Download Multiple Micronutrient Nutrition : Evidence from

28
MuLTIPLE MICRONuTRIENT NuTRITION
Multiple Micronutrient
Nutrition: Evidence
from History to Science
to Effective Programs
Workshop Proceedings: 2nd World Congress
of Public Health, Portugal, 2010
1
David I Thurnham
Northern Ireland Centre for Food and Health,
university of ulster, Coleraine, uK
06. The use of micronutrient powders (MNP) in emergency
situations has given variable results; however, this may be
due to the unsuitability of the biomarkers used.
07. A comprehensive guide on the use of biomarkers for
Key messages
01. Multiple micronutrient (MMN) supplements have been
introduced to overcome drawbacks in single micronutrient
programmers is needed.
08. More experimental work is advised before programs
are started.
supplementation to improve diets.
09. New work on the genetic polymorphisms affecting the
02. Main nutrients of interest are vitamin A, iron, zinc, folate
and vitamin B₁₂.
activity of the enzyme converting β-carotene to vitamin A
has shown the existence of potentially important ethnic
differences.
03. Evidence for the existence of other micronutrient
deficiencies is largely circumstantial and based on the
knowledge that many people in developing countries
10. Most micronutrient interventions to date have been
delivered using the “health” platform.
exist on very poor diets.
11. Three other delivery platforms exist: market-based,
04. Randomized controlled trials in pregnant and lactating
women have largely shown poor responses to MMN
agriculture and social protection. However, much information is still needed for their successful implementation.
supplements, compared to iron and folate.
12. The World Health Organization (WHO) is systematically
05. The poor response by women is partly due to the fact that
all women routinely receive iron and folate supplements.
The lack of macronutrients may also dilute any benefit
from the supplements.
collecting micronutrient statistics and program results to
provide an international database for programmers.
sIGHT AND LIFE | VOL. 26 (1) | 2012
“ Poor diets potenti ally limit
human growth and development,
and health is also impaired
direct ly or indirect ly ”
29
30
Multiple Micronutrient Nutrition
Introduction
Multiple micronutrient (MMN) preparations have been introduced to overcome the inadequacies of single micronutrient interventions to improve the diet. Their use has not been entirely
successful, in that the effects of MMN have not always shown
the expected added benefit over single nutrients. In 2010, a
symposium was organized in Portugal at the 2nd World Congress
of Public Health Nutrition to examine some of the issues emerging in workers’ attempts to incorporate MMN nutrition into effective programs. In the article below, I discuss some of the
highlights from the papers presented.
The rationale for MMN supplementation
Single nutrient intervention studies to prevent those deficiencies
with the greatest public health importance, namely vitamin A
and iron, have been carried out in many parts of the world. The
variable responses in different populations have led researchers
to speculate that they are due to other limiting dietary nutrients.
This seemingly reasonable explanation is understandable, since
a diet that lacks a specific nutrient is quite likely to be poor, i.e.
lacking in variety and /or quantity. Vitamin E, for example, is
present in almost every food we eat, as it is a component of
plant and animal membranes, and serious deficiencies are rare.
Vitamin A, on the other hand, is more limited in its distribution.
It occurs in its precursor form, β-carotene, in green vegetables
and orange /yellow fruits, and it is present in small amounts as
retinol or retinyl esters in animal products, such as liver, meat,
milk and eggs. If diets are poor in meat products, not only is the
risk of vitamin A deficiency increased, but also the risk of other
micro- and macronutrient deficiencies is raised. Animal products also supply fat to the diet, which is not only an important
source of energy but also a vehicle to enhance the absorption of
fat-soluble vitamins and β-carotene. Thus, the absence of animal or fish products in a diet potentially impairs the utilization
of other nutrients from other foods – that is, poor diets potentially limit human growth and development, and health is also
impaired directly or indirectly.
Eleven papers describe the symposium proceedings.1 The
first paper presents an overview of the issues discussed,2 while
the second traces the evolution of thought that brings us to
where we are today.3 Dr Ross4 tackles one of the thorny issues
that programmers overlook – namely, the need to justify an intervention and its methodology experimentally before embarking on human trials. Dr Lietz also outlines the need for experimental work to define the genetic profile of a target population,
where individual differences may influence the outcome of the
intervention.5 Three papers discuss MMN interventions, in terms
of the need,6 the evidence from randomized controlled studies
(RCT) for the effects of MMN interventions in developing countries,7 and the use of nutritional biomarkers for program evalu-
ation8 . One paper is devoted to the evidence obtained from program experience on the use of MMN powders.9 The final three
papers look at the issues around how to identify appropriate
“platforms” or mechanisms for the delivery of MMN (health, agriculture, market-based and social protection),10 considerations
concerning efficacy, adequacy and plausibility when examining
the results of MMN trials with a view to planning further implementation11 and, finally, translating research into action.12
The need for MMN supplements
The term “multi-micronutrient” first appeared in the 1950s and
was synonymous with essential nutrients, i.e. trace elements
and vitamins.3 In the proceedings, several of the authors point
out that very little is known about current MMN status in most
of the countries of the developing world, with the exception
of vitamin A, iron and iodine. The real needs are therefore not
known; the rest of the micronutrients in MMN supplements are
there “just in case.” That is, after providing nutrients to prevent
nutrient deficiencies known to be present in a population, the
growth and development of the recipients is not restricted by
the deficiencies of other micronutrients. As a result, the major
donor agencies have designed the MMN supplement to provide
a mixture of nutrients that provide enough of each ingredient to
meet the recommended nutrient intakes of each component, as
shown in Table 1 for pregnant and lactating women,13 and for
children aged six to 23 months.14 There is, however, one drawback, namely that the supplement is designed for individuals
who receive adequate amounts of the macronutrients energy,
protein and fat, although poor responses to MMN supplements
suggest that that might not always be the case.11
“Most of the investigative work on
MMN status internationally was
carried out in the 1950s and 1960s”
Most of the investigative work on MMN status internationally
was carried out in the 1950s and 60s, after the formation of the
Interdepartmental Committee on Nutrition for National Defense
(ICNND) in the United States. Nutritional surveys were conducted by the ICNND in 33 countries in which the United States had
strategic interests. The survey manual for these studies outlined
the main physical signs for the detection of malnutrition and
described biochemical methods for the detection of hemoglobin,
serum vitamins A and C, urinary riboflavin and thiamin. The results showed that micronutrient deficiencies, especially anemia
and vitamin A and iron deficiencies, were highly prevalent in
many countries. Dr Richard Semba,3 however, points out that
there were no cross-tabulations of results, i.e. the existence
MuLTIPLE MICRONuTRIENT NuTRITION
SIGHT AND LIFE | VOL. 26 (1) | 2012
TABLe 1: Multi-micronutrient supplements for pregnant and lactating women
Supplementary
Formulation for pregnant and
Micronutrient powder for children 6 –24 months of age b
micronutrient
lactating women a
Multi-micronutrient formulation
Vitamin A μg RE
Vitamin D μg
Nutritional anemia formulation
800
400
300
5
5
–
Vitamin E mg
10
5
–
Vitamin C mg
70
30
30
Vitamin B1 mg
1.4
0.5
–
Vitamin B2 mg
1.4
0.5
–
Niacin mg
18
6
–
Vitamin B₆ mg
1.9
0.5
–
Vitamin B12 μg
2.6
0.9
–
Folic acid μg
400
150 c
160 c
Iron mg
30
10
12.5
Zinc mg
15
4.1
5
Copper mg
2
0.56
–
65
17
–
150
90
–
Selenium μg
Iodine μg
Amounts recommended by uNICEF/WHO/uNu for pregnant and lactating women in developing countries for 6 and 3 months respectively.13
One sachet contains 1 Recommended Nutrient Intake (RNI) in ~1 g and is consumed in one day.14 Frequency of consumption will depend on estimated child
needs and programmatic feasibility for delivery. So 90 sachets for a 6 month period will provide on average 3 – 4 sachets per week or an additional intake
of 50% of the RNI for each micronutrient/day.
