there is the possibility of free (non-transferrin SAFETY OF INTERVENTIONS TO REDUCE
bound iron) enhancing pathogen proliferation. The form NUTRITIONAL ANEMIAS
and dose of iron will impact the rate of absorption. It is Klaus Schümann and Noel W. Solomons
postulated that the encapsulated form of iron in Sprin-
kles, and the fact that they are added to foods will result
in a safer alternative to other forms of iron supplementa- What is the problem and what do we know so far?
tion. However, more research is required. Anemias are widespread in developing countries and were
thought to be primarily of nutrient deficiency origin,
Research and development of Sprinkles for pregnant and although an increasing number of anemias are now recog-
lactating women is underway, as is their use in humani- nized as not being of nutritional origin but rather due to
tarian aid and emergency feeding. chronic disease or hemoglobinopathies. It is important
therefore to consider the safety of either therapeutic or pro-
Two things are key to the success of Sprinkles, and the phylactic clinical and public health interventions, as along
scale-up of interventions using them: firstly the secure- with the benefits of alleviating deficiencies by providing
ment of sustainable methods of distribution, which reach nutrients, there can also be associated risks in nutrient suf-
the most vulnerable populations in underdeveloped ficient or overloaded individuals. The overriding principle
countries, and secondly, making sure that the interven- of any intervention program is to ensure that it does no
tions also have a social marketing strategy. Partnering harm.
with organizations which specialize in these areas is
critical. The safety issues and concerns arise because adverse
consequences, and even toxic effects, can result either
The greatest challenge for the future is to advocate for the directly of indirectly from excess exposure to the vita-
adoption of Sprinkles in nutrition policies of underdevel- mins and minerals involved with nutritional anemia. The
oped countries. greatest concern is that specific individuals or, subgroups
within a population, can habitually receive excessive
What is the key message? exposure to micronutrients in supplements or fortified
Home fortification using single-dose sachets containing foods or have idiosyncratic reactions to other measures
a blend of micronutrient powder, that is mixed directly involved in the public health control of anemia. It is thus
into food (Sprinkles), is a safe and effective way of clear that protecting the public’s health involves both
reaching vulnerable groups in underdeveloped countries reducing the risk of nutritional anemia and exempting
and overcomes many of the limitations of traditional individuals from possible adverse consequences of the
interventions to address nutritional anemia. interventions.
38 18 · Safety of interventions to reduce nutritional anemias

It is well recognized that practitioners and public health in the diet and supplements. As a result age-related
authorities must ensure certain standards in order to guar- tolerable upper intake levels (UL) have been set in
antee the safety of any intervention. It is vital to consider the United States. They are 40 mg/day from infancy
the three major intervention strategies: to the younger ages and 45 mg/day for adults. The
1. Supplementation most common side effect of oral iron preparations are
Supplements may contain more than the physiological gastrointestinal: nausea, vomiting and epigastric dis-
daily requirements for a nutrient, in particular for iron. comfort and the lowest observed adverse effect level
In addition issues of quality control in manufacturing, in a single dose has been set at between 50 mg and
overages and dosing are important. In the case of iron 60 mg. Oral iron intake also leads to a harmless black
supplementation, it is critical to avoid new imbalances discoloration of the stools and either diarrhea or
that may arise from iron-induced corrosive effects or constipation is also noted in about 6% of individuals.
oxidative damage as a result of unintended overdosing. • Atherogenic effects: There have been some contro-
2. Fortification versial observations correlating dietary iron intake
When exogenous nutrients are placed in food, the and risk for acute myocardial infarction, but these
variation across a population of the consumption of findings may be confounded by concomitant meal
the fortified foods becomes important. For example consumption and thus by saturated fat and cholesterol
in cooking oil or sugar there can be a tenfold variance intake.
in the amount of product consumed between the high- • Inflammation effects: Iron supplementation increases
est and the lowest consumers. It is therefore impor- the indices of oxidative stress.
tant that the fortification level should provide safe • Bacterial infections: The problem in this regard is that
exposure for the upper distribution of consumers. iron is a nutrient that is required by both the pathogen
3. Dietary diversification and the host defense mechanisms. However, it would
The intervention related to promoting foods as a source seem that oral iron supplementation in deficient
of nutrients are not without potential safety issues and children is mostly beneficial and reduces infection
might encourage a dietary pattern that is less than prevalence.
healthy, by increasing the intake of foods promoting
chronic disease risk. Distorted intakes of red meat as a What should be considered regarding
natural source of bioavailable iron, for example, could iron supplementation?
increase the risk of colon cancer and many diseases • Therapeutic iron supplementation uses oral high doses
associated with saturated fat exposure. of between 50 mg and 400 mg iron/day and can be
individually monitored and should be continuously
Any intervention must be targeted. The group with below geared to a changing demand.
average intake should be the inherent target of micronu- • It is essential that worm infections be treated together
trient intervention programs. It is important to note that with any iron intervention.
if the effort is aimed at raising the mean intake of the • Prophylactic iron supplementation in two population
population, it may be inefficient (spreading resources subgroups, pregnant women and infants and toddlers
where they are not needed), ineffective (not targeting aged 6–24 months, is internationally recommended.
those most in need) and even potentially harmful (push- • The prenatal distribution of the combination of iron
ing some at the upper end of the distribution to an even and folic acid as a combined tablet is valuable.
higher habitual intake). In any intervention program, it is • Blanket supplementation in young children can be
critical that there is a diagnostic assessment and monitor- problematic as often dose is not monitored and
ing component. adapted to changes in demand in deficient children,
and in iron-adequate children there is an increased
IRON risk of imbalances caused by iron excess. Recent
research on iron supplementation in malaria-endemic
What are the safety concerns with iron? areas showed disturbing results of an increased
Iron by nature of its physicochemical characteristics and incidence of adverse effects and death. Thus iron
biological interactions, presents a series of challenges for supplementation of iron deficient children in malaria
its safe application: endemic areas is not recommended.
• Gastrointestinal effects: Of importance are the doses
of iron to which an individual may be exposed on a What about iron fortification?
daily basis from the combination of foods, fortificants The fortification of infant formula and complimentary
 18 · Safety of interventions to reduce nutritional anemias 39

