can multi-micronutrient food fortification improve the micronutrient status, growth, health, and...
TRANSCRIPT
Can multi-micronutrient food fortification improve themicronutrient status, growth, health, and cognition ofschoolchildren? A systematic reviewnure_378 186..204
Cora Best, Nicole Neufingerl, Joy Miller Del Rosso, Catherine Transler, Tina van den Briel, andSaskia Osendarp
Micronutrient deficiencies compromise the health and development of manyschool-age children worldwide. Previous research suggests that micronutrientinterventions might benefit the health and development of school-age children andthat multiple micronutrients might be more effective than single micronutrients.Fortification of food is a practical way to provide extra micronutrients to children.Earlier reviews of (multiple) micronutrient interventions in school-age children didnot distinguish between supplementation or fortification studies. The present reviewincludes studies that tested the impact of multiple micronutrients provided viafortification on the micronutrient status, growth, health, and cognitive developmentof schoolchildren. Twelve eligible studies were identified. Eleven of them tested theeffects of multiple micronutrients provided via fortified food compared to unfortifiedfood. One study compared fortification with multiple micronutrients to fortificationwith iodine alone. Multi-micronutrient food fortification consistently improvedmicronutrient status and reduced anemia prevalence. Some studies reportedpositive effects on morbidity, growth, and cognitive outcomes, but the overall effectson these outcomes were equivocal.© 2011 International Life Sciences Institute
INTRODUCTION
Many school-age children around the world suffer fromnutritional deficiencies, which can negatively affect theirphysical and mental development and increase suscepti-bility to infections.1–5 It has been estimated that iron defi-ciency anemia (IDA) affects 53% of school-age childrenworldwide.6 Recent national studies from Thailand,7
the Philippines,8 Nicaragua,9 and Colombia10 observedaverage rates of national anemia prevalence ranging from23% to 38%. Iodine deficiency has been observed withprevalence rates as high as 60–90% in schoolchildrenfrom multiple African, Asian, and Eastern Mediterraneancountries.11–16 Micronutrient deficiencies are also
observed frequently in developed countries. According tothe World Health Organization’s (WHO) database oniodine deficiency, the prevalence of iodine deficiencyamong all the world’s regions is actually highest inEurope.17 Iron deficiency is common among schoolchil-dren in Europe18,19 and the United States,20–24 especially inadolescent girls. Insufficient intakes of vitamin D andfolate have also been observed among European childrenand adolescents.19
Multiple micronutrient (MMN) deficiencies oftenoccur simultaneously as a result of a poor-quality diet. Indeveloping countries, low dietary intakes of animal-source foods,25 which are important sources of iron,zinc, vitamin A, B12, and protein, can lead to MMN
Affiliations: C Best and T van den Briel are with the United Nations World Food Programme, Programme Design and Support Service, Rome,Italy. N Neufingerl and S Osendarp are with the Unilever Research, Nutrition and Health Department, Vlaardingen, The Netherlands. JM DelRosso is with The Manoff Group, Washington, DC, USA. C Transler is with Unilever Research, Sensation, Perception and BehaviourDepartment, Vlaardingen, The Netherlands.
Correspondence: C Best, United Nations World Food Programme, Via Cesare Giulio Viola 68/70, 00148 Rome, Italy. E-mail:[email protected].
Key words: child development, deficiency, food fortification, multiple micronutrients
Special Article
doi:10.1111/j.1753-4887.2011.00378.xNutrition Reviews® Vol. 69(4):186–204186
deficiencies.26 Parasitic infections or diarrhea can alsolead to MMN deficiencies due to limited absorption orutilization of nutrients.27,28 In wealthier countries, theoverall quality of the diet of school-age children and ado-lescents is inadequate in large parts of the population.Families with a low socioeconomic status often cannotafford healthy diets29; they have less access tomicronutrient-rich foods like fruits, vegetables, meat, fish,and dairy.19 In addition, school-age children may developa more independent eating pattern30; this can includemore out-of-home food consumption without supervi-sion, which is likely to result in increased intake of foodsof low nutritional value, such as soft drinks and saltysnacks in place of micronutrient-rich foods.31,32
At the same time, school-age children and adoles-cents are in a life stage of considerable physical andmental development. They experience growth spurts andsexual maturation, and girls begin menstruating30; thebrain continues to mature until young adulthood, andcognitive functions, in particular the higher-order cogni-tive functions (reasoning, planning, abstract thinking,etc.), develop and become more structured during thisperiod.33–35 Meeting the nutritional demands required forthis stage of development is crucial for optimal health,including physical and mental performance, and caninfluence health and productivity later in life. Excessivelythin schoolchildren and adolescents can experience adelay in pubertal maturation and reduced muscularstrength and work capacity, even reduced bone densitylater in life.1 Undernutrition is also related to an increasedrisk of morbidity1,36: vitamin A and zinc deficiency areassociated with impaired immune function and highersusceptibility to infection and diarrhea.37,38 Mental devel-opment of children can be affected by malnutritiondirectly through insufficient supply of essential micronu-trients, like iodine,17 leading to structural and functionalimpairment of the central nervous system.39,40 Micronu-trient deficiencies can also have an indirect effect onmental and motor development. Undernourished oranemic children are less active and less likely to exploreand interact with their environment, which can lead tosuboptimal development.41
Interventions with (multiple) micronutrients haveled to beneficial effects on linear growth,42,43 health,44–49
and cognitive development50–54 in schoolchildren. Mostevidence is reported for iron, iodine, vitamin A, and zincsupplementation. There are data suggesting that com-bined supplementation of MMNs may have a greatereffect on certain outcomes than supplementation with asingle micronutrient. A meta-analysis on the effects ofmicronutrients on growth in children up to 18 years ofage found that interventions with iron or vitamin A alonedid not have an effect on either height or weight gain,whereas MMN interventions, 80% of which included
vitamin A, iron, and zinc, significantly improved lineargrowth and also had a small (not statistically significant)positive effect on weight gain.42
Eilander et al.55 reviewed the effects of MMNs deliv-ered through either supplements or fortified foods oncognition in schoolchildren and found that MMNs had asmall positive effect on fluid intelligence (reasoningability) and academic performance. However, a subgroupanalysis including only the studies that provided MMNsthrough fortified foods and excluding supplementationtrials showed no beneficial effects.55 The effect of the extraenergy and nutrients provided through food that alsobenefited children in the control group may have made itdifficult to detect an effect of the additional MMNs on thetreatment group receiving fortified food.
It is evident that energy and protein have an impacton the growth, health, and development of children. Lowenergy and protein intakes are the primary cause for poorgrowth,56 and undernutrition resulting from protein-energy deficiency is associated with increased susceptibil-ity to infectious diseases.57,58 Fortification of food is apractical way to combine the benefits of energy repletion,adequate supply of fat and protein, and MMNs to opti-mize the growth and development of children. Previousreviews on the effect of MMN interventions and feedingprograms in children exist,42,43,59–61 but they did not dis-tinguish between MMNs provided in the form of asupplement or through fortified foods. A Cochrane sys-tematic review by Kristjansson et al.60 investigating theeffectiveness of school feeding programs in low-incomeschoolchildren found that school meals and snacks canhave a positive yet small impact on growth and cognitiveoutcomes. The review, based on 18 studies, deliberatelyexcluded studies that modified the nutrient content of theschool meals, including through fortification. A reviewperformed by Rivera et al.61 distinguished particularinterventions providing animal-source foods, but onlyone of the four studies described in the review includedschool-age children. A review conducted by Eilanderet al.55 investigated cognitive outcomes and included pri-marily MMN supplementation trials and a limitednumber of fortified food interventions. To our knowl-edge, the present review is the first that investigates theimpact of MMN food fortification on the micronutrientstatus, growth, health, and cognitive development ofschool-age children.
LITERATURE SEARCH METHODS
A literature search for articles reporting the effects ofMMN food fortification on the micronutrient status,growth, health, and cognitive development of schoolchil-dren was conducted using the PubMed, ISI Web ofKnowledge, the Cochrane Database of Systematic Review
Nutrition Reviews® Vol. 69(4):186–204 187
(CDSR), and the Central Register of Controlled TrialsCENTRAL database. The search strategy was based onthe Cochrane highly sensitive search strategy to identifyreports of randomized controlled trials, which wasexpanded to incorporate other controlled experimentalstudy designs, and subject-specific terms to identify eli-gible participant groups, interventions, and outcomes.Whenever possible, use was made of medical subjectheading (MeSH) terms in PubMed, CDSR, andCENTRAL that related to children, micronutrients, forti-fied foods, and several of major health outcomes, such asgrowth, nutritional status, or cognition; the MeSH term“dietary supplements” was excluded in the search string.In ISI Web of Knowledge, the search string was adaptedand consisted of relevant text words instead of MeSHterms. The search was restricted to articles published inthe English language. Titles and abstracts from the initialsearch results were examined to identify potentially rel-evant studies; references of identified relevant studies andreviews were screened for further pertinent studies.
Eligibility criteria
Eligible study designs were restricted to experimentalcontrolled efficacy or effectiveness studies including ran-domized controlled trials (RCT), quasi-experimentalcontrolled clinical trials (CCT), and controlled before andafter studies (CBA), as defined by the Cochrane Collabo-ration. Studies describing the mathematical methodof randomization of individual subjects or clusterswere classified as an RCT. Studies that used a non-mathematical method of randomization or that onlymentioned a use of randomization but provided nodescription of the methodology were conservatively clas-sified as a CCT. Studies that compared the interventiongroup to a comparable control before and after the inter-vention but did not use random allocation were classifiedas a CBA.
Eligible studies must have been conducted in school-age children. To qualify for inclusion, the vast majority ofthe study population had to be between 6 and 18 years ofage; arbitrarily, the inclusion criteria was set at aminimum of 75% of the study sample being in this agerange. Studies were excluded when the study populationwas specifically selected based upon health conditionsthat are rare in the general population, e.g., genetic disor-ders such as thalassemia or phenylketonuria. Childrenfrom developing countries who were selected becausethey suffered from undernutrition, anemia, parasiticinfections, or HIV were not excluded as these conditionsare not rare in most developing countries.
Eligible studies must have provided an MMN-fortified food intervention in at least one of the experi-mental conditions. MMN-fortified food was defined as
food to which a minimum of three micronutrients wereadded. Micronutrients from the B-vitamin complex wereconsidered as one micronutrient, since these vitamins arefrequently part of the same biological processes. Foodinterventions were defined as interventions providingfortified foods or beverages as well as fortificants thatwere added to foods or drinks on-site or at home. Studieswere eligible if they properly tested the independent effectof MMN fortification by comparing an MMN-fortifiedfood to either an unfortified food or a food fortified withonly one or two micronutrients. Eligible studies assessedat least one of the following outcomes: biochemical mea-surements of micronutrient status or prevalence ofmicronutrient deficiencies; indicators of growth or bodycomposition, prevalence of stunting, wasting, or under-weight; indicators of morbidity (prevalence, incidence,duration, and/or severity), including absence fromschool; cognitive outcomes, including academicperformance.
Evaluation of study results
Among the reported study outcomes, the following dis-tinctions were made: 1) difference between groups inchange from baseline to follow-up; 2) difference betweengroups at follow-up; or 3) difference within groups frombaseline to follow-up. Differences between groups thattook into account baseline values, either as covariates orby comparing change from baseline, were considered themost meaningful results. Differences were considered sig-nificant if the P value was less than 0.05.
The relevant information and results of the reviewedstudies were assessed independently by two nutritionresearchers (CB and NN). A research psychologist (CT)was consulted to gauge the validity and reliability of themethods used to assess cognitive outcomes.