c
Dietary folate equivalents
a
b
of multiple deficiencies in individuals was not calculated. It is
interesting that the nutritional information that stimulated the
ICNND surveys arose from a nutritional survey in Korean army
troops, which showed a high prevalence of many micronutrient
deficiencies. young men are not usually the group within a community to show evidence of micronutrient deficiencies. However, at that time the army rations for the Korean troops were,
no doubt, modeled on local preferences and food availability.
Troops restricted to barracks would have had little opportunity
to supplement their diets. History has shown that groups of people living in restricted circumstances are more susceptible to
malnutrition than people eating similar diets, but without physical restriction of their movements. For example, thiamin deficiency has been reported in children living in boarding schools,
prisoners in jail15 and Chinese laborers working in the tin mines
of Malaya,16 while vitamin C and thiamin deficiency was found
in early migrants to North America who were restricted by the
long cold winter months to their cabins, with minimal food.17
Where diet is restricted through ignorance, poverty or social or
environmental circumstances, quality deteriorates and the risk
of dietary deficiencies increases.3
To what extent do the revelations of the 1950s apply today?
It is estimated that two billion people worldwide are anemic18
and, similarly, that millions are affected by iron deficiency and
deficiencies of other nutrients, such as vitamin A and zinc.6
Programs tend to focus on iron, iodine and vitamin A and, to a
slightly lesser extent, on zinc and folic acid, because evidence
of their deficiencies exists and they have important functional
outcomes of public health concern. Semba, however, illustrates
the strong circumstantial evidence for the existence of other micronutrient deficiencies in people who are extremely poor (Figure 1). The figure, based on the work of Bloem and colleagues
in Indonesia, shows that, if rice is virtually the only component
in the diet of poor people, it will not meet the essential requirements of most micronutrients. The composition of cooked white
rice and the recommended nutrient requirements for pre-school
children are shown in Table 2. They indicate that all fat-soluble
vitamins and most water-soluble vitamins and minerals need to
be obtained from other items in the diet. The epidemics of beriberi that spread through Asian countries with the introduction
of cheap white rice in the late nineteenth and early twentieth
centuries is ample evidence that rice alone will not supply sufficient thiamin to prevent deficiency in any member of the community.19 However, despite the high likelihood of the existence
of micronutrient deficiencies in developing countries, there is
currently little biochemical evidence for logistic reasons (invasive blood drawing, adequate laboratory facilities, the lack of a
cold chain, etc.).7
31
Multiple Micronutrient Nutrition
figure 1: Influence of socioeconomic status on food consumed and the risk of micronutrient deficiencies
Risk of micronutrient
deficiencies
Relative composition of the diet
n
ke
ic
ef
Be
il k
Ch
gs
M
Eg
Fi
sh
r
l
ga
Oi
Su
it
et
Fr
u
Ve
g
Ri
ce
ab
le
s
Socioeconomic status
LOW
Fr able
ui
s
t
Su
ga
r
Oi
l
Fi
sh
Eg
gs
M
il k
Ch
ic
ke
Be n
ef
et
Ve
g
Ri
ce
NOT POOR
Ve
ge
Fr tab
ui le
s
t
Su
ga
Oi r
l
Fi
sh
Eg
gs
Ri
ce
LESS POOR
Ri
Ve
ge
Fr tabl
ui e s
t
Su
ga
Oi r
l
Fi
sh
HIGH
ce
MODERATELY POOR
et
Fr abl
ui e s
Su t
ga
Oi r
l
Ve
g
ce
VERY POOR
Ri
32
EXTREMELY POOR
Diagram to illustrate the association between the relative composition of the diet and the risk of micronutrient deficiencies
(with acknowledgements to Dr R Semba and the Journal of Nutrition3)
VERY HIGH
MuLTIPLE MICRONuTRIENT NuTRITION
SIGHT AND LIFE | VOL. 26 (1) | 2012
TABLe 2: Nutrient composition of cooked, long-grain ricea and daily recommended nutrient intakes (RNI) for pre-school childrenb
Energy and fat-soluble vitamins
Rice
Energy
Vitamin A
Water-soluble vitamins
RNI
130 kcal
1198 kcal
0.55 MJ
5.0 MJe
0
400 – 450
(μg RE)c
Carotene
0
None
available
0.1
5.0 d
0
5.0
(mg)
Vitamin D
(μg)
Thiamin
RNI
0.16
0.5 – 0.6
(mg)
(μg RE)
Vitamin E
Minerals
Rice
Riboflavin
0.01
0.5 – 0.6
1.5
6.0 – 8.0
1.2
4.2 –12.6
0.09
0.5 – 0.6
97
150 – 200
0
0.9 – 1.2
0
30 – 35
Zinc
0.49
2.9 – 9.6
6
17 – 22
(mg)
(mg)
Pyridoxine
RNI
(mg)
(mg)
Niacin (total)
Iron
Rice
Selenium
(μg)
(mg)
Folate (μg
dietary folate
equivalents)
Vitamin B₁₂
(μg)
Vitamin C
(mg)
Values shown are for 100 g 43
Values shown cover the age range from 1–6 years and allowances for low to high bioavailability in the case of zinc and iron44
c
RE are retinol equivalents
d
mg α-tocopherol
e
RNI for energy is an average to cover the age range and differences between the sexes from 3.9 to 6.6 MJ/day45
a
b
“What may be adequate in one
person or dietary environment may
not be in another”
MMN requirements when planning interventions
The consequences of micronutrient limitations are also influenced by physiological requirements and bioavailability; what
may be adequate in one person or dietary environment may not
be in another. Infants, children and pregnant or lactating women
have higher requirements than other groups in the population,
relative to energy requirements, and thus are especially vulnerable to the effects of deficiencies when the diet is poor. However,
even mild deficiencies in children may impair both physical and
mental development. Seasonal factors are also extremely important in influencing the effects of a supplement on nutritional
outcome and should be considered when planning an intervention. Ross argues that public health nutrition has lagged behind
many of the other health sciences in embracing animal models
to better understand clinical disease. She argues that human
micronutrient intervention studies should be tested experimentally first, to refine the design (Table 3).4 However, the investigations outlined in Table 3 are particularly relevant to highdose, one- or two-nutrient(s) studies, such as the α-tocopherol,
β-carotene (ATBC) study,20 but could equally apply to the Pemba