foods has been common for a long time but the number and ical cord is an effective prophylactic measure that can
array (from traditional staples to beverages and condi- increase iron endowment at birth by up to 50% and that
ments) of other foods with added iron is increasing. Unlike offers a benefit of permitting longer periods of breast-
staples, which contribute only a fraction of an individual’s feeding. There are some concerns regarding an increased
daily needs, fortified infant formulas and complimentary risk for hyperbilirubinanemia but different meta-analyses
foods provide up to 100% of the day’s intake and so must show conflicting results.
be formulated with an appropriate iron density and bio-
availability. It is important to note that two different fortifi- VITAMIN B12
cation densities are required for children from 6–24 months
in order to avoid over exposure in the older age group. What about the safety of vitamin B12?
Fortification of cereal grains is mandatory in many Vitamin B12 is associated with anemia and its absence
countries and the levels of addition are around 20 mg to results in hypoproliferative anemia with large, immature
50 mg/kg, depending on the iron compound used, and macrocytic red cells in the circulation. Vitamin B12 is
generally provide a maximum of 22% of the daily iron remarkable for its high safety margin and no ULs have
needs. It must be noted that the unintended increase in been set. The traditional treatment for vitamin B12 defi-
sodium exposure may be a consideration when condiments ciency megaloblastic anemia is a single, intramuscular
are fortified. The WHO Guidelines on Food Fortification dose of parenteral cyanocobalamin in the order of 200 µg.
with Micronutrients are valuable. The only safety concern surrounds giving injections in the
age of blood-borne viral infections and so the use of sterile
What about iron biofortification? needles and their safe handling are paramount. Alterna-
Biofortification refers to the genetic modification of tively doses of 1000 µg–2000 µg of oral cyanocobalamin
energy-rich food crops such as rice, wheat, maize, potatoes have been found to be as effective.
and cassava. This technology uses systematic plant breed-
ing or genetic techniques to develop micronutrient-rich Prophylactic supplementation of vitamin B12 as a policy
staple foods. In contrast to other methods, the need for cen- measure is virtually unknown but vitamin B12 fortifica-
tralized processing and complex logistics is avoided. A pre- tion is practiced.
requisite for successful biofortification is that the soil must
contain enough trace elements and this might require fertil- FOLIC ACID
ization to avoid depletion. There are also controversies
regarding genetic modification, which might be addressed What should one consider regarding folate?
by conventional plant breeding and selection to optimize Folate has both a primary and secondary relationship
micronutrient content and availability. with nutritional anemia. It is important to note that the
daily recommendations for intake are not based on its
What about dietary diversification for increased hematological function but at a higher level for the pre-
iron intake? vention of neural tube defects. Excessive folate intake is
Encouraging populations to diversify their diets to include associated with adverse consequences and the major con-
richer sources of certain widely deficient micronutrients is cern is the potential for masking an underlying vitamin
an important strategy with specific relevance when dis- B12 deficiency.
cussing iron. Encouraging home and school gardening is
generally safe from possible excess due to the compara- For macrocytic anemia due to folate deficiency, a daily
tively low iron content and bioavailability of iron in fruits supplementation course in doses of 500 µg–5000 µg
and vegetables. Other interventions promote greater meat can be given and it is prudent to concurrently give vita-
consumption through small ruminant husbandry or subsi- min B12. When folic acid is given as a prophylactic inter-
dizing meat purchase, as well as poultry and fish farming. vention it is targeted to groups at risk of neural tube
Excessive consumption is unlikely and the safeness of the defects and the dose is 400 µg either given alone or in
intervention relies on sanitary issues and the long-term con- combination with iron or iron and other micronutrients.
sequences for chronic diseases associated with high meat Routine supplementation with iron and folic acid in
intakes. populations with high rates of malaria is not recom-
mended.
How does delayed umbilical cord clamping impact
on iron status? Folic acid fortification is widely practiced and the WHO
Research shows that delaying the clamping of the umbil- specifies 1.3 mg/kg of edible foodstuff as the maximal
40 18 · Safey of interventions to reduce nutritional anemias

addition for fortification of staples, and a maximum of RIBOFLAVIN

27 µg of folic acid per 40 kcal serving of product for
other fortified commercial foods. Are there safety concerns with riboflavin?
Riboflavin deficiency is not a cause of nutritional ane-
VITAMIN A mia, however, as with vitamin A, riboflavin is a support-
ive nutrient to maximize iron-mediated repletion of a full
What are the key safety issues around vitamin A? red cell mass. As there are no adverse effects associated
Vitamin A deficiency is not a cause per se of nutritional with riboflavin, no UL has been assigned.
anemia; however, vitamin A adequacy has been shown to
act as an adjunct to optimize iron utilization. The UL has Oral doses of approximately 2 mg daily are used to treat
been set at 10,000 IU (3,030 µg as retinol) daily. Total individuals with hyporiboflavinosis. Generally riboflavin
vitamin A exposure should be limited to a cumulative is also added to multinutrient supplements and in fortifi-
dose that maintains a hepatic vitamin A concentration of cation of staple cereals where it is typically added at a
<300 µg/g, which is considered the threshold of toxicity. concentration of up to 200 mg/kg of cereal flours.
Regular daily consumption of 30 mg of vitamin A in the
retinoid form is associated with chronic toxicity. COPPER

Sustained high intakes of b-carotene (a provitamin A What are the safety concerns pertaining to copper?
carotenoid) produces a yellow-orange discoloration Severe copper deficiency produces a hypochromic,
of the skin but is dermatologically harmless. Some microcytic anemia, but is not a public health problem as
research has shown an increased risk of death when primary copper deficiency is rarely seen and occurs
isolated b-carotene was used in supplements in the almost exclusively in infants and young children subsist-
30 mg–50 mg daily range in a clinical trials among ing on low copper, milk-based formulas or adults on total
individuals with a predisposition to lung cancer (smok- enteral or parenteral nutrition. Secondary copper defi-
ers, asbestos workers). ciency anemia, however, could be related to interven-
tions with zinc at levels in excess of its tolerable limits.
What about vitamin A supplementation and fortification?
Vitamin A supplementation is included as part of the Copper is a strong emetic, provoking nausea and vomit-
regime for the intensive rehabilitation of children with ing when ingested in even low amounts, and chronic
severe protein-energy malnutrition. Strict record keeping excess intake has been associated with abnormal eleva-
is required. It is no longer recommended that high dose tion of LDL cholesterol. The UL in the United States is
supplements of vitamin A be given postpartum to lactating set at 10 mg for adults, compared to 5 mg in the European
women to support milk vitamin A. Union.