SUMMARY OF FINDINGS
The literature search retrieved 1,053 citations. The vastmajority of the citations were discarded because theywere overview articles or reported on studies investigat-ing the effects of a single micronutrient. Other majorreasons for exclusion were that micronutrients were pro-vided as supplements rather than through fortification offood, the intervention was provided to an inappropriatetarget population, or the study utilized a non-experimental design. The initial screening of titles andabstracts revealed 85 publications of potential relevance.After in-depth review and manual searching of referencelists, 12 eligible intervention studies were identified andincluded in the review. For an overview of the screeningprocedure see Figure 1.
Nutrition Reviews® Vol. 69(4):186–204188
Of the 12 eligible studies, 11 investigated the effect ofMMN fortification by comparing the fortified food to anisocaloric unfortified food62–75; one of these studies alsoincluded a third intervention arm in which no food inter-vention was provided,62 and one study compared theeffect of MMN fortification to single fortification withiodine.76 Eleven of the 12 studies were conducted indeveloping or transitional countries according to theirHuman Development Index 2009,77 and 11 studies pro-vided the intervention at school.62–76 The carriers used forfortification were beverages (6 studies),63,64,68,69,72 milkproducts (2 studies),62,65 biscuits (2 studies),67,71 or season-ing powder/salt (2 studies).74,76 In most studies the addi-tional MMNs provided between 50 and 100% of therecommended dietary allowance78 of the individualmicronutrients daily. All foods were fortified with a com-bination of at least iron and vitamin A or b-carotene.Iodine, zinc, B-vitamins and vitamin C were usuallyincluded. Three studies also provided eicosapentaenoicacid, docosahexaenoic acid, taurine, or inulin togetherwith the MMN intervention while these ingredients werenot provided to the control group.62,63 For an overview ofthe individual study characteristics, see Table 1. Since 11of the 12 studies compared an MMN-fortified food to anunfortified food, the results from these studies are focusedupon. The results of the remaining study comparingMMN-fortified salt to iodized salt, which only investi-gated effects on micronutrient status, will be summarizedbriefly. Table 2 gives a concise overview of all outcomes
evaluated by the studies reviewed, while Table 3provides a summary of each study’s findings andlimitations.
Effects on micronutrient status
Ten studies assessed the effect of MMN fortification offoods compared to unfortified foods on the micronutri-ent status or prevalence of deficiencies in children(Table 3). All 10 studies measured a statistically signifi-cantly greater improvement in micronutrient status inthe intervention group compared to the control group,taking baseline values into account. The most frequentlyobserved (and investigated) effects were increases inhemoglobin (Hb), iron, vitamin A, iodine, and folatestatus. All 10 studies assessed Hb status; seven studiesreported a significant beneficial effect of MMN fortifica-tion on Hb status or anemia prevalence, taking baselinevalues into account. In addition, one study reported asignificantly lower prevalence of anemia at follow-up inthe MMN group (14.9%) compared to the control group(28.8%) (P = 0.03), while anemia prevalence at baselinewas comparable.64 Two studies reported a significanteffect in a sub-sample of children who were initiallyanemic65 or a significant inverse relationship betweeninitial Hb levels and response to the MMN intervention.64
Only one study, which was conducted in well-nourishedAustralian children who had adequate Hb levels at base-line, did not find any effect on Hb or anemia prevalence.63
1,053 citations from literature search
85 potentially relevant papers
Screening of titles and abstracts
Hand-searching reference lists of potentially relevant papers
100 potentially relevant papers
15 relevant papers identified
Reading full text of potentially relevant papers
968 articles excluded due to: • ineligible publication type or study design • single/double micronutrient fortification • supplementation instead of fortification • inappropriate study population
15 additional potentially relevant papers
85 articles excluded due to: • ineligible publication type (review) or
study design (observational) (n = 27) • supplementation study (n = 22) • inappropriate study population (n = 14) • single/double fortification (n = 8) • duplicate data (n = 9) • ineligible control (n = 5)
12 individual studies included in review
Figure 1 Flow chart of screening process for eligible articles.
Nutrition Reviews® Vol. 69(4):186–204 189
Tabl
e1
Char
acte
rist
ics
ofth
est
udie
sas
sess
ing
effec
tsof
MM
N-f
orti
fied
food
son
heal
thou
tcom
esin
scho
ol-a
gech
ildre
n.Re
fere
nce
Stud
yde
sign
Age
ofsu
bjec
tsN
o.of
subj
ects
Sam
ple
char
acte
ristic
sSt
udy
loca
tion
Inte
rven
tion
prod
ucta
ndad
min
istr
atio
n
Ener
gy(a
ndm
acro
-nut
rient
)co
nten
tper
daily
serv
ing
Dur
atio
nof
inte
rven
tion
MM
Nfo
rtifi
catio
n(d
aily
dosa
ge)
Rete
ntio
nra
teCo
mpl
ianc
eO
utco
mes
asse
ssed
Not
es
MM
N-fo
rtifi
edfo
odve
rsus
unfo
rtifi
edfo
odin
terv
entio
nsAb
ram
set
al.
(200
3)68
CBA
6–11
y31
1U
rban
,low
SES
Gab
oron
e,Bo
tsw
ana
240
mL
frui
t-fla
vore
dbe
vera
ge,
daily
100
kcal
8w
eeks
7.0
mg
iron,
2.4
mg
b-ca
rote
ne,6
0mg
iodi
de,
3.75
mg
zinc
,0.4
mg
B 2,
2.7
mg
niac
in,0
.5m
gpy
ridox
ine,
140
mgfo
licac
id,1
.0mg
B 12,
60m
gvi
tam
inC,
7.5
mg
vita
min
E,12
0m
gtr
ical
cium
phos
phat
e
85%
89%
Iron,
zinc
,vi
tam
inA,
B 2,
fola
te,B
12an
dH
bst
atus
,an
emia
prev
alen
ce,
heig
ht,
wei
ght,
MUA
C
Atba
selin
e12
%of
child
ren
anem
icin
com
bina
tion
with
ase
cond
mic
ronu
trie
ntde
ficie
ncy.
Less
than
10%
wer
est
unte
dor
was
ted.
Child
ren
with
seve
rean
emia
(Hb
<60
g/L)
,exc
essi
veth
inne
ss(<
15kg
),an
dac
ute
orch
roni
cill
ness
wer
eex
clud
ed
Ash
etal
.(2
003)
72CC
T6–
11y
830
Rura
lM
pwap
wa
dist
rict,
Maa
sai
Step
pe,
Tanz
ania
250
mL
frui
t-fla
vore
dbe
vera
ge,5
days
/wee
k
90kc
al6
mon
ths
5.4
mg
iron,
525
mgRE
vita
min
A,45
mgio
dine
,5.
25m
gzi
nc,7
2m
gvi
tam
inC,
0.6
mg
vita
min
B 2,0
.7m
gvi
tam
inB 6
,14
1mg
folic
acid
,3.0
mgvi
tam
inB 1
2,10
.5m
gvi
tam
inE
93%
80%
Iron,
vita
min
Ast
atus
and
defic
ienc
y,H
bst
atus
,ane
mia
prev
alen
ce,
heig
ht,w
eigh
t
Stud
yin
mal
aria
ende
mic
regi
on;a
tbas
elin
e20
%vi
tam
inA
defic
ient
,~20
%an
emic
;chi
ldre
nw
ithse
vere
anem
ia(H
b<
70g/
L),
xero
phth
alm
ia,o
rser
ious
chro
nic
dise
ase
wer
eex
clud
ed.
Child
ren
with
inte
stin
alhe
lmin
thin
fect
ions
atba
selin
ere
ceiv
edm
edic
atio
n
Hyd
eret
al.
(200
7)69
RCT
Mea
nag
e12
.0y
1125
Girl
s,ru
ral,
low
SES
Sher
purd
istr
ict,
Bang
lade
sh20
0m
Lof
frui
t-fla
vore
dbe
vera
ge,6
days
/wee
kon
scho
olda
ys
Not
repo
rted
12m
onth
s7.
0m
giro
n,38
8mg
REvi
tam
inA,
75mg
iodi
ne;
7.5
mg
zinc
,120
mg
vita
min
C,0.
91m
gB 2
,5.
0m
gni
acin
,1.0
mg
B 6,
120
mgfo
licac
id,1
.0mg
B 12,
10m
gvi
tam
inE
92%
Not
repo
rted
Iron,
zinc
,and
vita
min
Ast
atus
and
defic
ienc
y,H
bst
atus
,ane
mia
prev
alen
ce,
heig
ht,
wei
ght,
MUA
C,in
flam
mat
ion
(C-r
eact
ive
prot
ein)
Atba
selin
ehi
ghpr
eval
ence
ofzi
nc(5
8%)a
ndiro
n(3
1%)d
efici
ency
,80%
wer
eex
cess
ivel
yth
in(B
MI<
16kg
/m2 )a
tba
selin
e.Ch
ildre
nw
ithse
vere
anem
ia(H
b<
70g/
L),g
oite
r,ni
ghtb
lindn
ess,
orac
ute
infe
ctio
nw
ere
excl
uded
Lien
doet
al.
(200
9)62
CCT
7–8
y45
4N
otsp
ecifi
edYe
nPh
ong
Dis
tric
t,Ba
cni
nhPr
ovin
ce,
Nor
ther
nVi
etna
m
250
mL
milk
,tw
ice
daily
,6da
ys/w
eek
380
kcal
(15.
5g
prot
ein)
6m
onth
s6.
3m
giro
n,4.
5mg
REvi
tam
inA;
22mg
iodi
ne;
3.5
mg
zinc
,162
mg
vita
min
C,0.
45m
gvi
tam
inB 1
;35
mg
vita
min
B 2;1
2.2
mg
vita
min
E;2.
9IU
vita
min
D;2
25m
gCa
,15
mg
mag
nesi
um,
1.3
mg
man
gane
se;
60m
gpo
tass
ium
,5g
inul
invi
tam
inK,
B 3,B
6,fo
late
,pan
toth
en,b
iotin
,se
leni
um,t
aurin
e,in
unsp
ecifi
edam
ount
s
Not
repo
rted
Not
repo
rted
Stoo
lbac
teria
load
,acc
urac
y,effi
cien
cyof
wor
king
,sh
ort-
term
mem
ory,
IQ,
mat
hem
atic
s,Th
aila
ngua
ge
Stud
ysa
mpl
ew
ithpo
orov
eral
lnut
ritio
nals
tatu
s:30
–50%
prev
alen
ceof
anem
ia,z
inc
defic
ienc
y,st
untin
gan
dun
derw
eigh
tatb
asel
ine.
Inte
rven
tion
with
MM
N-fo
rtifi
edm
ilkve
rsus
unfo
rtifi
edre
gula
rmilk
vers
usno
food
.M
MN
-fort
ifica
tion
incl
uded
inul
inan
dta
urin
e.
Man
gere
tal.
(200
8)74
Win
icha
goon
etal
.(2
006)
66
RCT
5.5–
13.4
y56
9Ru
ral,
low
SES
Trak
anPh
utph
ondi
stric
t,N
orth
east
Thai
land
Seas
onin
gpo
wde
radd
edto
daily
lunc
h(g
ener
ally
cont
aini
ng1.
5m
giro
n,1.
3m
gzi
nc,
and
26mg
REvi
tam
inA)
,5da
ys/w
eek
288
kcal
(9.9
gpr
otei
n)
31w
eeks
5.0
mg
iron,
270
mgRE
vita
min
A,50
mgio
dine
,5.