trial, where doses akin to requirements were used.21 In the ATBC
study, 20 mg β-carotene was given daily to smokers, while children in the Pemba study received 12.5 mg iron. In both, there
were adverse effects of treatment. Ross believes that animal
studies to pre-test and refine such interventions might have led
to a better outcome.4
Both studies were done in subjects potentially exposed to
high levels of inflammation: tobacco smoke in the ATBC study
and endemic malaria in the Pemba trial. Inflammation alters the
serum concentrations or biomarkers of many nutrients (Table 4)
and is a factor which is commonly overlooked in micronutrient
studies. In such cases, it is easy to assume that deficiency exists, especially when there is uncertainty concerning the dietary
supply of most nutrients or sunlight irradiation, as in the case of
vitamin D, or a limited knowledge of lifestyle factors. Not only do
33
34
MuLTIPLE MICRONuTRIENT NuTRITION
TABLe 3: Some advantages from conducting animal studies prior to human intervention trials ⁴
Objective to investigate
Potential outcome /advantage for human study
Dose range
> Better dose selection if only a single dose can be tested
Single versus multi-nutrient
> Better understanding of interactive effects; better selection of treatments to be
included or not needed
Variability
> Better power analysis to assure adequate sample size
Biomarker testing
> Better biomarker selection
Direct testing on tissues that are not available in human studies
> Better understanding of physiological effects underpinning observed outcomes
Long-term follow-up
> Better understanding of potential safety and efficacy in vivo
depressed concentrations of serum nutrients contribute to overestimates of those at risk of deficiency, but supplements may
antagonize a potentially protective physiological mechanism.
Two recent studies in malaria-endemic areas have both shown
the adverse effects of iron-containing supplements: the Pemba
study21 and a second in a rural area of the Handeni District in
Tanzania.22 In both cases, iron was given with folic acid and, in
Tanzania, 30% of children displayed sub-clinical inflammation
(CRP > 8 mg/L). Inflammation is known to influence both zinc and
iron metabolism and the serum concentrations of both nutrients
fall substantially within the first 24 hours following the onset
of infection.23 Iron was associated with adverse effects in both
studies, but not the zinc supplement. Likewise, folate was probably not linked to the adverse effects, since earlier iron supplementation studies did not include folate but still increased the
risk of malaria.24,25 Furthermore, inflammation is not known to
have any effects on serum folate.26 Lastly, an important observation in the Tanzanian study was that the increase in malaria
TABLe 4: Serum micronutrients and biomarkers influenced by inflammation
Group
Serum biomarker
Effect of infection / inflammation
Fat-soluble micronutrients
Retinol a
> Rapid fall in serum concentration
25-Hydroxy-cholecalciferolb
> Rapid fall in serum concentration
Water-soluble micronutrients
Minerals
Carotenoids
> Low concentrations associated with inflammation
Vitamin C
> Rapid fall in serum concentration
Vitamin B₆
> Low concentrations associated with inflammation
Iron
> Rapid fall in serum concentration
Zinc
> Rapid fall in serum concentration
Selenium
> Low concentrations associated with inflammation
Copper
> Slow rise in concentration associated
Hemoglobinc
> Low concentrations associated with inflammation
Ferritinc
> Rapid rise in serum concentration
Transferrin receptorsc
> Low concentrations associated with inflammation
Zinc protoporphyrinc
> Low concentrations associated with inflammation
Ceruloplasmind
> Slow rise in concentration associated
with inflammation
Mineral biomarkers
with inflammation
Retinol is an important biomarker of vitamin A status 40
25-Hydroxy-cholecalciferol is the biomarker of vitamin D status 46
c
Biomarkers of iron status 41,47
d
Biomarker of copper status
a
b
sIGHT AND LIFE | Vol. 26 (1) | 2012
occurred in iron-deficient children and not in those that were
replete;22 this is contrary to the findings of the Pemba study,
which suggested that iron-replete children on iron supplements
were more at risk from malaria. It has been suggested that the
results of the Pemba trial could have been predicted,27 but they
also illustrate that much more research is needed to understand
the influence of nutrients on children exposed to disease and,
especially, to malaria.
In contrast to the two supplementation studies, a study using
Sprinkles™ to supply similar amounts of iron (12.5 mg/day) in a
malaria-endemic area in Kenya showed moderate reductions in
anemia and no adverse effects of treatment based on hospital
admissions.28 The MNP was given with food and therefore may
be better managed by a child than a concentrated dose of iron,
as provided by a capsule or tablet. However, it is doubtful if the
use of the MNP was as regular in Kenya as it was in Pemba or
Handeni, as the intervention was dependant on consumer purchases. Although almost 90% of the children had used Sprinkles™ in the period studied, over 60% only used it a little more
than once a week.29
In supplementation studies, most nutrients are supplied in
the form in which they are needed by the body; however, in the
case of vitamin A, trials involving β-carotene have been done,
especially in women of reproductive age, as vitamin A in this
form is not teratogenic. However, Lietz and colleagues described
some previously unexpected limitations in the enzyme converting β-carotene to retinal in this supplement. They showed that
there are a number of phenotypic variations of the enzyme responsible for converting β-carotene to retinal that reduce the
catalytic activity.5,30,31 The distribution of some of these enzyme variations with the poorer catalytic activity may also differ
depending on ethnic origin, being more common in Asian (70%)
than European/American (30%) or African (20%) populations.5
These observations reinforce the call for experimental work to
precede human intervention where trials with β-carotene are
involved.