The WHO does not specify a safety limit for fortification Copper deficiency anemia has been successfully treated
of staple foods with vitamin A, although food fortifica- with daily doses of copper as cupric sulphate of 1 mg–
tion with vitamin A is common. It is suggested that such 2 mg/day in adults and young children, and doses of up
fortification should provide at least 15% of the daily vita- to 9 mg/day in divided doses are safe and tolerable in
min A needs of the target group but should not exceed adults. Where high-dose zinc is given, copper should be
30%. For commercial products, the WHO recommends a included in the formulation to prevent distortion of cop-
maximum vitamin A addition of 60 µg per 40 kcal serv- per nutriture by the zinc.
ing.
MULTIPLE MICRONUTRIENT
Is there a role for biofortification of vitamin A? INTERVENTIONS
Biofortification is an emerging area of research in
micronutrient interventions and its promotion is coordi- What should be considered regarding the safety of
nated by the Harvest Plus initiative. Provitamin A-rich multiple micronutrient interventions?
carrot and sweet potato varieties have been developed As a result of the fact that nutrient deficiencies often
and exposure to these forms of b-carotenes should be occur in combination, there has been a shift from single
safe across the population. nutrient fortification to multiple micronutrient interven-
tions. Research in reproductive settings and in infants,
have shown contradictory effects of multinutrient supple-
 18 · Safety of interventions to reduce nutritional anemias 41

mentation and it would seem that both biological and • The WHO Guidelines on Food Fortification with
nutrient-nutrient interactions may be responsible for this. Micronutrients provides detailed information on for-
More research is required as the combination of several tification levels based on safety, and technological
nutrients complicates attribution of positive or negative and cost constraints. This can be ordered from the
health consequences of specific combinations and in spe- WHO website.
cific settings. • The WHO Guidelines suggest that no more than 3 mg
of fortificant iron be added to a 50 g serving portion
What is the way forward? of a solid food or 250 ml of beverage – contributing a
The recent studies showing a negative effect of iron maximum of 22% of daily iron needs from a diet with
supplementation in malaria-endemic areas suggest that high biological availability.
research is needed to develop and test adequate end eco- • Iron supplementation in malaria-endemic areas is not
nomic procedures for large-scale iron status determina- recommended due to the results of recent studies that
tion in the field and reminds us that there can be negative showed an increased incidence of adverse effects and
consequences of intervention programs. Safety monitor- death.
ing is critical. In any fortification intervention, the risk • Traditional treatment for vitamin B12 deficiency mega-
profile of the population should be carefully estimated loblastic anemia is a single, intramuscular dose of
and be repeatedly updated. parenteral cyanocobalamin in the order of 200 µg.
Alternately oral doses of 1000 µg–2000 µg of cyano-
What is the key message? cobalamin have been found to be as effective.
Interventions to address nutritional anemia are designed to • The UL for folate is set at 1000 µg/day for adults.
have a positive public health outcome. There is, however, • For macrocytic anemia due to folate deficiency, a
the potential to threaten lives and damage the reputation of daily supplementation course in doses of 500 µg to
intervention programs. Ongoing research in all the fields 5000 µg can be given and it is prudent to concurrently
of intervention, (supplementation, fortification and dietary give vitamin B12.
diversification) and with both single and multiple nutrient • Folic acid as a prophylactic intervention is targeted to
formulations, must therefore continue. Policy-makers and groups at risk of neural tube defects and the dose is
public health officials must be uncompromising with the 400 µg either given alone or in combination with iron
principle that any and every intervention program must or iron and other micronutrients. Note: Routine sup-
be safe for all consumers and must result in improved or plementation with iron and folic acid in populations
sustained health for all. with high rates of malaria is not recommended.
• The WHO specifies 1.3 mg folic acid/kg of edible food-
FACTS: stuff as the maximal addition for fortification of staples
• Iron deficiency accounts for approximately half of and a maximum of 27 µg of folic acid per 40 kcal serv-
the anemias in developing countries, with the other ing of product for other fortified commercial foods.
half being proposed as due to a lack of copper, zinc, • The WHO specifies 1.3 mg of folic acid/kg of edible
folate or vitamins A, B2, B12, or C. foodstuff as the maximal addition for fortification of
• The overriding principle of any intervention must be staples and a maximum of 27 µg of folic acid per
‘first do not harm’. 40 kcal serving of product for other fortified commer-
• The usual nutritional supplement doses are: cial foods.
• 30–60 mg iron for a 70 kg adult • The UL for vitamin A has been set at 10,000 IU
• Maximum of 120 mg iron during pregnancy (3,030 µg as retinol) daily.
• 2 mg iron/kg for children • Total vitamin A exposure should be limited to a
• Side effects of iron are not usually seen after oral cumulative dose that maintains a hepatic vitamin A
intakes of 30–60 mg. concentration of <300 µg/g, which is considered the
• An oral dose of 180–300 mg iron/kg body weight can threshold of toxicity.
be lethal to humans but oral doses below 10–20 mg • Regular daily consumption of 30 mg of vitamin A in
iron/kg of body weight represent a no observed the retinoid form is associated with chronic toxicity.
adverse-effect-level (NOAEL). • The WHO does not specify a safety limit for fortifica-
• In the United States, there are age-related ULs (toler- tion of staple foods with vitamin A, but it is suggested
able upper intake levels) for iron. For infants and that such fortification should provide at least 15% of
young child this is set at 40 mg/day and for adults, the daily vitamin A needs of the target group but
45 mg/day. should not exceed 30%.
42 19 · Food fortification and nutritional anemias