0m
gzi
nc
98%
75%
Iron,
iodi
ne,z
inc,
and
vita
min
Ade
ficie
ncy,
Hb
stat
us,h
eigh
t,w
eigh
t,M
UAC,
skin
fold
thic
knes
s,he
ight
-for-
age,
wei
ght-
for-
age,
wei
ght-
for-
heig
ht
Atba
selin
e,hi
ghpr
eval
ence
ofan
emia
(~30
%),
zinc
defic
ienc
y(~
54%
)and
iodi
nede
ficie
ncy
(~70
%);
one-
third
ofch
ildre
nha
dpa
rasi
ticin
fect
ions
.Ch
ildre
nw
ithse
vere
anem
ia(H
b<
80g/
L)or
acut
eor
chro
nic
illne
ssw
ere
excl
uded
Nutrition Reviews® Vol. 69(4):186–204190
Nga
etal
.(2
009)
67RC
T,2
¥2
desi
gn6–
8y
510
Rura
l,lo
wSE
SH
ung
Yen
Prov
ince
,Vi
etna
m
30g
bisc
uits
,5da
ys/w
eek
133
kcal
4m
onth
s6.
0m
giro
n,30
0mg
REvi
tam
inA,
35mg
iodi
ne,5
.6m
gzi
nc,
1.0
mg
B 1,0
.9m
gB 2
,1.
1m
gB 6
,10.
5m
gni
acin
,120
mgfo
licac
id,1
.5mg
B 12,
18mg
biot
in,2
8.4
mg
vita
min
C,15
0m
gCa
,74
mgvi
tam
inD
,40
mg
Mg,
6.8
mgSe
,378
mg
K,70
mg
Ph,3
mg
pant
othe
nic
acid
,2,
8mg
vita
min
E,10
mg5
vita
min
K
91%
95%
Iron,
iodi
ne,a
ndvi
tam
inA
stat
usan
dde
ficie
ncy,
anem
iapr
eval
ence
,par
asite
infe
ctio
n
Stud
ysa
mpl
ew
ithov
eral
lpo
ornu
triti
onal
stat
us:
25%
anem
ic,5
5%zi
ncde
ficie
nt,4
4%io
dine
defic
ient
;82%
para
sitic
infe
ctio
n,29
%un
derw
eigh
t.Ch
ildre
nw
ithH
b<
80g/
L,se
vere
mal
nutr
ition
(WH
Z<
3SD
,>2S
D,o
rBM
I>25
)orc
hron
icill
ness
wer
eex
clud
ed.
2¥
2de
sign
:MM
Nfo
rtifi
catio
nan
dde
wor
min
gtr
eatm
ent
Ose
ndar
pet
al.
(200
7)63
RCT,
2¥
2de
sign
6–10
y39
6U
rban
,hig
hSE
SAd
elai
de,
Aust
ralia
100
mL
frui
t-fla
vore
dso
ydr
ink,
cons
umed
atho
me,
daily
130
kcal
(8.6
gpr
otei
n)
12m
onth
s10
mg
iron,
400
mgRE
vita
min
A,5.
0m
gzi
nc,
150
mgfo
late
,1.0
mg
B 6,1
.5mg
B 12,
45m
gvi
tam
inC
70%
76%
Iron,
zinc
,fol
ate,
vita
min
B 12,
DH
A,EP
A,an
dH
bst
atus
,ge
nera
lint
ellig
ence
,ve
rbal
lear
ning
and
mem
ory,
visu
alat
tent
ion,
acad
emic
perf
orm
ance
Stud
ysa
mpl
ew
ithgo
odov
eral
lnut
ritio
nals
tatu
s:le
ssth
an5%
with
mic
ronu
trie
ntde
ficie
ncie
s;1%
anem
ic.
Seve
rely
mal
nour
ishe
d(W
HZ
<- 3S
D)o
rane
mic
(Hb
<80
g/L)
child
ren
wer
eex
clud
ed.
2¥
2de
sign
:MM
Nfo
rtifi
catio
n,om
ega-
3fa
tty
acid
fort
ifica
tion
Ose
ndar
pet
al.
(200
7)63
RCT,
2¥
2de
sign
6–10
y38
4U
rban
,low
SES,
mar
gina
llyno
uris
hed
Jaka
rta,
Indo
nesi
a10
0m
Lfr
uit-
flavo
red
soy
drin
kan
dth
ree
bisc
uits
,6
days
/wee
k
230
kcal
(12.
6g
prot
ein)
12m
onth
s11
mg
iron,
400
mgRE
vita
min
A,5.
0m
gzi
nc,
45m
gvi
tam
inC,
1.0
mg
B 6,1
50mg
fola
te,1
.5mg
B 12
96%
86%
Iron,
zinc
,fol
ate,
vita
min
B 12,
fola
te,
DH
A,EP
A,an
dH
bst
atus
,gen
eral
inte
llige
nce,
verb
alle
arni
ngan
dm
emor
y,vi
sual
atte
ntio
n,ac
adem
icpe
rfor
man
ce
Atba
selin
e~2
0%of
child
ren
wer
eiro
nor
zinc
defic
ient
,10%
anem
ic.
Seve
rely
mal
nour
ishe
d(W
HZ
<- 3S
D),
anem
ic(H
b<
80g/
L),o
rw
ell-n
ouris
hed
(WH
Z>
+ 0.44
)chi
ldre
nw
ere
excl
uded
;2¥
2de
sign
:MM
Nfo
rtifi
catio
n,om
ega-
3fa
tty
acid
fort
ifica
tion
Siva
kum
aret
al.
(200
6)65
Sarm
aet
al.
(200
6)70
Shat
rugn
aet
al.
(200
6).73
Vazi
reta
l.(2
006)
75
CCT
6–18
y32
8M
iddl
eSE
SN
eart
oH
yder
abad
,In
dia
150
mL
milk
porr
idge
320
kcal
(14.
8g
prot
ein)
14m
onth
s14
mg
iron,
400
mgRE
vita
min
A,75
mgio
dine
,2.3
mg
Zn,
80m
gvi
tam
inC,
0.7
mg
vita
min
B 1,
1.6
mg
vita
min
B 2,
0.9
mg
niac
in,2
.0m
gvi
tam
inB 6
,200
mgfo
licac
id,1
.0mg
vita
min
B 12,
2.5
mgvi
tam
inD
,22
4m
gCa
74%
Not
repo
rted
Iron,
iodi
ne,z
inc,
calc
ium
,vita
min
A,B 1
,B2,
B 6,f
olat
e,B 1
2,C,
D,a
ndH
bst
atus
,pa
rath
yroi
dho
rmon
e,tr
iiodt
hyro
nine
,th
yroi
d-st
imul
atin
gho
rmon
e,pr
eval
ence
ofgo
iter,
Bito
t’ssp
ots,
angu
lar
stom
atiti
s,gl
ossi
tisch
eilo
sis,
blee
ding
gum
s,he
ight
,w
eigh
t,he
ight
-for-
age,
wei
ght-
for-
age,
skin
fold
thic
knes
s,bo
dyco
mpo
sitio
n,bo
nem
iner
alco
nten
tand
dens
ity,
inte
llige
nce,
mem
ory,
atte
ntio
nan
dco
ncen
trat
ion,
scho
last
icac
hiev
emen
t
Stud
ysa
mpl
ew
ithov
eral
lpo
ornu
triti
onal
stat
us:
55%
anem
ic,h
igh
prev
alen
ceof
fola
te(1
00%
),ot
herB
vita
min
s(6
5%),
and
vita
min
Aan
dC
(55%
)defi
cien
cy.
Allc
hild
ren
rece
ived
dew
orm
ing
trea
tmen
ttw
ice
at6-
mon
thin
terv
als.
Nutrition Reviews® Vol. 69(4):186–204 191
Tabl
e1
Cont
inue
dRe
fere
nce
Stud
yde
sign
Age
ofsu
bjec
tsN
o.of
subj
ects
Sam
ple
char
acte
ristic
sSt
udy
loca
tion
Inte
rven
tion
prod
ucta
ndad
min
istr
atio
n
Ener
gy(a
ndm
acro
-nut
rient
)co
nten
tper
daily
serv
ing
Dur
atio
nof
inte
rven
tion
MM
Nfo
rtifi
catio
n(d
aily
dosa
ge)
Rete
ntio
nra
teCo
mpl
ianc
eO
utco
mes
asse
ssed
Not
es
Solo
net
al.
(200
3)64
CCT,
2¥
2de
sign
Mea
nag
e,10
�2.
1y
851
Rura
lBa
lete
,Bat
anga
s,Ph
ilipp
ines
200
mL
beve
rage
s,tw
ice
daily
,on
scho
olda
ys
Not
repo
rted
16w
eeks
9.6
mg
iron,
240
mgRE
vita
min
A,96
mgio
dine
,7.5
mg
zinc
,15
0m
gvi
tam
inC,
0.92
mg
vita
min
B 2,
5.0
mg
niac
in,
1.0
mg
vita
min
B 6,
120
mgfo
licac
id,
1.0
mgvi
tam
inB 1
2,5.
0m
gvi
tam
inE
95%
Not
repo
rted
Iodi
nest
atus
,wei
ght,
heig
ht,h
eigh
t-fo
r-ag
e,w
eigh
t-fo
r-ag
e,w
eigh
t-fo
r-he
ight
,an
emia
prev
alen
ce,
phys
ical
fitne
ss,h
eart
rate
,ver
bal,
nonv
erba
l,an
dqu
antit
ativ
em
enta
lab
ilitie
s
Stud
ysa
mpl
ew
ithov
eral
lpo
ornu
triti
onal
stat
us:
52%
anem
ic,9
0%io
dine
defic
ient
,54%
with
helm
inth
infe
ctio
ns.O
vera
llpr
eval
ence
ofm
oder
ate-
to-s
ever
em
alnu
triti
onin
stud
yar
eaw
as25
%.C
hild
ren
with
Hb
<80
g/L
wer
eex
clud
ed.2
¥2
desi
gn:
MM
Nfo
rtifi
catio
nan
dde
wor
min
gtr
eatm
ent
Van
Stui
jven
berg
etal
.(19
99)71
CCT
6–11
y22
8Ru
ral,
low
SES
60km
NW
ofD
urba
n,Kw
aZul
u-N
atal
,So
uth
Afric
a
3sh
ortb
read
bisc
uits
and
150
mL
cold
drin
k,5
days
/w
eek
250
kcal
(4.1
gpr
otei
n)
12m
onth
s5.
0m
giro
n,2.
1m
gb-
caro
tene
,120
mgio
dine
,90
mg
vita
min
C
Not
repo
rted
93%
Iron,
iodi
ne,a
ndvi
tam
inA
stat
usan
dde
ficie
ncy,
Hb
stat
us,a
nem
ia,a
ndgo
iter
prev
alen
ce,h
eigh
t,w
eigh
t,he
ight
-for-
age,
wei
ght-
for-
age,
whi
tebl
ood
cell
coun
ts,
illne
ss-r
elat
edab
senc
e,pr
oces
sing
spee
d,w
orki
ngm
emor
y
Atba
selin
e41
%of
child
ren
wer
evi
tam
inA
defic
ient
,20%
had
goite
rand
28%
had
anem
ia.O
ne-t
hird
ofch
ildre
nha
dpa
rasi
tein
fect
ions
.Al
lchi
ldre
nw
ere
dew
orm
edat
base
line
and
durin
g4-
mon
thin
terv
als.