“People who are replete are less likely
to respond to MMN supplements
and the effect will dilute the overall
response to an intervention program”
Factors affecting MMN delivery
The objective of the paper by Neufeld and Cameron6 was to review the information from dietary intake, serum biomarkers and
formal and informal health systems that can be used to identify
the need for and assist in designing micronutrient programs.
Multiple Micronutrient Nutrition
They point out that most biomarkers identify deficiency and cannot be used to assess whether intakes are optimized or in excess.
The inability to assess whether iron intakes are optimal from iron
biomarkers is particularly well illustrated in communities where
hemoglobinopathies are common (see below). The authors recognized the confounding effects of inflammation on ferritin, but
failed to note that several other important micronutrients are affected by inflammation or that depression of serum vitamin concentrations through inflammation can lead to overestimations of
nutrient deficiencies (Table 4). People who are replete are less
likely to respond to MMN supplements and the effect will dilute
the overall response to an intervention program. In the case of
diet, they recognize that there are many ways to calculate nutrient intake (information from consumers, wholesalers, importers,
etc.) but that bioavailability is more difficult to estimate, as uptake by the body depends on multiple factors. So, in the case of
iron, there are facilitators and inhibitors (vitamin C and phytate,
respectively) and the type of iron used will also influence bioavailability. However, dietary data are particularly scarce for
those regions of the world with higher vulnerability to micronutrient deficiencies: the authors only found published data for
five countries in Africa, four in South and Central America and
four in South East Asia.
Hemoglobinopathies also influence iron metabolism.32 Thalassemia mutations are extremely common in South East Asia
and the Middle East: up to 25% of Thai people are carriers of
α-thalassemia; there are regions of Thailand, Laos and Cambodia where up to 60% of people are carriers of hemoglobin E
(HbE);33 and there are many millions of people in China who
are carriers of the α- and β-thalassemia gene.34 People who
carry the homozygote or compound heterozygotes (HbE/βthalassemia) of these genes display ineffective erythropoiesis,
which stimulates iron absorption even if stores are adequate,
and have an increased risk of iron excess. Recent work with
heterozygotes of these conditions suggests that some may also
display similar, although milder, characteristics32 and a higher
risk of anemia.33 In heterozygotes for α- or β-thalassemia, iron
utilization is lower than in controls and iron absorption is not
appropriately regulated, despite modestly higher concentrations of serum ferritin and storage iron. In the compound heterozygote (HbE/β-thalassemia), iron utilization was depressed,
iron absorption and body iron stores were markedly higher and
additional dietary iron would not be beneficial, despite the
presence of anemia. In people carrying the HbE trait (heterozygotes), the most common hemoglobinopathy in Thailand, iron
utilization and absorption did not differ from that of the controls. Thus, in regions where there is a high prevalence of these
traits, particularly the thalassemias, iron should be targeted at
groups vulnerable to iron deficiency (women and children). If
food fortification with iron is used, iron stores should be moni-
35
36
MuLTIPLE MICRONuTRIENT NuTRITION
TABLe 5: Population biomarkers for nutrients vitamin A, iron, zinc, folate and vitamin B12
Nutrient
Measurement of statusa
Vitamin A
> Serum retinol and history of night blindness
> Supported by dose response test in subsample if possible
Iron
> Hemoglobin and serum ferritin
> Supported by serum transferrin receptors and zinc protoporphyrin
> Supported by indicators of underlying infection to interpret serum ferritin
Folate
> Serum folate and red blood cell folate
Vitamin B12
> Serum B12
a
Dietary intake should be determined as an indicator of nutrient deficiency and underlying infection should be measured using the acute phase proteins,
serum C-reactive protein and α1-acid glycoprotein.40,41 See also Table 4 for influence of inflammation on biomarkers.
tored in groups with a low iron turnover, such as men or postmenopausal women, to detect excessive exposure, if present.32
Knowledge of other programs ongoing within countries and of
global data resources may help to design context-appropriate
interventions to improve micronutrient status. Within-country
programs may also provide access to pre-existing structures
within countries. There are also national and other sources of
data available from WHO and uNICEF, such as Multiple Indicator Cluster Survey (MICS) reports to assist in planning trials and
Vitamin and Mineral Nutrition Information System (VMNIS),12
Department of Health Surveys (DHS), reports from ministries
and non-governmental organizations and peer-reviewed literature. (See also the paper on WHO activities in this supplement.)12 These provide data of varying quality and usefulness,
but should be used to identify the need and its location within
country. They emphasized that monitoring and evaluation systems should be in place to detect changes in micronutrient
status over time. Consistent collection and reporting of such
information would allow for more accurate mapping of nutritional shortfalls and provide information on whether existing
interventions are meeting the required need.6
Where are we now?
The objectives of the review by Christian and Tielsch were, first,
to show the role of statistical methods to demonstrate the efficacy of nutritional intervention in the developing world and,
secondly, to summarize some of the evidence for the beneficial
impacts of MMN supplements in pregnant women and young
children on a number of outcomes.7 A randomized control trial
(RCT) is considered the gold standard to evaluate the efficacy
of a nutritional intervention. The key characteristic is the concept of comparing like with like. That is, the intervention and
control groups should have the same degree of risk for the outcome being examined. Ideally, neither the investigators nor the
subjects will be aware of who is receiving which treatment, to
avoid introducing bias. In addition, subjects are randomly allocated to the treatment groups, which can be at the level of
the individual or, in large trials, at a village or community level.