• For commercial products the WHO recommends a cases there are many factors that can limit its potential
maximum vitamin A addition of 60 µg per 40 kcal use and efficacy.
serving.
• It is no longer recommended that high dose supple- There are WHO Guidelines for Food Fortification, and
ments of vitamin A be given postpartum to lactating these identify three approaches:
women to support vitamin A in milk. 1. Mass – Addition of micronutrient to foods generally
• Oral doses of approximately 2 mg daily are used to consumed by the general public. Provides greater
treat individuals with hyporiboflavinosis. population coverage but may satisfy only partially the
• Riboflavin is generally added to multinutrient supple- micronutrient needs of the at-risk subgroups.
ments and in the fortification of staple cereals where it 2. Targeted – Fortification that focuses on coverage of
is typically added at a concentration of up to 200 mg/kg specific, at-risk subgroups. Delivery can be sufficient
of cereal flours. to satisfy nutritional requirements.
• The UL for copper in the United States is set at 10 mg 3. Market-driven – Where a food manufacturer takes the
for adults compared to 5 mg in the European Union. initiative to fortify products in order to increase sales
• Copper deficiency anemia has been successfully and profits. Has a very small coverage in developing
treated with daily doses of copper as cupric sulphate countries.
of 1 mg–2 mg per day in adults and young children
and doses of up to 9 mg/day in divided doses are safe There is, in addition, a relatively new concept, namely
and tolerable in adults. household fortification. This is the consumption of dietary
• Where high-dose zinc is given, copper should be supplements (usually in powder forms) mixed with food
included in the formulation to prevent distortion of at meals. In the case of mass fortification, the main
copper nutriture by the zinc. advantage over the other interventions is that it uses
already existing distribution and trade systems, and
therefore the cost is basically restricted to the added vita-
mins and minerals and the fortification process.
19
Addressing nutritional anemia in the target group of chil-
dren younger than 24 months requires special attention
THE IMPORTANCE AND LIMITATIONS and products, such as complementary foods (targeted for-
OF FOOD FORTIFICATION FOR THE tification) and age-specific dietary supplements. There is
MANAGEMENT OF NUTRITIONAL ANEMIA another important group that requires attention and that is
Omar Dary women of reproductive age.

What are the possible limitations of mass

What is the problem and what do we know so far? fortification?
Two main approaches are used to address micronutrient • Vehicle selection is a critically important factor to be
deficiencies in populations; supplementation and food considered. The low cost of using mass fortification
fortification. Supplements are highly dense in vitamins only holds true in industrial settings where the pro-
and minerals in order to provide large amounts of nutri- duct is produced by formal, centralized production
ents in one or few doses. Their formulation can be tai- centers.
lored to the requirements of a specific population group • The dilution factor of the fortificant in the food must
and they are designed to deliver the recommended be high, i.e. a small amount of fortificant in a large
amount of micronutrients and avoid interactions between quantity of the food.
micronutrients and absorption inhibitors. They do, how- • Increase in the price of the product due to fortification
ever, require a voluntary and educated decision for con- should be small, otherwise it will be difficult to get
sumption, and studies show that their population cover- compliance and a level playing field among produc-
age and acceptance is low. A fortified food is an edible ers is difficult to establish.
product manufactured by the food industry with an • The content of vitamin and minerals is determined by
enhanced (added vitamins and minerals) nutritional com- the individuals who consume the food in large amounts,
position. Food fortification could be considered the most and hence the additional supply of micronutrient
favorable and cost-effective approach if it is supported given to the most at-risk individuals, frequently con-
under industrial settings. Nevertheless, even in these suming the food in lower amounts, may be insuffi-
 20 · Food-based approaches for combating iron deficiency 43

cient using only one fortified vehicle. Therefore, • In mass fortification under truly industrial settings,
complimentary measures might still be required. approximately 80–90% of the cost corresponds to the
• Technological barriers might limit the levels and purchase of micronutrients, with the exception of rice
forms of micronutrients in specific vehicles due pri- where 50–90% of the cost is linked to the production
marily to undesirable organoleptic changes. This is of the fortified kernels.
the main limitation to supplying sufficient amounts of • In supplementation, the cost of the micronutrients
iron through fortified flours. corresponds to only 10–40% of the overall cost. How-
ever supplementation requires a distribution system,
How can one assess the potential impact which is already in place with mass fortification.
of fortification interventions? • Iron is a difficult nutrient to be provided through
The WHO Guidelines suggest potential benefit estimates mass fortification especially for satisfying the needs
using the proportion of the population that moves from of women of reproductive age. Therefore, targeted
below to above the corresponding Estimated Average fortification and preventive supplementation should
Requirement (EAR). It is, however, difficult to estimate be kept in mind for the comprehensive management
the distribution profile of EAR in populations and it is of nutritional anemias.
therefore suggested that a proxy calculation of the addi-
tional EAR obtained from fortified foods is valuable. It is
suggested that, as a convention, a food providing at least
20% EAR could be considered a ‘good’ source and foods 20
providing 40% EAR as an excellent source. The impor-
tance of mass fortification could then be estimated by the
absolute and relative number of individuals from vulner- FOOD BASED APPROACHES FOR COMBATING
able groups that reach those categories of EAR. IRON DEFICIENCY
Brian Thompson
What is the role of control and enforcement?
Success of any intervention depends primarily on ensuring
that the target population/s receive the micronutrients in the What is the problem and what do we know so far?
amount and quality required. This makes quality control Iron deficiency is a serious and widespread public health
and assurance actions by producers, and inspection and and social problem. Though prevalence rates are often
enforcement by governmental authorities, essential. Values higher amongst women and children, iron deficiency can
of reference and compliance criteria responding to the affect the growth, development and performance of all. The
reality of the programs have to be set, but unfortunately are scale and magnitude of the problem, combined with the
frequently neglected in planning programs. Micronutrient functional impact such deficiencies have on the quality of
and premixes should be certified for both micronutrient life, both physiologically and socioeconomically, require
amounts and for quality as well as microbiological safety the urgent adoption of known and effective control meas-
and should be supervised by government authorities. ures.

What is the key message? We know that in the majority of cases the main cause of
Fortified products as well as dietary supplements appear micronutrient malnutrition is poor dietary intake, both in
to be a reasonable way to proceed to reduce iron defi- terms of the total quantities of food consumed and the
ciency anemia in developing countries. However, the contribution made by micronutrient-rich foods to the
challenge is to ensure that such strategies are permanent diet. Consequently the Food and Agriculture Organiza-
and sustainable. Food fortification has a number of chal- tion of the United Nations (FAO) encourages a range of
lenges, but these can be addressed and overcome through actions that promote an increase in the supply, access and
the setting of standards, quality control, certification and consumption of an adequate quantity, quality and variety
government supervision and enforcement. of foods for all populations. In developing countries
where micronutrient deficiencies predominantly exist in
FACTS: the context of food insecurity, meeting overall energy
• To supply women of reproductive age with the Esti- needs from a diversified micronutrient-rich diet contin-
mated Average Recommendation (EAR) of most micro- ues to remain a major challenge. In such cases, where
nutrients (except calcium and vitamin C), the overall food insecurity is driven by poverty and agricultural
cost ranges from $0.25 (US) to $1.00 per year. underdevelopment, the FAO is focusing support on food-
44 20 · Food-based approaches for combating iron deficiency