Asc
hool
-feed
ing
prog
ram
had
been
inpl
ace
for2
year
sbe
fore
base
line
asse
ssm
ents
butw
asst
oppe
dbe
fore
stud
yst
arte
d;Sa
ltio
diza
tion
beca
me
man
dato
ryha
lfway
thro
ugh
stud
y→
usua
lco
nsum
ptio
nsw
itche
dfr
omno
n-io
dize
dto
iodi
zed
salt
MM
N-fo
rtifi
edve
rsus
sing
le-n
utrie
nt-fo
rtifi
edfo
odZi
mm
erm
ann
etal
.(20
04)76
CCT
6–14
y15
9Ru
ral
Rifm
ount
ain
villa
ge,
nort
hern
Mor
occo
2kg
ofsa
ltde
liver
edto
hous
ehol
dsea
chm
onth
(~10
gsa
ltpe
rda
ype
rchi
ld)
Not
repo
rted
10m
onth
s2.
0m
giro
n,60
mgRE
vita
min
A,an
d25
mgio
dine
perg
ofsa
ltve
rsus
iodi
zed
salt
only
(25
mgpe
rg).
Dai
lyin
take
~19
mg
iron,
570
mgvi
tam
inA,
240
mgio
dine
99%
100%
Iron,
iodi
ne,v
itam
inA
stat
usan
dde
ficie
ncy,
prev
alen
ceof
iron
defic
ienc
yan
emia
Effec
tiven
ess
stud
y.M
MN
-fort
ified
salt
vers
usio
dize
dsa
lt.St
udy
carr
ied
outi
nar
eaen
dem
icfo
rgoi
ter
Abbr
evia
tions
:BM
I,bo
dym
ass
inde
x;CB
A,co
ntro
lled
befo
rean
daf
ters
tudy
(obs
erva
tions
are
mad
ebe
fore
and
afte
rthe
inte
rven
tion,
both
ina
grou
pth
atre
ceiv
esth
ein
terv
entio
nan
din
agr
oup
that
does
not)
;CCT
,con
trol
led
clin
ical
tria
l(co
ntro
lled
tria
lwhe
retr
eatm
enta
lloca
tion
ispe
rfor
med
with
inte
ntto
prev
entb
ias
usin
gso
me
non-
mat
hem
atic
alm
etho
dsu
chas
aco
infli
p,da
ysof
the
wee
k,or
even
-odd
num
bers
);H
b,he
mog
lobi
n;IQ
,int
ellig
ence
quot
ient
;MM
N,m
ultip
le-m
icro
nutr
ient
;MUA
C,m
iddl
e-up
per-
arm
circ
umfe
renc
e;RB
C,re
dbl
ood
cell;
RCT,
rand
omiz
edco
ntro
lled
tria
l(co
ntro
lled
clin
ical
tria
lin
whi
chtr
eatm
enta
lloca
tion
isra
ndom
ized
usin
gso
me
mat
hem
atic
alm
etho
dsu
chas
ara
ndom
-num
bers
tabl
e);S
ES,s
ocio
econ
omic
stat
us;W
HZ,
wei
ght-
for-
heig
htz-
scor
e.
Nutrition Reviews® Vol. 69(4):186–204192
Tabl
e2
Sum
mar
yof
resu
lts
ofin
terv
enti
onst
udie
ste
stin
gth
eeff
ects
ofM
MN
–for
tifie
dfo
odon
heal
than
dde
velo
pmen
talo
utco
mes
.Re
fere
nce
Mic
ronu
trie
ntde
ficie
ncie
sG
row
than
dw
eigh
tM
orbi
dity
Cogn
itive
perf
orm
ance
Iron
Hb/
Anem
iaIo
dine
Vita
min
AZi
ncB– vi
tam
ins
Hei
ght/
stun
ting
Wei
ght/
BMI/
unde
rwei
ght
Resp
irato
ry–
rela
ted
dise
ases
Dia
rrhe
aO
ther
dise
ases
(mar
kers
)
Mem
ory
Flui
din
telli
genc
eSc
hool
perf
orm
ance
Oth
erco
gniti
veou
tcom
esM
MN
–for
tified
food
vers
usun
fort
ified
food
Abra
ms
etal
.(20
03)68
✓✓
–✕
–✓
✕✓
––
––
––
–As
het
al.(
2003
)72✓
✓–
✓–
–✓
✓–
––
––
––
Hyd
eret
al.(
2007
)69✓
✓–
✓✕
–✕
✓–
–✕
2–
––
–Li
endo
etal
.(20
09)62
––
––
––
––
––
✓3
✕–
–✕
10
Man
gere
tal.
(200
8),66
,74
✕✓
✓✕
✓–
✕✕
✓✓
✕4
✓–
✕–
Nga
etal
.(20
09)67
✓✓
✓✓
✓–
––
––
(✓)5
––
––
Ose
ndar
pet
al.(
2007
)63
(Aus
tral
ia)
✓✕
––
✕✓
––
––
–✓
✕✕
9✕
11
Ose
ndar
pet
al.(
2007
)63
(Indo
nesi
a)✓
✓–
–✕
✓–
––
––
(✓)8
✕✕
9✕
11
Siva
kum
aret
al.
(200
6)65
,70,
73,7
5✓
(✓)1
✓✓
✕✓
✓✓
✕✕
✓6
✕✕
✕✕
11
Solo
net
al.(
2003
)64–
✓✓
––
–✕
✕–
–(✓
)7–
––
(✓)12
van
Stui
jven
berg
etal
.(1
999)
71✓
✓✓
✓–
–✕
✕✕
✓✕
✓–
–✕
13
MM
N–f
ortifi
edfo
odve
rsus
sing
le–f
ortifi
edfo
odZi
mm
erm
anet
al.(
2004
)76✓
✓–
✓–
––
––
––
––
––
1Eff
ecto
nly
inde
ficie
nt/a
nem
ic/m
alno
uris
hed
child
ren.
2O
utco
me
mea
sure
:pre
vale
nce
ofin
flam
mat
ion.
3O
utco
me
mea
sure
:sto
olba
cter
ialo
ad.
4O
utco
me
mea
sure
:fev
er.
5Po
sitiv
ein
tera
ctio
neff
ectw
ithde
wor
min
gtr
eatm
ento
npa
rasi
ticin
fect
ion,
noin
depe
nden
teffe
ctof
MM
N.
6O
utco
me
mea
sure
:dur
atio
nof
allr
epor
ted
dise
ases
.7
Sign
ifica
nteff
ecto
nhe
artr
ate
only
inan
emic
orio
dine
-defi
cien
tsub
sam
ple.
8Eff
ecto
nve
rbal
lear
ning
and
mem
ory,
only
ingi
rls.
9Re
sults
onac
adem
icpe
rfor
man
cew
ere
inte
grat
edin
acl
uste
rofo
ther
cogn
itive
test
s.10
Out
com
em
easu
re:a
ccur
acy
and
effici
ency
ofw
orki
ng.
11O
utco
me
mea
sure
:att
entio
nan
dco
ncen
trat
ion.
12To
talc
ogni
tive
scor
e;eff
ecto
nly
inse
vere
lyto
mod
erat
ely
anem
icch
ildre
n.13
Out
com
em
easu
re:s
peed
perf
orm
ance
.✕
No
sign
ifica
nteff
ect.
✓Si
gnifi
cant
bene
ficia
leffe
ctof
MM
N(c
ompa
ring
chan
gefr
omba
selin
ebe
twee
nor
with
ingr
oups
,orm
eans
betw
een
grou
psat
follo
w-u
p).
(✓)S
igni
fican
tben
efici
aleff
ecto
fMM
Nin
subg
roup
only
(com
parin
gch
ange
from
base
line
betw
een
orw
ithin
grou
ps,o
rmea
nsbe
twee
ngr
oups
atfo
llow
-up)
.–
Para
met
erno
tass
esse
d.Ab
brev
iatio
ns:B
MI,
body
mas
sin
dex;
Hb,
hem
oglo
bin.
Nutrition Reviews® Vol. 69(4):186–204 193
Tabl
e3
Ove
rvie
wof
the
resu
lts
ofst
udie
sas
sess
ing
effec
tsof
MM
Ns
prov
ided
ina
food
mat
rix
onth
ebi
oche
mic
alin
dica
tors
ofnu
trit
iona
lsta
tus,
anth
ropo
met
ry,m
orbi
dity
,and
cogn
itiv
eou
tcom
esin
scho
ol-a
gech
ildre
n.Re
fere
nce
Stat
istic
alan
alys
esN
utrit
iona
lsta
tus
resu
ltsAn
thro
pom
etric
resu
ltsM
orbi
dity
resu
ltsCo
gniti
vere
sults
Not
es
MM
N-fo
rtifi
edfo
odve
rsus
unfo
rtifi
edfo
odin
terv
entio
nAb
ram
set
al.
(200
3)68
Diff
eren
ces
inch
ange
from
base
line
tofo
llow
-up
betw
een
grou
psw
ere
test
edus
ing
ANCO
VA,a
djus
ted
for
age,
sex,
wei
ght,
and
grou
p.Fo
rbet
wee
n-gr
oup
diffe
renc
esin
prev
alen
ceof
defic
ienc
ies/
anem
iaat
follo
w-u
p,od
dsra
tios
wer
eco
mpu
ted
usin
glo
gist
icre
gres
sion
,co
ntro
lling
fora
ge,s
ex,a
ndw
eigh
t.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inse
rum
ferr
itin,
fola
te,
ribofl
avin
,Hb,
and
MCV
vers
usco
ntro
l(P
<0.
05);
noeff
ects
onvi
tam
inB 1
2an
dre
tinol
stat
us.T
heod
dsof
zinc
(OR
=0.
29),
fola
te(O
R=
0.02
),vi
tam
inB 2
(OR
=0.
36)
defic
ienc
y,an
dan
emia
(OR
=0.
48)a
tfo
llow
-up
wer
esi
gnifi
cant
lylo
wer
inth
eM
MN
vers
usco
ntro
lgro
up(P
<0.
05).
Hb
leve
lsde
crea
sed
and
prev
alen
ceof
anem
iain
crea
sed
inbo
thgr
oups
(but
muc
hm
ore
inth
eco
ntro
lgro
up).
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inw
eigh
t,BM
I,M
UAC,
and
wei
ght-
for-
age
Z-sc
ore
vers
usco
ntro
l(P
<0.
01),
but
noeff
ecto
nhe
ight
.
Non
eN
one
Child
ren
inth
eM
MN
grou
pw
ere
5.4
mon
ths
olde
rtha
nch
ildre
nin
the
cont
rol
grou
p.An
alys
esw
ere
adju
sted
acco
rdin
gly.
Base
line
data
ofzi
ncst
atus
nota
vaila
ble.
Diff
eren
tm
easu
rem
entm
etho
dsus
edfo
rmea
surin
gH
bat
base
line
and
follo
w-u
p.Iro
nw
aspr
ovid
edin
chel
ated
form
.
Ash
etal
.(20
03)72
Diff
eren
ces
inch
ange
from
base
line
tofo
llow
-up
betw
een
grou
psw
ere
test
edus
ing
inde
pend
entt
-tes
t.D
iffer
ence
sin
chan
gefr
omba
selin
eto
follo
w-u
pw
ithin
grou
psw
ere
test
edus
ing
paire
dt-
test
s.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inse
rum
ferr
itin,
prot
opor
phyr
in,H
ble
vels
,and
anem
iapr
eval
ence
vers
usco
ntro
l(P
<0.
01).
Hb
leve
lsde
crea
sed
and
prev
alen
ceof
anem
iain
crea
sed
inbo
thgr
oups
(but
muc
hm
ore
inth
eco
ntro
lgro
up).