However, comparability, blinding and randomization alone are
not sufficient to guarantee a satisfactory result, since factors
specific to a community (infections such as malaria, exposures
such as arsenic, aflatoxin or genetic conditions such as hemoglobinopathies) may obscure any differences in the outcome of
the intervention. There is therefore also a need to replicate RCTs
under different settings. Data from RCTs are analyzed by metaanalysis or systematic reviews to provide an average effect for
the outcome of interest. In the case of systematic reviews, the
data included will be restricted to only those studies that meet
defined criteria.7
“The impact on birth weight was
larger in women with a higher BMI
and there was also an increase
in large-for-gestational-age births”
In the last decade, there has been a global interest in establishing the efficacy of the united Nations International Multiple
Micronutrient Preparation (uNIMAPP) formulation of 15 micronutrients for pregnancy (Table 1).13 Meta-analyses of the effects
of antenatal MMN supplements in 12 RCTs35,36 revealed a small
but significant increase in birth weight (22.4 g, 95% CI 8.3, 36.4)
and an 11% reduction in low birth weight (CI 3,19). There were
no significant effects on preterm births or prenatal mortality. The
uNIMAPP preparation was tested in nine of the trials. However,
the fact that all trials were largely conducted using the standard
sIGHT AND LIFE | Vol. 26 (1) | 2012
of care of iron-folic acid as the control groups probably accounts
for the small effects. That is, folate and iron deficiencies are the
major micronutrient deficiencies in pregnant women in developing countries and the addition of other micronutrients had little
impact on birth outcomes. However, an important observation
was that the impact on birth weight was larger in women with a
higher BMI. There was also an increase in large-for-gestationalage births.35 Habicht and Pelto suggest that the latter observations may indicate that many women were also deficient in one
or more macronutrients and therefore could not benefit fully
from the supplement.11
In children, MMN as supplements, powders or fortified readyto use foods are being used to address MMN deficiencies in developing countries. Outcomes of interest range from birth weight
to child growth, infant morbidity, mortality and nutrient status
and cognitive function. Christian and Tielsch reported that comparisons of height/length or weight for those receiving three or
more micronutrients, compared to fewer micronutrients, found
small effects of 0.13 cm (0.06, 0.21) and 0.14 g (0.03, 0.25)
respectively. There was little evidence of effects on morbidity
or cognitive function7 and other workers also report that evidence for the effectiveness of micronutrient supplements given
as powders (MNP) in large-scale programs on these outcomes is
scarce.9
The efficacy of MNP in the treatment of anemia in moderately anemic children and well-controlled trials has been clearly
demonstrated.37 Nevertheless, information about the impact
of MNP in large-scale programs is scarce. The aim of the paper
by Rah and colleagues was to briefly review experience and
data collected during impact evaluation in recent large-scale
MNP programs. More than 80 MNP programs have been carried out at sub-national or pilot scale, targeting children under
five years of age and conducted in many different countries
across several regions. Most programs have been implemented
either in refugee camps or as part of an emergency response.
They report that consumption of 90 sachets by a child within
a flexible time-frame of 90 to 180 days is considered sufficient
to improve micronutrient intake to approach recommended
levels (Table 1). The recommendation of 60 doses over two to
four months is efficacious in reducing anemia; however, these
results were obtained under controlled conditions. The joint
statement recommended 15 micronutrients38 and, in general,
that composition was maintained in the MNP in different studies, except where there were known to be other components in
the diet or environment that might compete (malaria, tannins
and phytic acid) or lead to an excess (on-going supplementation programs, fortified foods, e.g., vitamin A in oil, etc.) when
small changes were made. Examples of the changes made to
maintain the availability of the MNP contents are provided by
the authors.9
Multiple Micronutrient Nutrition
“Because anemia is influenced by so
many factors, hemoglobin may not be
the most appropriate biomarker to use”
The impact of MNP (MixMe™) is reported in a number of
refugee camps. The main outcome assessed was hemoglobin
concentration, as a proxy indicator of micronutrient deficiencies,
and anthropometric measurements and morbidity in the prior
two weeks, to assess nutritional status and health. In all cases,
prevalences of anemia were high (> 45%) at the start but, after
the introduction of MNP, some results increased, some fell and
others did not change. There was mostly a small positive effect of
MNP on stunting and, in one camp, there was evidence that the
cumulative incidence of diarrhea fell over three years. Subjects
were mostly used as their own controls in these evaluations, so
other changes could have taken place to negate any impact of
MNP. The authors recognized these considerations as important
and suggested that, because anemia is influenced by so many
factors, it may not be the most appropriate biomarker to use.9
Biomarkers of program impact evaluation
in developing countries
Wasantwisut and Neufeld8 outlined the activities of the program group within the Biomarkers of Nutrition for Development
(BOND) initiative. In countries where micronutrient deficiencies are prevalent, the programs in place require biomarkers
of exposure and status to monitor programs and evaluate impact. The goal of BOND is to provide guidance for the selection
and interpretation of biomarkers that meet ranges of interests
among food and nutrition stakeholders.39 The BOND group has
focused on five micronutrients: iron, zinc, vitamin A, folate and
vitamin B12. Although the focus of the working groups was at
the population level, the individual use and interpretation of appropriate biomarkers was also discussed (Table 5). The authors
also pointed out that biomarkers of micronutrients within a program context are not enough; there is a need to include proxy
measures of factors that influence micronutrient utilization or
metabolism, e.g., growth, dietary intake (of both nutrients and
inhibitory factors like phytate) and infection rates. Biomarkers
of iron, vitamin A and zinc are strongly influenced by inflammation,40,41 (Table 4) but there is no evidence for any effects
on folate or vitamin B12.26 The information is needed so that
program managers have a clear understanding of the situation
to effectively plan and implement programs. Finally, the group
suggested that program managers would benefit from specific
information related to the use of biomarkers, e.g., sample size,
timing and frequency of measurements to meet specific program
37
38
MuLTIPLE MICRONuTRIENT NuTRITION
TABLe 6: Methods of delivery of MMN
Platform of program delivery
Methods
Health
> Tablets or syrups
> Fortification
> Micronutrients commercially incorporated in foods
> Bio-fortification
> Home fortification e.g. MNP
> Diet modification
Agriculture
> Promote consumption of bio-fortified crops; homestead food production (HFP) generally limited in scale;
HFP targeted at women to increase household availability as well as generating income from sale of crops.
Market based
> In many setting delivery has been through the private sector in retail markets; promotion of staple foods as
well as fortified complementary foods; uncertainty as to whether can reach the poorest people.
Social protection of individuals
and households
> CCTs (conditional cash transfers) provide monetary transfers conditional on compliance with a number of
criteria e.g. attend preventive health services, maintain school-age children at school.
> SFPs (school feeding programs) can be a vehicle for MMN interventions and particularly effective at reaching
girls. However, they fail to reach children in the critical window of pregnancy to 24 months.
objectives. Capacity development for in-country processing of
samples is also required. The group considered that there was
a good case for the development of a guide to encompass this
information, to assist program managers to plan and implement
programs.
Identify ing potential programs and platforms to deliver
MMN interventions to at-risk populations
The paper by Olney and colleagues discussed the types of MMN
intervention programs available and those that might be used
more effectively to improve status.10 They identified four broad
types of delivery platform (health, agriculture, market-based
and social protection) (Table 6), seven performance criteria and
four program elements. They discussed the critical knowledge
gaps and highlighted what was needed to improve the effectiveness of current intervention methods in at-risk populations.
The Health platform has been widely used to promote MMN
interventions and, together with messages to promote behavioral change, has been well accepted and appropriately utilized in
many countries. There has been high coverage, excellent compliance and a positive impact in reducing some micronutrient
deficiencies. Programs are well targeted at women and children.
However, the potential to deliver MMN intervention is largely
dependent on the reliability and consistency of supplies, and
inputs, well-trained health staff and sustainability may well depend on services of beneficiaries. In developing countries, these
are often critical constraints.