based strategies, including dietary diversification and • Implement large-scale commercial livestock and
food fortification aimed at increasing the availability and vegetable and fruit production to provide accessible
consumption of a nutritionally adequate micronutrient- micronutrient foods at reasonable prices to all sectors
rich diet made up from a variety of available foods to of the population.
those who are food insecure. • Stimulate the small-scale, community agricultural
sector and promote potential dietary sources, includ-
Such broad food-based interventions tend to be neglected ing many leafy vegetables and legumes that contain
in favor of singular fortification and supplementation important quantities of iron, with special emphasis on
programs as they are considered attractive for their increasing the consumption of animal products with
apparent simplicity and cost-effectiveness. In practice, high bioavailable iron and high-in-iron absorption
however, many such programs are proving difficult to enhancers.
manage, more costly than expected to implement, and • Improve the micronutrient content of soils and plants
less effective than promised. Consequently, for combat- to improve the composition of plant foods and
ing iron and other micronutrient deficiencies, we need to improve agricultural practices to enhance yields.
ensure that a fully comprehensive approach is taken and • Develop plant breeding through conventional or with
that dietary diversification is recognized as essential and genetic modification (biofortification) to increase the
does not lose out in attracting country and donor interest micronutrient content of staple and other crops.
and support. • Introduce crop diversification to promote micro-
nutrient-rich crops.
What is the way forward? • Address regulations that prohibit urban gardening or
The promotion of dietary improvement/diversification with which reduce the availability or sale of fresh foods by
a focus on improving the intake of bioavailable iron street vendors.
through greater consumption of animal products, fruit and • Examine profitability of producing, processing and
vegetables, especially vitamin C-rich foods, is the preferred marketing of micronutrient-rich foods.
intervention as it can lead to sustainable improvements, • Investigate processing, preservation and preparation
not only of iron status but also of intakes of other micro- practices that reduce losses, increase dietary absorp-
nutrients. Neither supplementation nor fortification can be tion enhancers and minimize the impact of absorption
effective on their own. Since food-based approaches have a inhibitors.
higher potential for achieving far-reaching and long-lasting • Educational efforts directed at securing appropriate
benefits for the control of iron and other micronutrient defi- within-family distribution of food, considering the
ciencies, increasing the availability and consumption of a needs of the most vulnerable family members.
nutritionally adequate diet must be placed high on the • Develop Food Based Dietary Guidelines (FBDGs) and
development policy agenda. public nutrition education and communication pro-
grams to bring about changes in eating practices.
Micronutrient deficiencies need to be addressed by • Improve food quality and food safety and set and
focusing on a broad set of mutually reinforcing strategies enforce regulations for quality control and hygiene.
including dietary diversification, fortification, supple-
mentation and public health measures. These together What is the key message?
provide maximum coverage and impact and this compre- Overcoming micronutrient deficiencies can only be
hensive approach needs to be widely implemented if this achieved if a comprehensive approach is taken which
critical global problem is to be tackled and overcome. includes ensuring all people have access to and consume
adequate quantities of nutritious food. This will not only
Virtually all traditional dietary patterns can satisfy the raise iron status but also the levels of other micronutri-
nutritional needs of the population. However, one of the ents. Dietary diversification and enhancement are an
main causes of iron deficiency anemia in low-income essential part of food-based strategies and key to the
countries is the low bioavailability of iron in poor cereal long-term success and sustainability of interventions for
and tuber based diets, since these contain high amounts addressing nutritional anemia. This apporach is in keep-
of iron inhibitors. The following are practical actions and ing with the right to food, a pledge whose fulfillment
interventions that can boost access to and consumption of means that all people are able to gain access to a varied
an adequate and nutritious diet and hence increase the diet consisting of a variety of foods that provide all
bioavailability of iron, especially to the hungry and those the energy and macro- and micronutrients sufficient to
most vulnerable to deficiencies: achieve a healthy and productive life.
 21 · Global perspectives on nutritional anemia control 45

FACTS:
• Food security exists when all people, at all times,
21
have physical, social and economic access to suffi-
cient, safe and nutritious food that meets their dietary
needs and food preferences for an active and healthy GLOBAL PERSPECTIVES:
life. ACCELERATING PROGRESS ON PREVENTING
• An estimated 854 million people are hungry, 20 mil- AND CONTROLLING NUTRITIONAL ANEMIA
lion children under 5 suffer from severe malnutrition Ian Darnton-Hill, Neal Paragas
and around 1 million children die due to malnutrition and Tommaso Cavalli-Sforza
each year. Over two billion people – more than 30%
of the world’s population – are anemic.
• Asia has the highest number of cases of anemia, while What is the problem and what do we know so far?
Africa has the highest prevalence rates of anemia in Nutritional anemias, especially iron deficiency anemia,
pre-school children. are currently the greatest global nutrition problem. They
• Underlying causes of such high levels of malnutrition mainly affect women and children and significantly
are poverty and agricultural underdevelopment lead- negatively impact on many nations’ chances of improved
ing to food insecurity. Meeting overall energy needs public health and economic development. Sadly, in the
and dietary diversity is the major challenge. first decade since the UN goal was set to reduce iron defi-
• The recommended daily intake (RDI) of iron for men ciency by one third, virtually no progress has been made.
ranges between 9 mg in diets with high bioavail- Although there is little documented success in addressing
ability to 27 mg where bioavailability is only 5%. In the problem at a public health level in less affluent coun-
premenopausal women (aged 19–50) the RDI for iron tries, there is many years of programmatic experience
is 59 mg. and a vast amount of science lie behind the complex
• Food based strategies, by increasing availability and picture of iron metabolism. Surprisingly there is still
consumption of a nutritionally adequate micronutri- much that is unknown and new areas continue to emerge
ent-rich diet, are the sustainable way to improve from the ongoing research.
nutrition.
• Heme-iron from flesh foods (meats, poultry, fish) is Poor diets lead to high levels of iron and other micronutri-
well absorbed with an average absorption of 25%, ent deficiencies and are aggravated by dietary inhibiting
ranging from 40% during iron deficiency to 10% factors such as phytates, high parasite loads and infections
when iron stores are replete. such as malaria, sociocultural factors including poverty and
• Nonheme-iron, present in plant foods such as cereals, gender discrimination, all of which contribute to the high
pulses, legumes, grains, nuts and vegetables, has an levels of anemia seen in poorer populations.
absorption rate of 2% to 10% depending on the bal-
ance of iron absorption inhibitors and enhancers in How is anemia risk affected by age?
the meal. Normal hemoglobin distributions vary with genetics,
• Addition of vegetables and fruits containing ascorbic age and gender, at different stages of pregnancy, altitude
acid can double or triple iron absorption. Each meal and smoking. This affects the interpretation of hemoglo-
should preferably contain at least 25mg of ascorbic bin and hematocrit values. In addition, the risk of iron
acid. deficiency anemia varies throughout the lifecycle, with
several periods of greater vulnerability. This variation
is due to changes in iron stores, level of intake, and needs
in relation to growth or iron losses. The most vulnerable
groups are:
• Children from 6 months to 5 years of age
• Women of childbearing age
• Pregnant women
• The aged.