Prev
alen
ceof
vita
min
Ade
ficie
ncy
decr
ease
dsi
gnifi
cant
lyin
MM
Ngr
oup
(from
21%
to11
%,
P-va
lue
notg
iven
)but
noti
nco
ntro
lgr
oup.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inw
eigh
t,he
ight
,and
BMIv
ersu
sco
ntro
l(P
=0.
001)
.Chi
ldre
nin
MM
Ngr
oup
gain
edon
aver
age
0.55
kgm
ore
wei
ght,
0.57
cmm
ore
heig
ht,a
nd0.
35kg
/m2
BMI
com
pare
dto
cont
rolg
roup
.
Non
eN
one
Stud
ysa
mpl
ew
ithpo
orov
eral
lnut
ritio
nals
tatu
s.H
ighe
rpre
vale
nce
ofiro
nde
ficie
ncy
atba
selin
ein
MM
N(1
3%)t
han
cont
rol
grou
p(5
%).
No
adju
stm
ents
ofan
alys
esfo
rdem
ogra
phic
orba
selin
eva
lues
.Bas
elin
eda
taw
ere
asse
ssed
indr
yse
ason
(ple
nty
offo
od,l
ittle
mal
aria
)whe
reas
follo
w-u
pfe
llin
wet
seas
on(li
ttle
food
,ple
nty
ofm
alar
ia)
whi
chm
ight
have
affec
ted
nutr
ition
alst
atus
.
Hyd
eret
al.
(200
7)69
Diff
eren
ces
inch
ange
ofbi
oche
mic
alin
dica
tors
ofnu
triti
onal
stat
usfr
omba
selin
eto
follo
w-u
pbe
twee
ngr
oups
wer
ete
sted
usin
gin
depe
nden
tt-t
est.
Diff
eren
ces
inch
ange
sof
anth
ropo
met
ricm
easu
res
from
base
line
tofo
llow
-up
betw
een
grou
psw
ere
test
edus
ing
gene
ral
linea
rmod
elin
gad
just
edfo
rbas
elin
eva
lues
.Co
mpa
rison
sbe
twee
npr
opor
tions
wer
ete
sted
usin
gW
ilcox
on’s
Sign
edRa
nkte
st.
Diff
eren
ces
inm
eans
with
ingr
oups
wer
ete
sted
usin
gpa
ired
t-te
sts.
Ford
iffer
ence
sin
prev
alen
ceof
defic
ienc
ies
atfo
llow
-up
betw
een
grou
ps,o
dds
ratio
sw
ere
com
pute
dus
ing
logi
stic
regr
essi
onad
just
edfo
rag
e.Ch
ange
inan
emia
prev
alen
cefr
omba
selin
eto
follo
w-u
pw
ithin
grou
pste
sted
byM
cNam
ara’
ste
st.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inse
rum
ferr
itin,
retin
ol,a
ndH
ble
vels
(P<
0.00
1)bu
tnot
zinc
vers
usco
ntro
laft
er6
mon
ths.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inpr
eval
ence
ofID
and
VAD
vers
usco
ntro
l(P
<0.
01)a
fter
6m
onth
s.Pr
eval
ence
ofID
Ade
crea
sed
sign
ifica
ntly
inM
MN
(P<
0.01
)but
notc
ontr
olgr
oup.
At6
mon
ths,
girls
inco
ntro
lgro
upw
ere
sign
ifica
ntly
mor
elik
ely
toha
veVA
D(O
R=
5.47
),ID
(OR
=5,
38),
IDA
(OR
=11
,19)
,or
anem
ia(O
R=
2.04
)(P
<0.
05)
com
pare
dto
MM
Ngr
oup.
Anem
iapr
eval
ence
decr
ease
dw
ithin
MM
Ngr
oup
durin
gfir
st6
mon
ths
(P<
0.00
1)an
din
crea
sed
with
inth
eco
ntro
lgro
upun
tilth
een
dof
the
stud
y(P
=0.
02).
No
furt
here
ffect
son
nutr
ition
alst
atus
wer
ese
enbe
twee
n6
and
12m
onth
sex
cept
for
furt
heri
ncre
asin
gse
rum
ferr
itin
leve
ls.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
inw
eigh
t,M
UAC,
and
BMIv
ersu
sco
ntro
l(P
<0.
001)
at6
mon
ths.
No
furt
here
ffect
sw
ere
seen
betw
een
6an
d12
mon
ths.
No
sign
ifica
nteff
ects
wer
ese
enon
incr
emen
tin
heig
htbe
twee
ngr
oups
.
Prev
alen
ceof
infla
mm
atio
n(h
igh
CRP)
did
notd
iffer
betw
een
grou
psth
roug
hout
the
stud
y.
Non
eO
vera
llgo
odqu
ality
ofst
udy.
Gro
ups
sim
ilara
tbas
elin
e.N
oad
just
men
tofa
naly
ses
ford
emog
raph
icva
lues
.St
udy
sam
ple
with
poor
over
alln
utrit
iona
lsta
tus.
Nutrition Reviews® Vol. 69(4):186–204194
Lien
doet
al.
(200
9)62
Diff
eren
ces
inch
ange
ofm
orbi
dity
outc
omes
from
base
line
tofo
llow
-up
betw
een
the
thre
egr
oups
(MM
N-fo
rtifi
ed/
unfo
rtifi
ed/n
ofo
odin
terv
entio
n)w
ere
test
edus
ing
ANO
VA.
Diff
eren
ces
inth
efin
alco
gniti
vesc
ores
betw
een
the
thre
egr
oups
wer
ete
sted
usin
gAN
COVA
.
Non
eN
one
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
-fort
ified
milk
vers
usun
fort
ified
milk
onch
ange
into
talb
acte
ria,
bifid
obac
teria
,and
bact
eroi
des
at3
mon
ths
(P<
0.05
),w
ithhi
gher
amou
nts
ofba
cter
iain
the
MM
Ngr
oup.
Mea
sure
men
ts:e
xerc
ises
tode
term
ine
the
spee
d,ac
cura
cy,a
ndeffi
cien
cyof
wor
king
bym
akin
gus
eof
Bour
don
alph
abet
s;ex
erci
ses
inm
emor
izin
gw
ords
and
num
bers
(no
refe
renc
es).
No
sign
ifica
ntdi
ffere
nce
betw
een
MM
N-fo
rtifi
edan
dun
fort
ified
grou
pat
follo
w-u
p;th
efo
rtifi
edm
ilkgr
oup
perf
orm
edbe
tter
than
milk
grou
pon
reca
llof
wor
dsan
ddi
gits
butd
iffer
ence
did
notr
each
sign
ifica
nce
(aut
hor’s
pers
onal
com
mun
icat
ion)
.
Hig
hert
otal
bact
eria
load
atba
selin
ein
MM
Nth
anun
fort
ified
grou
p.N
oad
just
men
tsof
anal
yses
for
dem
ogra
phic
and
base
line
valu
es.M
MN
-fort
ified
food
also
incl
uded
inul
inan
dta
urin
e.St
udy
sam
ple
with
poor
over
alln
utrit
iona
lsta
tus.
Qua
lified
cogn
itive
test
asse
ssor
san
dcu
ltura
llyre
leva
ntte
sts
adap
ted
from
the
WIS
Cte
sts
(aut
hor’s
pers
onal
com
mun
icat
ion)
,th
usop
timiz
ing
test
s’ps
ycho
met
ricpr
oper
ties.
Man
gere
tal.
(200
8)74
and
Win
icha
goon
etal
.(20
06)66
Diff
eren
ces
inm
eans
betw
een
grou
psat
follo
w-u
pw
ere
test
edus
ing
mul
tiple
linea
rreg
ress
ion
anal
ysis
(MAN
OVA
)adj
uste
dfo
rag
e,se
x,sc
hool
,and
base
line
valu
e(n
otav
aila
ble
forc
ogni
tive
test
s).F
ordi
ffere
nces
inpr
eval
ence
ofde
ficie
ncie
sbe
twee
ngr
oups
atfo
llow
-up,
odds
ratio
sw
ere
com
pute
dus
ing
logi
stic
regr
essi
onad
just
edfo
rage
,sex
,and
scho
ol.C
hang
ein
anem
iapr
eval
ence
from
base
line
tofo
llow
-up
betw
een
grou
psw
aste
sted
usin
gra
tioof
risk
ratio
s.D
iffer
ence
sbe
twee
ngr
oups
inin
cide
nce
ofm
orbi
dity
epis
odes
atfo
llow
-up
wer
eex
pres
sed
asra
tera
tios
usin
gne
gativ
ebi
nom
inal
regr
essi
on,a
djus
ted
fora
ge,s
ex,a
ndsc
hool
s.
Atfo
llow
-up,
MM
Ngr
oup
had
sign
ifica
ntly
high
erse
rum
zinc
,UI,
and
Hb
vers
usco
ntro
l(P
<0.
02),
but
ther
ew
asno
effec
ton
seru
mfe
rriti
n,re
tinol
,orM
CV.T
heod
dsof
iodi
nede
ficie
ncy
(OR
=0.
52)a
ndzi
ncde
ficie
ncy
(OR
=0.
63)a
tfol
low
-up
wer
esi
gnifi
cant
lylo
wer
inth
eM
MN
vers
usth
eco
ntro
lgro
up(P
<0.
05),
butn
otfo
riro
nor
vita
min
Ade
ficie
ncy.
No
sign
ifica
nteff
ecto
fM
MN
fort
ifica
tion
onch
ange
inpr
eval
ence
ofan
emia
.
No
sign
ifica
ntdi
ffere
nces
inan
yof
the
anth
ropo
met
ricm
easu
res
(hei
ght,
wei
ght,
knee
heig
ht,B
MI,
skin
fold
thic
knes
s,M
UAC)
atfo
llow
-up
betw
een
MM
Nan
dco
ntro
lgro
ups.
Atfo
llow
-up
MM
Ngr
oup
had
sign
ifica
ntly
low
erin
cide
nce
ofre
spira
tory
-rel
ated
sym
ptom
s(R
R=
0.83
)an
ddi
arrh
ea(R
R=
0.38
)ve
rsus
cont
rol(
P<
0.05
).N
odi
ffere
nces
betw
een
inci
denc
eof
feve
r,sk
inra
sh,o
roth
erdi
arrh
eal-r
elat
eddi
seas
esbe
twee
ngr
oups
atfo
llow
-up.
No
sign
ifica
ntdi
ffere
nces
atfo
llow
-up
indu
ratio
nof
mor
bidi
tyep
isod
es(i.
e.,
resp
irato
ry-r
elat
eddi
seas
es,r
unny
nose
,or
coug
h)be
twee
ngr
oups
.
Mea
sure
men
ts:d
igit
span
forw
ard,
digi
tspa
nba
ckw
ard
(from
WIS
C-III
),an
dvi
sual
reca
llta
skw
ithfa
mili
arob
ject
;bot
hte
sts
unde
rcon
ditio
nof
incr
ease
dan
xiet
yin
duce
dby
inst
ruct
ion
effec
ts.A
vera
gegr
ade
scor
es.S
igni
fican
tlyhi
gher
scor
esof
MM
Nve
rsus
cont
rolg
roup
atfo
llow
-up
onvi
sual
reca
ll.
Ove
rall
good
qual
ityof
the
stud
y.G
roup
ssi
mila
rat
base
line.