The agriculture platform is particularly suitable for promotion of the production and intake of micronutrient-rich foods,
including biofortified crops. Programs have generally been
successful in promoting increased intake of micronutrient-rich
foods, but have been criticized for their low coverage. However,
it was pointed out that the Helen Keller International (HKI) program to promote homestead food production was reported to
have improved food security in five million vulnerable Bangladeshi people.
Market-based programs are gaining increased attention, as
it is hoped that consumer demand for the MN-rich products
will promote sustainability and increase health and welfare.10
However, there is concern that a marketing approach will not
reach the very poor. The marketing of Sprinkles™ in Kenya29 has
shown that sellers have to be well trained to convey the right
messages to consumers and must be regularly encouraged to
buy stocks by inducements. Tracking of sales and use by the local population in the Kenyan study suggested that only 33% of
households had purchased Sprinkles™ at the time of the visits
but, although 90% of children had used MNP at some time, consumption was only ~1 sachet per week. Both increased consumer
awareness of the product and a perceived benefit to the children
may be needed to increase the effectiveness of a market-based
approach.
Olney and colleagues discussed two social protection platforms. The first, conditional cash transfer programs, have been
praised for their remarkable impact on reducing poverty, food
insecurity and, in some cases, gender inequalities, although they
have only had a variable impact on micronutrient status.10,42
Other workers have pointed out that more research on beliefs
around traditional and modern biomedical practices, socio-
sIGHT AND LIFE | Vol. 26 (1) | 2012
cultural norms, gender relations and the everyday experience of
poverty in many dimensions are needed to obtain a better understanding of the many influences on health care decisions, before
these programs can be used to impact on micronutrient status.42
The second platform discussed was the school-feeding program
as a means of intervention. The programs are popular because
of the logistic simplicity of targeting schools and reaching girls
before pregnancy (Table 6). The programs are not necessarily
independent, since a condition of receiving a cash donation may
be to ensure that girls attend school to a certain age.
Multiple Micronutrient Nutrition
by baseline birth weight values. They argued that present standards for implementing and interpreting RCT in nutrition needed
to be re-examined. They considered that the current approach
to efficacy studies did not enable the adequacy of the dose and
the plausibility of the results to be assessed and they called for
modifications to include intermediary behavioral and biological
steps between intervention and biological outcomes. As ethical
considerations will restrict much alteration in the design of human intervention studies, the request translated into a need for
more experimental work to precede the human interventions.
“Governments must have the political “Individuals who are replete do not
will to make long-term investments
in the provision of effective MMN
programs for pregnant and lactating
women and young children”
The authors concluded that each of the systems described
has the potential to deliver MMN interventions, but that much
still needs to be done. Key strengths include good targeting of
poor populations and, in some cases, women and children under
two years of age. However, all of the programs were found to
have weaknesses which should be addressed. Sustainability was
believed to be most likely achieved through agricultural and/or
market-based platforms and profits could potentially feed back
into the system to reach the poorest of the poor. Finally, governments have to be encouraged and have the political will to make
long-term investments in the provision of effective MMN programs for pregnant and lactating women and young children.
Is more research needed?
In the last paper in the proceedings, Habicht and Pelto questioned whether there had been sufficient scientific scrutiny of the
results of RCT to justify their implementation without further research. They pointed out that the efficacy of MMN supplementation had been established by state-of-the-art RCT and that these
trials had also provided strong evidence of widespread deficiencies. However, the magnitude of the impact of the trials intended
to demonstrate a health benefit had generally been inadequate.
The authors gave as an example the small benefits to birth weight
obtained by MMN supplementation of pregnant women, where
the mean added weight gain by the infants of the supplemented
mothers was only 22 g.35 The authors recognized that the controls were also being supplemented with iron and folate, so any
effect from the comparison of the two groups was due to the other micronutrients in the supplement. Even so, the impact of the
MMN was not related to the presumed need of the infants judged
respond to additional micronutrients
and will clearly dilute the impact
of the intervention”
Adequacy and plausibility of response
The authors argued that RCT, which compared MMN against iron
and folate and did not contain a third group that received no
intervention, was most likely to underestimate the added benefit
of the other micronutrients. The danger of such a result was that
the magnitude of results might not be sufficiently large to demonstrate a public health benefit for MMN. The benefit must be
weighed against all the other costs of implementing the program
and had to be adequate for policy considerations. The benefit or
response to the MMN supplement would also be diluted by the
fact that, in any population with endemic undernutrition, there
will always be individuals who were not deficient. Individuals
who are replete do not respond to additional micronutrients;
clearly, these individuals will dilute the impact of the intervention. Other factors can also dilute the response, such as the lack
of fat to enable the absorption of fat-soluble vitamins or genetic
factors that impair the response to the added micronutrients.
Thus, assessment of the potential to respond to an intervention
requires knowledge of many factors. However, a partial solution may be to include a group of nutritionally replete individuals in the study, who are exposed to the same environmental
circumstances to provide a “replete normal response.” As well
as assessing the adequacy of the response, the plausibility of
the results must also be interpreted. The authors argued that,
where results were counter-intuitive, they should be followed up
to identify the factors to explain them. They suggested that the
absence of a dose response in relation to a baseline deficiency
may occur because the supplement cannot be used by the people receiving the intervention. Food is not supplied in MMN trials
and limitations in dietary protein and energy are very likely to
diminish any response to MMN.
39
40
Multiple Micronutrient Nutrition
Finally, the authors pointed out that failure to properly account for
adequacy and plausibility following efficacy studies can impact
on implementation. There is already evidence from the limited
impact documented from the MMN efficacy trials that donors are
losing interest in MMN interventions. To meet this challenge, the
efficacy trial findings should be put into the context of what is
already known about the essentiality of micronutrients for performance, health and survival. However, efficacy research must
also be expanded and better linked to program development
and implementation. The authors argued that more research is
needed on the factors influencing the program impact pathway.
They pointed out that understanding the relative merits of the
different pathways will become overridingly important when a
variety of program platforms (health, agriculture, market-based
and social protection)10 are tested as potential delivery mechanisms for MMN.
Translating research into action
For the WHO, research is defined as the development of knowledge with the aim of understanding health challenges and mounting an improved response to them. In 2009, the WHO adopted
a new process by which recommendations for safe and effective
micronutrient intervention were developed, ensuring the use
of best practices and available evidence. Pena-Rosas and colleagues12 outlined the steps involved, leading to the methodology to assess overall evidence quality and strength. Guidelines
were being developed for iron and vitamin A supplementation,
home fortification with MNP and the fortification of staple foods.
The paper focused on the process currently being followed by
the WHO Department of Nutrition for Health and Development
to produce global guidelines on safe and effective nutrition interventions, especially in respect of micronutrients.