What is the key reason for the apparent failure in

reducing prevalence in many programs?
One of the key reasons is that many programs have been
46 21 · Global perspectives on nutritional anemia control

designed with the assumption that the only cause found among those in remote rural areas, but also
of anemia is iron deficiency. In fact the main causes of because these individuals are usually peripheral to the
anemia are: concerns of the urban, political class. It is therefore
• Dietary iron deficiency; important to keep undernutrition on the national planning
• Infectious diseases such as malaria, hookworm infec- agenda to reinforce the government’s responsibility to
tions, schistosomiasis, HIV/AIDS, tuberculosis and provide for the good health and nutritional status of all
other chronic diseases including almost any inflam- their people. This is a complex task and requires the col-
matory illness that lasts several months or longer, and laboration of various sectors of society – national gov-
some malignancies; ernment, local government, the private food and health
• Deficiencies of other key micronutrients including sector, the media, consumers’ associations and commu-
folate, vitamin B12, vitamin C, vitamin A, protein, nity organizations.
copper and other minerals;
• Inherited conditions that affect red blood cells, such The role that the food and health industry can play is
as thalassemia; important for all the key strategies, from efforts to
• Severe acute hemorrhage (such as occurs in child- improve the supply, distribution and consumption of ani-
birth); mal and vegetable food, to fortification and supplementa-
• Chronic blood losses (e.g. in peptic ulcer); tion. Reduction of anemia is most likely to be achieved
• Trauma. through a combination of the three key approaches (sup-
plementation, fortification and dietary diversification),
For effective intervention programs and proper monitor- while also aiming to reduce social inequalities – given
ing of their impact, better information is needed, not only that anemias are most often the consequence of poverty.
of the iron status of populations, but also the other causes
of anemia. Even when taking into account all known Food fortification: This can offer a partial solution in the
causes of anemia, a large proportion in many high-risk medium to long-term and is probably the most cost effec-
populations remain unexplained. tive approach, but requires food producers to work with
micronutrient premix suppliers and the consumers and
Why is there a lack of information? public health community to encourage the government to
A reason for the lack of information on the other causes adopt legislation and regulations and to provide effective
of anemia is that only hemoglobin or hematocrit tests communication of the importance of this approach
can routinely be performed in field settings, while more through the media so that people to demand it. There
precise, multiple biochemical tests are usually only have been both success and failures in fortifying foods
conducted in resource-adequate countries under special with iron and commercially fortified foods are not
research conditions. Advances in laboratory methods to always available or affordable to those most at risk.
allow for the determination of causes of anemia at low
cost, either in the field or later in the laboratory, without Supplementation: These programs should be seen as an
refrigeration of samples (dried spots), would greatly con- opportunity to promote improved diets, as it is a less sus-
tribute to better assess the causes of anemia and allow for tainable means to address deficiencies due to inadequate
more appropriate interventions. food intake and/or other factors.

What roles do the private and public sector play in Diet-based interventions: The role of these interventions
preventing anemia? in addressing nutritional anemia has not been clearly elu-
One of the main constraints in the fight against anemia cidated but there is some interesting work being done in
and other micronutrient deficiencies, is the limited will- this regard. Limited availability, accessibility and intake
ingness of governments (and donors) to invest suffi- of animal source foods at the household level and lack of
ciently to improve diets and reduce social inequalities, as knowledge about their value in the diet and role in health,
this requires long-term investments to improve the sup- contribute to poor diet quality which has a profound
ply, distribution and consumption of animal and veg- impact on the necessary micronutrients that play a role in
etable foods, and needs to especially target those who are iron status.
in greatest need. In addition, health systems in the most
affected countries are seriously underresourced. These The private and nongovernmental sectors may in many
factors involve not only problems of access and related cases have multiple advantages in delivering health care
costs, as the highest undernutrition rates are usually interventions over poorly resourced government serv-
 21 · Global perspectives on nutritional anemia control 47

ices. Yet governments must still be held responsible for tion approach is necessary for sustainable success and
the wellbeing of the very poorest. In countries where must include improved social conditions by poverty alle-
both have worked together with communities, we see the viation measures, as well as the more direct measures of
greatest chance of success. fortification, supplementation and improved health care.
Countries, however, must begin interventions themselves
What are the key lessons that have been learnt? and should not wait until all aspects of a comprehensive
The identified constraints and facilitating factors in program are in place, as each individual intervention will
addressing nutritional anemia can be broadly grouped as: have some impact and the need for action is great.
• Sociocultural (poverty, gender discrimination);
• Delivery factors (targeting, supplementation, fortifi- FACTS:
cation and food-based approaches); • 200 million under 5 year olds fail to reach their
• Systems (health, private sector marketing, logistics); cognitive and socioemotional development, due to
• End-user (accessibility, compliance). undernutrition, including iron deficiency and inade-
quate stimulation.
It would seem that for successful interventions, key fac- • The total attributed global burden of iron deficiency
tors that are required include improved logistics, better anemia amounts to 841,000 deaths and 35,057,000
compliance and involvement of multiple stakeholders. In DALYs.
addition any single intervention must be seen as just one • It has been estimated that the median value of produc-
part of a comprehensive strategy. Integrated community tivity losses due to iron deficiency is about $4.00
approaches require combining interventions and need to (US) per capita or 0.9% of GDP.
include mass deworming, health education, improved • It has been calculated that the productivity of adult
water and sanitation as well as considering multiple anemic agricultural workers or other heavy manual
micronutrient supplementation. laborers is reduced by 1.5% for every 1% decrease in
hemoglobin concentrations below established thresh-
There also needs to be a realistic assessment of both olds for safe health.
accessibility and availability of iron and other relevant • Eliminating severe anemia in pregnancy has been
micronutrients, whether they are being delivered as sup- estimated to potentially reduce maternal disease bur-
plements, by fortification or by other channels, including den by 13%.
poverty reduction programs. This may include assess- • 2.5% of any average population is expected to fall
ment of the viability of health systems, feasibility of below the WHO cut-offs for iron. As a result, iron
social marketing and reach of health education. deficiency anemia is considered a public health prob-
lem when the prevalence of low hemoglobin concen-
What is the way forward? trations exceeds 5% of the population.
Adequate iron status is necessary for the health of all • Severe anemia in pregnancy is defined as hemoglobin
but especially for infants, young children and pregnant of <70 g/L and requires medical treatment.
women. The Copenhagen Consensus has attributed high • Very severe anemia is defined as hemoglobin of
cost-effectiveness to iron and other micronutrient pro- <40 g/L and is a medical emergency.
grams. There is now considerable evidence that not • Estimates suggest that fortifying flour with iron has
addressing iron deficiency and other anemias will cost the potential to increase national IQ by 5%, increase
countries up to 2% of GNP, and impair the intellectual national GDP by 2% and eliminate 60,000 deaths of
development of their children and future national eco- pregnant women every year.
nomic productivity. • Fortifying with folic acid can significantly reduce
the 200,000 cases of neural tube defects every year
International health and national partners need to get in newborn babies.
firmly behind these statements, so that consistent meas-
ures and approaches reinforce one another and so that
well planned and monitored interventions become a real-
ity.