Stud
ysa
mpl
ew
ithpo
orov
eral
lnut
ritio
nals
tatu
s.Bo
thgr
oups
expe
rienc
edim
prov
emen
tsin
bioc
hem
ical
para
met
ers,
whi
chm
ayha
vebe
enaff
ecte
dby
the
impr
oved
scho
olm
eals
give
nto
both
grou
ps.I
ron
prov
ided
asH
-red
uced
elem
enta
liro
n,w
ithlo
wbi
oava
ilabi
lity.
Vita
min
Apr
ovid
edas
retin
ylpa
lmita
te,w
hich
isin
stab
lein
dry
mat
rices
.Cog
nitiv
eas
sess
men
tdoe
sno
tfol
low
stan
dard
proc
edur
e:Th
eob
serv
edch
ange
sco
uld
bedu
eto
the
impa
ctof
mic
ronu
trie
nts
onm
emor
yor
onre
duct
ion
ofan
xiet
yin
all
orin
asu
bgro
upof
anxi
ety-
pron
ech
ildre
n.
Nga
etal
.(20
09)67
Diff
eren
ces
inm
eans
betw
een
grou
psat
follo
w-u
pw
ere
test
edus
ing
ANCO
VAad
just
edfo
rba
selin
eva
lues
,sex
,age
,and
CRP
(non
para
met
ricte
stus
edif
data
notn
orm
ally
dist
ribut
ed);
mul
tiple
com
paris
ons
mad
ew
ithBo
nfer
roni
post
hoc
test
.Fo
rdiff
eren
ces
inpr
eval
ence
ofde
ficie
ncie
san
din
fect
ions
betw
een
grou
psat
follo
w-u
p,od
dsra
tios
wer
eco
mpu
ted
usin
glo
gist
icre
gres
sion
adju
sted
forb
asel
ine
valu
es,
age,
sex,
and
CRP.
Atfo
llow
-up,
MM
Ngr
oup
had
sign
ifica
ntly
bett
erH
ble
vels
and
nutr
ition
alst
atus
ofal
lvita
min
san
dm
iner
als
asse
ssed
vers
usco
ntro
l,i.e
.,pl
asm
afe
rriti
n,bo
dyiro
n,re
tinol
,vi
tam
inA
liver
stor
es(D
R/R-
ratio
),pl
asm
azi
nc,U
I,P
<0.
05.T
heod
dsof
zinc
(OR
=0.
52)a
ndio
dine
defic
ienc
y(O
R=
0.53
)as
wel
las
prev
alen
ceof
low
vita
min
Aliv
erst
ores
(OR
=0.
65)a
ndan
emia
(OR
=0.
56)a
tfol
low
-up
wer
esi
gnifi
cant
lylo
wer
inth
eM
MN
vers
usth
eco
ntro
lgro
up(P
<0.
05).
No
inte
ract
ion
betw
een
dew
orm
ing
trea
tmen
tand
MM
Nfo
rtifi
catio
non
nutr
ition
alst
atus
outc
omes
.
Non
eN
osi
gnifi
cant
effec
tof
MM
Nfo
rtifi
catio
nal
one
onpa
rasi
ticin
fect
ions
atfo
llow
-up,
buts
igni
fican
tin
tera
ctio
nw
ithde
wor
min
gtr
eatm
ent:
agr
eate
rred
uctio
nin
prev
alen
ceof
para
sitic
infe
ctio
nob
serv
edin
child
ren
who
rece
ived
MM
Npl
usde
wor
min
gtr
eatm
entc
ompa
red
toon
lyde
wor
min
gtr
eatm
ent(
P<
0.02
).
Non
eO
vera
llgo
odqu
ality
ofth
est
udy.
Gro
ups
sim
ilara
tba
selin
e.St
udy
sam
ple
with
poor
over
alln
utrit
iona
lsta
tus.
Nutrition Reviews® Vol. 69(4):186–204 195
Tabl
e3
Cont
inue
dRe
fere
nce
Stat
istic
alan
alys
esN
utrit
iona
lsta
tus
resu
ltsAn
thro
pom
etric
resu
ltsM
orbi
dity
resu
ltsCo
gniti
vere
sults
Not
es
Ose
ndar
pet
al.(
2007
)63
Aust
ralia
Diff
eren
ces
inch
ange
from
base
line
tofo
llow
-up
betw
een
grou
psw
ere
test
edus
ing
ANCO
VAad
just
edfo
rba
selin
eva
lues
,se
x,ag
e,an
dco
hort
ofre
crui
tmen
t.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inse
rum
ferr
itin,
body
iron
stor
es,R
BCfo
late
,and
vita
min
B 12,
vers
usco
ntro
l(P
<0.
05);
butn
oeff
ecto
nse
rum
zinc
orH
ble
vels
.
Non
eN
one
Mea
sure
men
ts:d
igits
back
war
ds,
codi
ng,b
lock
desi
gn,a
ndvo
cabu
lary
(4su
b-sc
ales
from
WIS
C-III
),vi
sual
atte
ntio
n2,
fluen
cy(2
sub-
scal
esfr
omN
EPSY
).Ac
adem
icte
sts
wer
ere
adin
g,sp
ellin
g,an
dm
athe
mat
ical
reas
onin
g(3
test
sfr
omW
IAT
Scre
ener
).Af
terf
acto
riala
naly
sis
ofth
eco
gniti
vete
sts,
test
sw
ere
clus
tere
din
tofa
ctor
1(fl
uid
inte
llige
nce)
,fac
tor2
(ver
bal
lear
ning
and
mem
ory)
,and
fact
or3
(att
entio
nan
dco
ncen
trat
ion)
.Si
gnifi
cant
bene
ficia
leffe
cton
chan
gein
fact
or2
inM
MN
vers
usco
ntro
lgro
up.
Two
recr
uitm
entr
ound
sw
ere
nece
ssar
y;ba
selin
eva
lues
ofch
ildre
nfr
omth
edi
ffere
ntro
unds
wer
edi
ffere
nt,a
djus
ted
acco
rdin
gly.
Stud
ysa
mpl
ew
ithgo
odov
eral
lnu
triti
onal
stat
us.O
nly
smal
lsub
-sam
ple
(26%
ofto
tals
ampl
e)av
aila
ble
for
bioc
hem
ical
para
met
ers
beca
use
pare
nts
and
child
ren
refu
sed
bloo
dsa
mpl
ing.
Hig
hnu
mbe
rof
part
icip
ants
(30%
)was
lost
tofo
llow
up.S
tand
ardi
zed
cogn
itive
test
sof
high
psyc
hom
etric
valu
e,qu
alifi
edas
sess
ors.
Ose
ndar
pet
al.(
2007
)63.
Indo
nesi
aD
iffer
ence
sin
chan
gefr
omba
selin
eto
follo
w-u
pbe
twee
ngr
oups
wer
ete
sted
usin
gAN
COVA
,ad
just
edfo
rba
selin
eva
lues
,se
x,an
dag
e.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
inse
rum
ferr
itin,
tran
sfer
rinre
cept
or,b
ody
iron
stor
es,H
ble
vels
,RB
Cfo
late
,vita
min
B 12,
plas
ma
DH
A,an
dto
talp
lasm
aom
ega-
3ve
rsus
cont
rol(
P<
0.05
,but
noeff
ecto
nse
rum
zinc
.
Non
eN
one
Mea
sure
men
ts:s
ame
asin
Aust
ralia
(Ose
ndar
p20
0763
)exc
eptr
eadi
ngte
stin
Baha
mil
angu
age
(Nea
leAn
alys
isof
Read
ing)
and
nosp
ellin
gte
st.N
osi
gnifi
cant
effec
tsin
MM
Nve
rsus
cont
rolg
roup
onch
ange
inco
gniti
vesc
ores
base
don
omni
bus
ANO
VA.A
post
erio
rian
alys
essh
owed
sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onch
ange
infa
ctor
2(v
erba
llea
rnin
gan
dm
emor
y)ve
rsus
cont
roli
ngi
rlsbu
tnot
boys
.
Ove
rall
good
qual
ityof
the
stud
y.St
udy
sam
ple
with
poor
nutr
ition
alst
atus
.St
anda
rdiz
edco
gniti
vete
sts
ofhi
ghps
ycho
met
ricva
lue,
qual
ified
asse
ssor
s.Ve
rbal
mem
ory
test
had
floor
effec
tsth
atqu
estio
nits
valid
ityin
this
sam
ple;
coul
dex
plai
nla
ckof
repl
icat
ion
ofre
sults
from
Aust
ralia
nsa
mpl
e.
Sarm
aet
al.(
2006
)70
Siva
kum
aret
al.(
2006
)65
Shat
rugn
aet
al.(
2006
)73
Vazi
reta
l.(2
006)
75
Diff
eren
ces
inm
eans
betw
een
grou
psan
dch
ange
from
base
line
tofo
llow
-up
betw
een
grou
psup
wer
ete
sted
usin
gw
eigh
ted
paire
dt-
test
s.If
base
line
mea
nsdi
ffere
dbe
twee
ngr
oups
,th
ese
diffe
renc
esw
ere
corr
ecte
dus
ing
are
gres
sion
mod
el.D
iffer
ence
sin
prop
ortio
nsbe
twee
ngr
oups
wer
ete
sted
usin
gth
eW
ilcox
on’s
sign
edra
nkte
st.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
ofRB
Cfo
late
,se
rum
retin
ol,v
itam
inD
,and
vita
min
B 2st
atus
asw
ella
son
thyr
oid-
stim
ulat
ing
horm
one
(TSH
)an
dpa
rath
yroi
dho
rmon
e(P
TH)
vers
usco
ntro
l(P
<0.
001)
.No
sign
ifica
nteff
ecto
fMM
Ns
onch
ange
ofvi
tam
inB 1
,B6,
B 12,
vita
min
C,zi
nc,
calc
ium
,pho
spho
rus,
and
Hb
leve
ls.
Amon
gsts
ub-s
ampl
eof
anem
icch
ildre
n,m
ean
Hb
leve
lsat
follo
w-u
pw
ere
sign
ifica
ntly
high
erco
mpa
red
toco
ntro
l(P
<0.
05).
Atfo
llow
-up,
vita
min
Can
dfe
rriti
nle
vels
wer
esi
gnifi
cant
lyhi
gher
inM
MN
com
pare
dto
cont
rolg
roup
(P<
0.00
1).N
osi
gnifi
cant
diffe
renc
esob
serv
edbe
twee
nM
MN
and
cont
rol
grou
pson
prev
alen
ceof
clin
ical
sign
sof
defic
ienc
yth
roug
hout
stud
y,i.e
.,go
iter,
Bito
t’ssp
ots,
angu
lar
stom
atiti
s,gl
ossi
tisch
eilo
sis,
blee
ding
gum
s.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
inw
eigh
t,he
ight
,BM
I,H
AZ,W
AZ,a
ndw
eigh
tve
loci
tyve
rsus
cont
rol
(P<
0.05
).Al
so,s
igni
fican
tbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
infa
t-fr
eem
ass,
perc
enta
geof
fat,
who
le-b
ody
bone
min
eral
cont
ent,
who
le-b
ody
area
and
neck
min
eral
dens
ityve
rsus
cont
rol(
P<
0.05
),bu
tno
effec
ton
bone
para
met
ers
ofhi
por
spin
e.
No
sign
ifica
nteff
ecto
fMM
Nfo
rtifi
catio
non
num
bero
fep
isod
esof
illne
ss(i.
e.,
feve
r,co
ugh
and
cold
,di
arrh
ea,e
arin
fect
ion)
,but
mea
ndu
ratio
nof
all
dise
ases
was
sign
ifica
ntly
shor
teri
nM
MN
grou
p(5
days
)com
pare
dto
cont
rol
(7.4
days
)(P
<0.