“Appeals were made for all interventions to be monitored and
reported so that others can benefit
from the collective experience”
cases, specific evidence that suggests that other micronutrient
deficiencies co-exist. Unfortunately, randomized controlled trials of MMN in pregnant and lactating women have demonstrated
only small benefits and several speakers discussed the reasons
for this limited effectiveness. MNPs have been shown to be effective under controlled conditions, but their use in emergency
situations produced inconsistent results. Speakers discussed
the limited usefulness of some biomarkers and indicated that
better biomarkers were needed for those working in the field.
An appeal was made for more experimental work to precede
micronutrient intervention programs, to gather appropriate
background information in target populations to improve effectiveness and reduce the risk of tragedies. It was also pointed out
that most programs to date had approached intervention from a
health perspective. Three other options were presented, namely
agricultural, market-based and social protection schemes. The
authors noted some successes, but also that a lot more information was needed on biomedical practices, sociocultural norms,
gender relations and everyday experience of poverty before
some of these platforms could be adapted for MMN interventions. Finally, it was pointed out that the WHO is collecting
information on intervention programs. The data is available to
assist researchers, but appeals were made for all interventions
to be monitored and reported so that others can benefit from the
collective experience.
Editor’s note: Workshop Proceedings: 2nd World Congress
of Public Health, Portugal, 2010: Evidence in Multiple Micronutrient Nutrition: From History to Science to Effective
Programs can be obtained from Sight and Life upon request.
Correspondence: David I Thurnham,
46 High Street, Little Wilbraham, Cambridge, CB21 5JY, UK
E-mail: [email protected]
References
01.Kraemer K, Semba RD, Neuhouse M. Multiple micronutrient
nutrition: Evidence from history to science to effective programs.
J Nutr 2012; 142:136–209.
Conclusions
A workshop on MMN interventions was held in Lisbon, Portugal in 2010. The objective was to discuss the successes and
shortcomings of the programs in developing countries that aim
to provide up to one recommended nutrient intake (RNI) per
day of the major micronutrients to women of reproductive age
and young children. Vitamin A, iron and iodine deficiencies are
known to affect many millions of women and children in developing countries, but there is also circumstantial and, in some
02.Kraemer K, de Pee S, Badham J. Evidence in multiple micronutrient
nutrition: from history to science to effective programs. J Nutr 2012;
142:138S–142S.
03.Semba RD. The historical evolution of thought regarding multiple
micronutrient nutrition. J Nutr 2012; 142:143S–156S.
04.Ross AC. Use of laboratory studies for the design, explanation,
and validation of human micronutrient intervention studies. J Nutr
2012; 142:157S–160S.
05.Lietz G, Oxley A, Leung WC et al. Single nucleotide polymorphisms
Multiple Micronutrient Nutrition
sIGHT AND LIFE | Vol. 26 (1) | 2012
upstream from the ß-carotene 15,15'-monoxygenase gene influence
22.Veenemans J, Milligan P, Prentice AM et al. Effect of supplementa-
provitamin A conversion efficiency in female volunteers. J Nutr
tion with zinc and other micronutrients on malaria in Tanzanian
2012; 142:161S–165S.
children: A randomised trial. PLoS Med 2011; 8:e1001125.
06.Neufeld LM, Cameron BM. Identifying nutritional need for multiple
micronutrient interventions. J Nutr 2012; 142:166S–172S.
07.Christian P, Tielsch JM. Evidence for multiple micronutrient effects
based on randomized controlled trials and meta-analyses in developing countries. J Nutr 2012; 142:173S–177S.
08.Wasantwisut E, Neufeld LM. Use of nutritional biomarkers in program evaluation in the context of developing countries. J Nutr 2012;
142:186S-190S.
09.Rah JH, de Pee S, Kraemer K et al. Program experience with micronutrient powders and current evidence. J Nutr 2012; 142:191S–196S.
10.Olney DK, Rawat R, Ruel MT. Identifying potential programs and
doi:10.1371/journal.pmed.1001125.
23.Beisel WR. Trace elements in infectious processes. Med Clin North
Am 1976; 60:831–849.
24.Smith AW, Hendrickse RG, Harrison C et al. The effects on malaria
of treatment of iron-deficiency anaemia with oral iron in Gambian
children. Ann Trop Paed 1989; 9:17–23.
25.Oppenheimer SJ, Gibson FD, MacFarlane SBJ et al. Iron supplementation increases prevalence and effects of malaria: report on clinical
studies in Papua New Guinea. Trans R Soc Trop Med Hyg 1986;
80:603–612.
26.Galloway P, McMillan DC, Sattar N. Effect of the inflammatory
platforms to deliver multiple micronutrient interventions. J Nutr
response on trace element and vitamin status. Ann Clin Biochem
2012; 142:178S–185S.
2000; 37:289–297.
11.Habicht JP, Pelto GH. Multiple micronutrient interventions are efficacious, but research on adequacy, plausibility, and implementation needs attention. J Nutr 2012; 142:205S–209S.
12.Pena-Rosas JP, De-Regil LM, Rogers LM et al. Translating research
27.Oppenheimer SJ. Comments on background papers related to iron,
folate, malaria and other infections. Food Nutr Bull 2007;
28:S550–S509.
28.Suchdev PS. Nyando integrated child health and education project.
into action: WHO evidence-informed guidelines for safe and effec-
2009. Nairobi, 4th Africa Nutritional Epidemiology Conference
tive micronutrient interventions. J Nutr 2012; 142:197S–204S.
<http://imtf.org/blog/2010/10/29/ANEC%204%20Nairobi%20
13.UNICEF/UNU/WHO. Composition of a multi-micronutrient
supplement to be used in pilot programmes among preg-
Declaration>.
29.Suchdev PS, Ruth L, Obure A et al. Monitoring the marketing,
nant women in developing countries. [http://www.idpas.org/
distribution, and use of Sprinkles™ micronutrient powders in rural
pdf/059CompositionofMult-MicronutrientSupplement.pdf]. 1999.
western Kenya. Food Nutr Bull 2010; 31:S168-S178.
New York, UNICEF.
30.Leung WC, Hessel S, Méplan C et al. Two common single nucleotide
14.HF-TAG. Programmatic guidance brief on use of micronutrient pow-
polymorphisms in the gene encoding beta-carotene 15,15’-monoxy-
ders (MNP) for home fortification. 2011. Home Fortification Techni-
genase alter beta-carotene metabolism in female volunteers. FASEB
cal Advisory Group, <http://www.gainhealth.org/hftag/document>.
15.de Montmollin D, MacPhail J, McMahon J et al. Outbreak of beri-beri
in a prison in West Africa. Trop Doct 2002; 32:234–236.