What is the key message?

Nutritional anemias are currently the greatest global
nutrition problem. A comprehensive, multiple interven-
48 22 · Conclusions and research agenda

22 Hb <120 g/L for nonpregnant women). For preschool

children and women, national surveys cover a large propor-
tion of the population and the data suggest that the
global burden of anemia is high, although the proportion
CONCLUSION AND RESEARCH AGENDA of severe anemia still remains unknown. The analysis sug-
Klaus Kraemer, Elisabeth Stoecklin and Jane Badham gests that almost 50% of preschool children are affected
worldwide, with the highest rates in Africa (64.6%) and
Asia (47.7%). This number amounts to almost 300 million
Introduction children under 5 years of age. The anemia prevalence is
The United Nations’ goal of reducing by one third the 41.8% in pregnant women and 30.2% in nonpregnant
prevalence of anemia by 2010 is unlikely to be met. women. Globally, 818 million women (pregnant and non-
Nutritional anemia remains common in many countries pregnant) and children under 5 years of age are affected
of the world and its eradication through effective inter- by anemia. Individual studies from South Asia point to
ventions must be a priority for attention and action. far higher prevalence numbers in pregnant women and
Anemia impairs individual growth and development, as adolescent girls.
well as family, community, and national socioeconomic
development. There has unfortunately been little docu- Four key messages can be concluded from the analysis:
mented success in addressing the problem at a public 1. More countries should assess anemia prevalence
health level over the last decades, although there is now a more precisely at the national level and also deter-
great deal of programmatic experience and a vast and mine the degree of severity of anemia.
growing amount of scientific data and new information 2. Countries should assess iron deficiency in more
on iron metabolism and the role of other nutrients in the detail, as it is uncertain how much anemia is due to
etiology of nutritional anemia. However, much is still iron deficiency and how much is due to other causes.
unknown and many new areas requiring attention and It is important to distinguish between anemia due to
research continue to emerge. nutritional causes and anemia as a result of chronic
endemic infections, (e.g., malaria, helminth infec-
This final chapter aims to summarize some of the conclu- tions, and HIV/AIDS).
sions drawn from the previous chapters in this volume, 3. Subclinical inflammation may be very common in
draw attention to the unchanged magnitude of the prob- apparently healthy people, and may lead to misclassi-
lem and its resulting economic implications, and deter- fication of anemia.
mine the crucial points for going forward in addressing 4. More comparative evaluation of the advantages and
nutritional anemia by specifying critical factors for future disadvantages of currently available methods for
research related to micronutrients and identifying key the measurement of iron status (ferritin, sTfR and
components that ensure that programs and interventions indicators of infection/inflammation) is required, in
really work. addition to reducing the costs of these analyses while
maintaining their accuracy.
Dimension of the problem
Previously, global estimates on the prevalence of anemia Weakness and fatigue have long been associated with
did not include nationally representative data from iron deficiency anemia only. More recent research how-
China, which accounts for ~20% of the world’s popula- ever points to functional consequences even before the
tion. In this volume, new global estimates on anemia clinical onset of anemia. Longitudinal studies caution
prevalence for preschool children and nonpregnant and that chronic iron deficiency in infancy permanently
pregnant women have been released, compiled by the retards cognitive, motor, and socioemotional develop-
World Health Organization (WHO) for its Vitamin and ment. This is an especially grave concern as more than
Mineral Nutrition Information System (VMNIS). 200 million children under 5 years of age, mostly living
in South Asia and sub-Saharan Africa, fail to reach their
Surveys included in the database assessed anemia by cognitive and socioemotional development potential due
measuring hemoglobin using standard methodology and to malnutrition, including iron and iodine deficiency and
excluded those that used clinical signs to confirm anemia inadequate stimulation. These children are likely to fail at
prevalence. Only representative data from countries were school, miss their income potential, and thus remain in
included in the analysis and adjusted for WHO cut-offs (Hb the poverty trap. There is consensus among a broad range
<110 g/L for preschool children and pregnant women and of scientists from academia and UN agencies that global
 22 · Conclusions and research agenda 49