05).
Mea
sure
men
ts:M
alin
’sin
telli
genc
esc
ale
forI
ndia
nch
ildre
n(In
dian
adap
tatio
nof
WIS
C-R)
incl
udin
g6
verb
alan
d5
perf
orm
ance
sub-
scal
es:
stan
dard
ized
scor
esof
verb
alIQ
,pe
rfor
man
ceIQ
,and
gene
ralI
Q,P
GI
mem
ory
scal
e(7
sub-
scal
espl
usto
tal
scor
e),K
nox-
cube
imita
tion
test
,le
tter
canc
ella
tion
test
,3ac
adem
icsc
ores
(mat
h,sc
ienc
e,so
cial
stud
ies)
,an
dth
eag
greg
ated
scor
e.Si
gnifi
cant
bene
ficia
leffe
ctof
MM
Non
chan
gein
Knox
-cub
ete
st.S
igni
fican
tlylo
wer
scor
eson
lett
erca
ncel
latio
nte
sts
(att
entio
nan
dsp
eed)
inM
MN
vers
usco
ntro
lgro
upat
follo
wup
,but
nosi
gnifi
cant
effec
ton
chan
gein
scor
esfr
omba
selin
eto
follo
w-u
p.
Two
clas
ses
inea
chgr
ade
wer
era
ndom
ized
toM
MN
orco
ntro
ltre
atm
enta
ndco
nsid
ered
am
atch
edpa
ir.Pa
ired
t-te
sts
wer
eap
plie
dto
thes
em
atch
edpa
irsto
test
ford
iffer
ence
s.St
udy
sam
ple
with
poor
over
all
nutr
ition
alst
atus
.Gro
ups
sim
ilara
tbas
elin
e.N
oad
just
men
tsof
anal
yses
for
dem
ogra
phic
varia
bles
.Bi
oche
mic
alas
sess
men
ton
lyin
subs
ampl
e(n
=32
7).
Hig
hnu
mbe
rofp
artic
ipan
ts(2
5%)l
ostt
ofo
llow
up.D
ata
onsi
ckne
ssba
sed
onse
lf-re
port
ing.
Cogn
itive
asse
ssm
entm
etho
dsen
sure
good
psyc
hom
etric
prop
ertie
s:se
lect
edte
sts
stan
dard
ized
and
valid
ated
fort
his
popu
latio
n;te
sts
pilo
ted;
asse
ssor
str
aine
d.St
atis
tical
met
hods
lack
cons
iste
ncy.
Inco
nsis
tenc
ies
inou
tcom
esas
repo
rted
and
pres
ente
din
figur
es.
Nutrition Reviews® Vol. 69(4):186–204196
Solo
net
al.(
2003
)64D
iffer
ence
sin
mea
nsbe
twee
ngr
oups
and
chan
gefr
omba
selin
eto
follo
w-u
pbe
twee
ngr
oups
wer
ete
sted
usin
gAN
OVA
.If
sign
ifica
nt,a
mul
tiple
-ran
gete
stw
asdo
neto
iden
tify
whi
chgr
oups
diffe
red
from
each
othe
r.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
inU
Iver
sus
cont
rol(
P<
0.00
1)bu
tnot
Hb
leve
ls.
Sign
ifica
ntin
vers
eco
rrel
atio
nbe
twee
nba
selin
eU
Ista
tus
and
incr
ease
inU
Ilev
els
upon
fort
ifica
tion,
P<
0.00
01.E
ffect
ofM
MN
fort
ifica
tion
onch
ange
inio
dine
stat
usw
assi
gnifi
cant
lyhi
gher
inno
n-an
emic
child
ren
than
inan
emic
child
ren
(P<
0.01
).Si
gnifi
cant
inve
rse
corr
elat
ion
obse
rved
betw
een
base
line
Hb
leve
lsan
deff
ecto
fMM
Nfo
rtifi
catio
non
Hb
leve
ls(P
<0.
0001
).Th
enu
mbe
rof
child
ren
who
rem
aine
dan
emic
atfo
llow
-up
was
sign
ifica
ntly
low
erin
MM
N(1
5%)v
ersu
sco
ntro
lgro
up(2
9%)(
P=
0.03
).
No
sign
ifica
nteff
ecto
fMM
Nfo
rtifi
catio
non
any
anth
ropo
met
ricou
tcom
esve
rsus
cont
rol(
heig
ht,
wei
ght,
wei
ght-
for-
age,
heig
ht-fo
r-ag
e,an
dw
eigh
t-fo
r-he
ight
).
No
sign
ifica
nteff
ectb
utpo
sitiv
etr
end
seen
for
MM
Nfo
rtifi
catio
non
chan
gein
hear
trat
ean
dfit
ness
inde
x.Si
gnifi
cant
effec
tson
chan
gein
hear
tra
tew
ere
obse
rved
insu
b-sa
mpl
eof
anem
ican
dio
dine
-defi
cien
tchi
ldre
n(P
<0.
05).
Mea
sure
men
ts:P
rimar
ym
enta
lab
ilitie
ste
stfo
rFili
pino
child
ren
(not
publ
ishe
d).N
oeff
ects
ofM
MN
vers
usco
ntro
lbas
edon
omni
bus
ANO
VA.A
post
erio
rian
alys
eson
smal
lsub
-sam
ple
ofm
oder
atel
yto
seve
rely
anem
icch
ildre
n(n
=24
)sho
wa
sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
onto
talc
ogni
tive
scor
eve
rsus
cont
rol.
Gro
ups
sim
ilara
tbas
elin
e.N
oad
just
men
tsof
anal
yses
for
dem
ogra
phic
orba
selin
eva
lues
.Stu
dysa
mpl
ew
ithpo
orov
eral
lnut
ritio
nal
stat
us.P
sych
omet
ricpr
oper
ties
ofco
gniti
vete
stun
know
nan
dte
stad
min
istr
atio
ndi
ffers
betw
een
grad
es:t
his
jeop
ardi
zes
the
chan
ces
ofde
tect
ing
effec
ts.
van
Stui
jven
berg
etal
.(19
99)71
Diff
eren
ces
inch
ange
from
base
line
tofo
llow
-up
betw
een
grou
psw
ere
test
edus
ing
Wilc
oxon
2-sa
mpl
ete
st.
Diff
eren
ces
inpr
eval
ence
sof
defic
ienc
ies
betw
een
grou
psw
ere
test
edus
ing
repe
ated
-m
easu
res
ANO
VAfo
rca
tego
rical
data
.D
iffer
ence
sin
abse
ntda
ysbe
twee
ngr
oups
wer
ete
sted
usin
gth
ech
i-squ
are
test
.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
inal
lmar
kers
ofiro
nst
atus
,UI,
seru
mre
tinol
,Hb
leve
ls,a
ndH
tcve
rsus
cont
rol
(P<
0.00
01).
Prev
alen
ceof
vita
min
A,iro
n,an
dio
dine
defic
ienc
yde
crea
sed
sign
ifica
ntly
mor
ein
MM
Ngr
oup
vers
usco
ntro
l(P
<0.
0001
),bu
tno
effec
tofM
MN
fort
ifica
tion
was
obse
rved
onpr
eval
ence
ofgo
itero
ran
emia
.
No
sign
ifica
nteff
ecto
fMM
Nfo
rtifi
catio
non
any
anth
ropo
met
ricou
tcom
esve
rsus
cont
rol(
heig
ht,
wei
ght,
wei
ght-
for-
age,
heig
ht-fo
r-ag
e).
Sign
ifica
ntly
few
erab
sent
days
due
todi
arrh
ea-
rela
ted
illne
ssin
MM
Ngr
oup
vers
usco
ntro
l(52
vers
us79
days
,P=
0.01
3);
few
erda
ysw
ere
mis
sed
due
tore
spira
tory
illne
ssin
MM
Nve
rsus
cont
rolg
roup
.
Mea
sure
men
ts:F
ive
test
sre
cord
ing
spee
dpe
rfor
man
ce–
digi
tco
pyin
g,co
untin
gle
tter
s,ca
ncel
ling
lett
ers,
read
ing
num
bers
,cou
ntin
gba
ckw
ard.
Perf
orm
ance
unde
rtim
eco
nstr
aint
:ver
balfl
uenc
y,w
ritin
gcr
osse
s,di
gits
pan
forw
ard,
digi
tspa
nba
ckw
ard.
Out
com
es:s
igni
fican
tben
efici
aleff
ecto
fMM
Non
digi
tspa
nfo
rwar
dve
rsus
cont
rol.
Tend
tosh
owgr
eate
rand
mor
etr
eatm
ente
ffect
sof
MM
Nin
child
ren
with
low
seru
mfe
rriti
nan
dH
ban
dth
ose
with
goite
rat
base
line.
No
adju
stm
ents
ofan
alys
esfo
rde
mog
raph
icva
lues
.N
othi
ngm
entio
ned
ondo
uble
-blin
ding
and
drop
outr
ate.
Met
hods
used
forc
ogni
tive
asse
ssm
ent
follo
wpu
blis
hed
guid
elin
esfo
rnut
ritio
nst
udie
s;te
sts
sele
cted
fort
heir
good
psyc
hom
etric
prop
ertie
s;cu
ltura
lada
ptat
ion,
pilo
ting,
stan
dard
ized
proc
edur
e(t
rain
edas
sess
ors)
optim
izin
gte
sts
psyc
hom
etric
prop
ertie
s.St
udy
sam
ple
with
poor
nutr
ition
alst
atus
.Sal
tio
diza
tion
beca
me
man
dato
ryha
lfway
thro
ugh
stud
yan
dus
ual
cons
umpt
ion
switc
hed
from
non-
iodi
zed
toio
dize
dsa
lt.
MM
N-fo
rtifi
edfo
odve
rsus
sing
le-fo
rtifi
edfo
odin
terv
entio
nZi
mm
erm
ann
etal
.(2
004)
76D
iffer
ence
sin
chan
gefr
omba
selin
eto
follo
w-u
pbe
twee
ngr
oups
wer
ete
sted
usin
gtw
o-fa
ctor
repe
ated
mea
sure
sAN
OVA
.Ifs
igni
fican
t,in
depe
nden
tt-t
ests
and
paire
dt-
test
sw
ere
used
tote
stfo
rdi
ffere
nces
betw
een
and
with
ingr
oups
.D
iffer
ence
sin
chan
geof
prev
alen
ceof
defic
ienc
ies
from
base
line
tofo
llow
-up
betw
een
grou
psw
ere
test
edus
ing
logi
stic
regr
essi
on.
Sign
ifica
ntbe
nefic
iale
ffect
ofM
MN
fort
ifica
tion
onch
ange
inal
lmar
kers
ofiro
nan
dvi
tam
inA
stat
us,H
ble
vels
,iro
nde
ficie
ncy
anem
ia,a
ndvi
tam
inA
defic
ienc
y(P
<0.
01).
No
effec
tsof
MM
Nfo
rtifi
catio
non
UI
thro
ugho
utth
est
udy;
med
ian
UI
sign
ifica
ntly
incr
ease
din
both
grou
ps.
Non
eN
one
Non
eEff
ectiv
enes
sst
udy:
inte
rven
tion
prod
uct(
salt)
dist
ribut
edto
hous
ehol
ds,
cons
umpt
ion
notc
ontr
olle
d.St
udy
carr
ied
outi
nar
eaof
ende
mic
goite
r.D
ieth
igh
inph
ytic
acid
,low
inas
corb
icac
id,t
here
fore
low
iron
abso
rptio
n.G
roup
ssi
mila
rat
base
line.