16.Platt BS. Epidemiology and clinical features of endemic beriberi.
Proceedings of a conference on beriberi, endemic goitre and hypervitaminosis A. Proc F A S E B 1958; 17(Suppl 2):3–20.
17.Carpenter KJ. The history of scurvy and vitamin C. Cambridge:
Cambridge University Press; 1986.
18.World Health Organization, Centres for Disease Control and Preven-
J 2009; 23:1041–1053.
31.Lietz G, Lange J, Rimbach G. Molecular and dietary regulation
of beta,beta-carotene 15,15’-monooxygenase 1 (BCMO1). Arch
Biochem Biophys 2010; 502:8–16.
32.Zimmermann MB, Fucharoen S, Winichagoon P et al. Iron metabolism in heterozygotes for hemoglobin E (HbE), alpha-thalassemia 1,
or beta-thalassemia and in compound heterozygotes for HbE/betathalassemia. Am J Clin Nutr 2008; 88:1026–1031.
33.George J, Yiannakis M, Main B et al. Genetic hemoglobin disorders,
tion (CDC). Assessing the iron status of populations. 2nd. Geneva:
infection, and deficiencies of iron and vitamin A determine anemia
WHO Press; 2007.
in young Cambodian children. J Nutr 2012; in press.
19.Thurnham DI. Beriberi. In: Caballero B, Allen L, Prentice A, eds.
Encyclopedia of Human Nutrition. 2nd ed. Oxford: Elsevier; 2005.
269–278.
20.Rowe PM. Beta-carotene takes a collective beating. Lancet 1996;
347:249.
21.Sazawal S, Black RE, Ramsan M et al. Effects of routine prophylactic
34.Angostiniosis M, Modell B. Global epidemiology of hemoglobin
disorders. Ann N Y Acad Sci 1989; 850:251–269.
35.Fall CH, Fisher DJ, Osmond C et al. Multiple micronutrient supplementation during pregnancy in low-income countries: a metaanalysis of effects on birth size and length of gestation. Food Nutr
Bull 2009; 30:S533–S546.
supplementation with iron and folic acid on admission to hospital
36.Ronsmans C, Fisher DJ, Osmond C et al. Multiple micronutrient
and mortality in preschool children in a high malaria transmission
supplementation during pregnancy in low-income countries: a
setting: community-based, randomised, placebo-controlled trial.
meta-analysis of effects on stillbirths and on early and late neonatal
Lancet 2006; 367:133–143.
mortality. Food Nutr Bull 2009; 30:S547–S555.
41
42
MuLTIPLE MICRONuTRIENT NuTRITION | OPINION 1
37. De-Regil LM, Suchdev PS, Vist GE et al. Home fortification of foods
with multiple micronutrient powders for health and nutrition in
children under two years of age. Cochrane Database Syst Rev 2011;
9:CD008959.
38. WHO/WFP/UNICEF. Preventing and controlling micronutrient deficiencies in populations affected by an emergency. 2010. Internet,
http://www.who.int/nutrition/publications/WHO_WFP_UNICEFstatement.pdf.
39. Raiten DJ, Namaste S, Brabin B et al. Executive summary--Biomarkers of Nutrition for Development: Building a Consensus. Am J Clin
Nutr 2011; 94:633S-650S.
40. Thurnham DI, McCabe GP, Northrop-Clewes CA et al. Effect of subclinical infection on plasma retinol concentrations and assessment
of prevalence of vitamin A deficiency: meta-analysis. Lancet 2003;
362:2052-2058.
41. Thurnham DI, McCabe LD, Haldar S et al. Adjusting plasma ferritin
concentrations to remove the effects of subclinical inflammation in
the assessment of iron deficiency: a meta-analysis. Am J Clin Nutr
2010; 92:546-555.
42. Adato M, Roopnaraine T, Becker E. Understanding use of health
qualitative research in Latin America and Turkey. Soc Sci Med 2011;
72:1921-1929.
43. National nutrition database for standard reference. [Release 24].
2011. http://www.ars.usda.gov/bhnrc/ndl, United States Department of Agriculture.
44. FAO/WHO. Vitamin and mineral requirements in human
nutrition. 2ed. 2004. http://www.who.int/nutrition/publications/
micronutrients/9241546123/en/index.html, Geneva: World Health
Organisation, 2004.
45. FAO/WHO/UNU. Human energy requirements Report of a Joint FAO/
WHO/UNU Expert Consultation. http://www.fao.org/docrep/007/
y5686e/y5686e06.htm#bm06.4, Geneva: World Health Organisation, 2001.
46. Reid D, Toole BJ, Knox S et al. The relation between acute changes
in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.
Am J Clin Nutr 2011; 93:1006-1011.
47. Grant FK, Suchdev PS, Flores-Ayala R et al. Correcting for inflammation changes estimates of iron deficiency among rural Kenyan
preschool children. J Nutr 2012; 142:105-111.
services in conditional cash transfer programs: insights from
Opinion 1: A Perspective on the Delivery of
Micronutrient Interventions: What are the Needs?
Shibani Ghosh and Jeffrey B Blumberg
Friedman School of Nutrition Science and Policy
Tufts university, Boston, MA, uSA
In Response to:
Evidence in Multiple Micronutrient Nutrition:
From History to Science to Effective Programs
David I Thurnham
Northern Ireland Centre for Food and Health
university of ulster, Coleraine, uK
Despite substantial evidence collected for over a hundred years
concerning the impact of micronutrient deficiencies on health,
and some notable successes, such as the fortification of staple
foods in North America and Europe, efforts to control micronutrient deficiency disorders only gained prominence in the international nutrition community at the beginning of the 1980s.1, 2
This situation has been attributed to the hidden nature of the ef-
fects of complex micronutrient disorders; the slow generation of
a suitable evidence base; and the emphasis on treating clinical
manifestations of malnutrition associated with specific macroand micronutrients with supplementation or fortification.1 We
now have a greater understanding of common multiple and concurrent deficiencies, but we continue to debate important issues
regarding the need for basic and applied research, along with
the ways to identify the most effective approaches to program
implementation.3
In this issue of Sight and Life magazine, Dr David Thurnham
provides a comprehensive overview of a workshop held during
the 2nd World Congress of Public Nutrition in September 2010 in
Portugal that examined the current knowledge, gaps and future
needs concerning multiple micronutrient (MMN) programs.4 It
is clear that we must soon address several crucial areas to generate an actionable evidence base for MMN and more quickly
translate this into effective policies and programs. For example,
on a translational level, we need to understand the role of inflammation and infection in altering MMN needs and utilization
and the factors that affect the targeting and delivery of MMN