and national priority should be given to the prevention of and multifactorial and there appears to be a clear role
even mild anemia in infants and young children because for multiple micronutrients (vitamins and minerals) in
of the risk of impaired intellectual development. Also of nutritional anemia prevention as well as generally
concern is the fact that amongst breastfed infants, only improved nutrition and health. The challenge is to create
about 50% of their iron requirement during the first 6 optimal combinations of micronutrients that will work
months can be obtained from breast milk, indicating a best together and even synergize each other. No single
need for early supplementation for all infants. intervention will revert or prevent anemia in any popula-
tion. However, there is still limited scientific information
In the past, the wide-ranging consequences of iron defi- about multiple micronutrients in the prevention of nutri-
ciency and anemia have primarily been dealt with as a tional anemia. Moreover, the findings from these clinical
medical problem, rather than emphasizing the mental and studies remain controversial and some need to be inter-
economic consequences. The economic gain from reduc- preted with caution.
ing any micronutrient deficiency comes from both cost
reduction and from enhanced productivity. This includes Several factors have to be considered when planning
reduced mortality, reduced health care costs, reduced future intervention studies with fortified food or supple-
morbidity, improved productivity, and intergenerational ments in populations with impaired nutritional status and
benefits through improved health. It is clear that anemia health:
at all stages of the life cycle is associated with a signifi-
cant health burden and has a potentially large negative 1. Nutritional factors
impact on productivity and hence also income and gross The impact of the composition of the habitual diet
domestic product (GDP) loss; current estimates are as including micro- and macronutrients should be evaluated
high as $50 billion (US). The total loss per capita due to with priority. A poor quality diet, often due to limited
physical as well as cognitive losses amounts to billions intake of animal source food as well as fruits and vege-
annually and is considerable when compared to the mod- tables, is one of the main causes of multiple micronutrient
est costs of decreasing nutritional anemia. deficiencies which do not occur in isolation, but rather
concurrently. Furthermore, poor bioavailability of nutrients
We have derived five key findings from the analysis: and diets high in plant-based food containing constituents
1. Iron interventions in adults have been shown to have such as phytates and polyphenols limits the absorption of
productivity impacts of around 5% in light manual iron and other trace elements.
labor and as high as 17% in heavy manual labor.
2. It can be inferred that anemia potentially reduces 2. Health environment and non-nutritional factors
adult earnings (due to its cognitive effects) by 2.5%. Infectious diseases such as malaria, tuberculosis,
3. Iron fortification is one of the most attractive public HIV/AIDS, parasitic infections, and certain chronic
health interventions, as seen in the cost per disability inflammations are other factors that contribute to anemia
adjusted life year (DALY) saved or in the cost-bene- and impair nutritional and health status. It is therefore
fit ratio. The cost per person per year for fortification important to take the total health environment into
is in the range of $0.10–$1.00 with a cost-benefit account and to control and/or treat any underlying dis-
ratio of:1:6 (physical benefits to adults) or as high as ease. An integrated intervention approach that considers
1:9 (including estimated cognitive benefits to children). each population group’s epidemiological, socioeco-
4. Supplementation costs per person are around nomic, and cultural context is required.
$2.00–$5.00 but are five times more costly than forti-
fication in DALY terms and it is noted that the results 3. Target population
of large-scale programs have to date been disappoint- The most vulnerable segments of the population are
ing. pregnant and lactating women, infants, young children,
5. More research urgently needs to be done to quantify and adolescent girls. Infancy is the age group in which
the economic loss of mental retardation due to iron micronutrient deficiencies start and progress with poten-
deficiency anemia. tially severe consequences later in life, yet poor nutrition
starts in utero. Thus, adequate nutrition and health status
Critical points in anemia research related to should receive high priority during both pregnancy and
micronutrients infancy. The message is clear: a life cycle approach is
There is no easy solution to overcoming the global required, taking the diverse requirements of the different
scourge of anemia. The etiology of anemia is complex target populations into account.
50 22 · Conclusions and research agenda

4. Recommended intake and composition ments. Controlling iron deficiency anemia is different
of micronutrients from controlling other recognized deficiencies such as
For efficacy of interventions, the optimal dose and VADD and IDD, where ‘bullet orientated’ approaches of
composition of micronutrients is still unknown. The capsules and fortification, respectively, seem to have
potential risks of interactions have to be taken into worked.
account when food fortification or supplementation
programs are initiated, especially when directed to popu- It is a sobering statistic that in the year 2000, the number
lation groups with a generally poor nutritional status. of iron supplements supplied by UNICEF to developing
The interactions between various micronutrients (e.g., countries was only enough for 3% of all pregnant women
iron, zinc, and other minerals, and antinutritional factors in those countries – and that is before one considers com-
inhibiting iron absorption) appear to be especially im- pliance. This highlights the view that a key hindrance to
portant. Different combinations and doses as well as achieving the global goals is the fact that operational
new delivery forms of micronutrients still need to be components of controlling iron deficiency anemia are
investigated. less well developed in comparison to research and devel-
opment efforts, and that neither of these are generally
5. Deliveries through the health system linked to communication, which includes political advo-
It is also important to take into account existing preven- cacy, funding, motivation for acceptance of better nutri-
tion programs such as high dose vitamin A, iron/folic tion practices, health education, and promotion. In fact,
acid supplementation, and parasitic disease and malaria the greatest challenge probably does not lie in the need
control. These programs have to be integrated and moni- for more scientific research, although there are still
tored carefully in new clinical trials. many unanswered questions and areas for new or
renewed focus, but rather in communicating and inter-
6. Duration preting the research findings and exceptions so as to fine-
Long-term outcomes and effectiveness is not yet fully tune programs.
defined with regard to nutrition, health, and general
wellbeing and should receive priority. Endpoints of Advocacy communication needs to focus on the benefits
short- and long-term studies vary considerably. Func- throughout the life cycle and the associated impact of
tional outcomes as true indicators of the effects are interventions on improving productivity, which ulti-
needed and should be addressed as endpoints in studies. mately lead to the economic uplift of both individuals
and countries. Emphasizing the fact that the damage
Making programs and interventions work to intellectual development caused by iron deficiency
Scientific knowledge relating to interventions has in early childhood cannot be reversed later in life and
expanded beyond iron and now a range of other nutrients quantifying the loss of GDP when iron deficiency is left
(such as vitamin A and multiple micronutrients) as well untreated should be the key messages to mobilize action
as infectious disease and parasitic infestation are being across a wide range of sectors for the eradication of
considered. In addition, it is now recognized that inter- iron deficiency and anemia. What we need are effective
ventions don’t always turn out the way we had hoped; bridges between science and technology, service pro-
consider the results showing possible negative effects in viders and political as well as financial decision makers.
malaria-endemic areas. So too it has been learned that The problem is not the lack of knowledge about tailored
food-based strategies such as biofortification and dietary solutions but rather a lack of clear political and financial
diversification are also important. It would seem, that commitment to undertake interventions to match the
although often a specific angle is emphasized or an magnitude of the problem. The problem is clearly
approach advocated, the key message should be that all described. What remains is to accept the challenge and
the recognized and documented causes and intervention accelerate the action.
approaches must work together and that supplementa-
tion, fortification (food and home), biofortification, food
based approaches, and public health measures have to be
viewed and practiced as complementary to one another.
For the long-term success and sustainability of nutri-
tional anemia control programs, all the factors and
options must be viewed together as a whole and be
adjusted to suit the specific local conditions and require-
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