No
adju
stm
ents
ofan
alys
esfo
rdem
ogra
phic
and
base
line
valu
es.
Abbr
evia
tions
:BM
I,bo
dym
assi
ndex
;CRP
,C-r
eact
ive
prot
ein;
HAZ
,hei
ght-
for-
age
z-sc
ore;
Hb,
hem
oglo
bin;
ID,i
ron
defic
ienc
y;ID
A,iro
nde
ficie
ncy
anem
ia;I
Q,i
ntel
ligen
cequ
otie
nt;M
MN
,mul
tiple
-mic
ronu
trie
nt;M
UAC,
mid
dle-
uppe
r-ar
mci
rcum
fere
nce;
NIM
HAN
S,N
atio
nalI
nstit
ute
ofM
enta
lHea
lthan
dN
euro
logi
calS
cien
ces;
OR,
odds
ratio
;PG
I,Po
stG
radu
ate
Inst
itute
ofM
edic
alEd
ucat
ion
and
Rese
arch
;RR,
rate
ratio
;UI,
urin
ary
iodi
ne;W
ISC,
Wec
hsle
rInt
ellig
ence
Scal
efo
rChi
ldre
n;W
HZ,
wei
ght-
for-
heig
htz-
scor
e;W
AZ,w
eigh
t-fo
r-ag
ez-
scor
e;VA
D,v
itam
inA
defic
ienc
y.
Nutrition Reviews® Vol. 69(4):186–204 197
Eight of nine studies assessing indicators of iron statusdetected a beneficial effect of MMN fortification on ironstatus, including the study with well-nourished Australianchildren. The only study that did not find an effect pro-vided 5 g of elemental iron via an MMN powder added tothe school lunch.66
Among six studies that investigated the effect ofMMNs (including zinc) compared to unfortified foodinterventions on zinc status, only two studies found asignificant beneficial effect.66,67 After 16 and 31 weeks ofintervention, respectively, zinc levels adjusted for baselinezinc values were significantly higher and odds of zincdeficiency significantly lower in the MMN group com-pared to the control group. Nga et al.67 estimated an inter-vention effect of 0.61 (95% CI: 0.25–0.95) mmol/L plasmazinc and reduced odds of zinc deficiency at follow-up inthe intervention group (odds ratio [OR]: 0.52; 95% CI:0.36–0.76). Winichagoon et al.66 reported higher levels ofserum zinc in the intervention group, with a mean differ-ence at follow-up of 0.34 mmol/L (95% CI: 0.08–0.60) andreduced odds of deficiency at follow-up (OR: 0.63; 95%CI: 0.42–0.94). Abrams et al.68 also found that the preva-lence of zinc deficiency at follow-up was significantlylower in the MMN group (4.6%) compared to the controlgroup (14.5%) (P < 0.05). However, baseline data on zincstatus was not reported. Therefore, no judgment can bemade on whether the change was due to the MMN inter-vention. Other studies comparing interventions withMMNs to those with unfortified food did not find anyeffect on biochemical zinc status or deficiency,63,69 noteven in a population with a high prevalence of zinc defi-ciency.63 Across all studies, zinc was included at relevantdosages of 2.3–7.5 mg per day.
All five studies evaluating iodine status found a ben-eficial effect of MMN fortification on urinary iodineexcretion levels or concentrations of thyroid-stimulatingand parathyroid hormones. However, two studies thatalso assessed prevalence of goiter did not find any effectof MMN fortification after either a 12- or a 14-monthintervention period, despite a high prevalence at base-line.70,71 One study also looked at the effects of MMNfortification on prevalence of other clinical symptoms ofmicronutrient deficiencies (i.e., Bitot’s spots, bleedinggums, glossitis, cheilosis, and angular stomatitis).70 In theexperimental and control groups, the prevalence of thesesymptoms was less than or equal to 6% at baseline andnearly absent after 14 months, but there was no differ-ence in prevalence between the groups at either timepoint.
The study that compared MMN-fortified salt toiodized salt measured a greater positive impact in theintervention group for all of the biochemical markers ofnutritional status that were assessed, i.e., Hb, vitamin A,iron, and iodine status.76
Effects on anthropometric status
Seven studies investigated the effects of MMN-fortifiedfoods compared to unfortified foods on anthropometricoutcomes, mainly height, weight, and prevalence ofundernutrition (Table 3). Four of the seven studies foundsignificant beneficial effects on weight and BMI; onaverage, children in the MMN-fortified group gainedbetween 0.47 and 0.56 kg more weight than controls andtheir gains in BMI compared with controls were 0.23–0.35 kg/m2 greater.68–70,72 Two of seven studies found asignificant beneficial effect on height gain, with mean dif-ferences of about 0.6 to 1.0 cm in height incrementsbetween the groups after 6 or 14 months, respectively.70,72
One of the studies also reported a significantly greaterincrease in absolute fat-free mass (mean difference [MD],0.9 kg), percentage of body fat (MD, 0.81%), and whole-body bone mineral content (MD, 22 g) compared to con-trols.73 This14-month intervention supplied a fortifiedmilk porridge that provided extra vitamin D and calciumtogether with other micronutrients. The other threestudies did not find any effects on height or weight.64,71,74
Effects on morbidity outcomes
Seven studies investigated the effect of MMN-fortifiedfoods compared to unfortified foods on morbidity out-comes (Table 3). Two studies that assessed the effects ofMMN fortification on respiratory- and diarrhea-relatedillness reported a beneficial effect.73,74 Van Stuijvenberget al.71 reported fewer school absences attributed torespiratory- and diarrhea-related illness over a 1-yearperiod in the MMN-fortified group compared to thecontrol group, 33 versus 47 missed days per 100 childrenfor respiratory- (P = 0.097) and 52 versus 79 missed daysfor diarrhea-related diseases (P = 0.013). Manger et al.74
found that children receiving MMN powder for 31 weekshad a significantly lower incidence of respiratory-relatedsymptoms and diarrhea compared to children in thecontrol group, with rate ratios of 0.83 (95% CI: 0.73–0.94)and 0.38 (95% CI: 0.16, 0.90), respectively. No differencebetween the groups was seen for incidence of fever, otherdiarrhea-related illnesses (vomiting, nausea, and stomachpain), or the duration of morbidity episodes forrespiratory-related diseases, such as runny nose andcough. A third study did not find any beneficial effect offortification on the incidence of diarrhea, fever, coughand cold, or ear infection, but the reported episodes ofany illness were, on average, 2.4 days significantly shorterin the MMN-fortified group compared to the controlgroup.70
One study evaluated the impact of MMN fortifica-tion on physical fitness and heart rate,64 and one studyeach looked at the following secondary outcomes:
Nutrition Reviews® Vol. 69(4):186–204198
parasitic infections,67 stool bacteria load,62 inflamma-tion,69 and white blood cells.71 Nga et al.67 reported thatMMN fortification did not have an independent effect onparasitic infection but it interacted positively withde-worming treatment: The prevalence of parasitic infec-tions was found to be reduced to a greater extent in chil-dren who received MMN-fortified biscuits in additionto de-worming treatment compared to children whoreceived de-worming treatment and unfortified biscuits.Significantly higher amounts of total bacteria, bifidobac-teria, and bacteroides were reported in the stools of chil-dren who had received MMN-fortified milk for 3 monthscompared to children who had received regular unforti-fied milk.62 In this study, the intervention product wasfortified with inulin and taurine as well as MMNs. Theremaining studies did not provide conclusive data onmarkers of immune capacity or response.
Effects on cognitive outcomes
Seven studies investigated the effects of MMN-fortifiedfoods compared to unfortified foods on cognitive abili-ties; among them were four studies that also investigatedchanges in academic performance (Table 3). Threestudies found significant beneficial effects of MMN-fortified beverages compared to unfortified beverages onmemory tests: one study found that visual recall of famil-iar objects – as measured on a scale from 0 to 15 –improved on average by 0.5 points more74; one studyreported that a cluster of outcomes from auditory verbalmemory test improved significantly more with an esti-mated effect size of 0.23 standard deviation (95% CI:0.01–0.46)63; and one study reported one statistically sig-nificant positive finding (in a set of nine cognitive out-comes) on working memory.71
Four studies found mixed results or no beneficialeffects on cognition or academic performance. Osendarpet al.63 (Indonesia sample) did not find effects in theoverall study population, but in subgroup analyses, apositive effect on verbal learning and memory wasobserved in girls but not in boys. Solon et al.64 did not findan overall effect in the population but found somebeneficial effects of the MMN intervention on verbal,non-verbal, and total cognitive scores in a rather smallsub-sample of children with anemia (Hb < 11 g/dL) atbaseline. Vazir et al.75 reported only two significant find-ings on tests assessing attention and concentration from aset of about 20 standard cognitive tests and three aca-demic tests: 1) a positive effect of MMN fortificationon performance in a Knox-test; 2) a negative effect(unfortified > MMN-fortified) on letter cancellation. Liendo et al.62 did not report any significant effect of theMMN-fortified food versus unfortified foods on any of
the outcomes in a small set of three standard tests onworking speed, efficacy, and working memory.
RELEVANCE AND LIMITATIONS OF LITERATURE REVIEW
Overall, the studies in this review found that MMN for-tification resulted in positive effects on biochemical indi-cators of micronutrient status and reduced anemiaprevalence compared to unfortified foods or food forti-fied with a single micronutrient. Eight of ten studies con-sistently reported that MMN fortification improved ironand Hb status. Only one study, conducted among well-nourished Australian children who had adequate Hblevels at baseline, found no effect of MMN fortification onHb status.63 Another study that did not find an effect oniron status provided iron at a relatively low dose (5 mgper day) in a form with low bioavailability (elementaliron) via a seasoning powder added to school lunch.66 Thefortified food interventions that did improve iron statusprovided between 5 mg and 14 mg of iron daily in avariety of chemical forms for at least 8 weeks.
Beneficial effects of MMN fortification on iodine,vitamin A, and B vitamin status were reported repeat-edly, yet, only two of six studies observed a positive effecton zinc status. This could be due to poor absorption ofzinc, possibly related to the combined fortification ofzinc with iron at a ratio ranging from 1:1 to 1:3. Previousresearch suggested that combined supplementation withiron and zinc can lead to a smaller effect on biochemicaland functional outcomes than supplementation witheither nutrient alone. It has been postulated that zinc andiron may interact in such a way that they compete fortransporters necessary for absorption, but the evidence isconflicting and there is not enough evidence to discour-age joint administration.79 In both studies that measureda significant beneficial effect on serum zinc levels, lessthan 5% of the study participants had low iron stores atbaseline, whereas more than 50% had low levels of zincin serum or plasma.66,67 Absorption of zinc could alsohave been reduced due to a high phytate content of thecarrier food or the general diet. Otherwise, the equivocaleffects on zinc could be attributed to the low reliability ofserum or plasma zinc as an indicator of individual zincstatus.
Though iodine status, as well as concentrationsof thyroid-stimulating hormone and parathyroidhormone, was consistently shown to improve upon inter-vention with MMN fortification, no effects were seenon the prevalence of goiter after 12 or 14 months ofintervention.70,71 While low urinary iodine excretion(<100 mg/L) is a sign of mild iodine deficiency, goiter is aclinical symptom of iodine deficiency disorder resultingfrom prolonged iodine deficiency.4 The results suggestthat the dosage (75–120 mg iodine) and/or the duration of
Nutrition Reviews® Vol. 69(4):186–204 199
the intervention was sufficient to reduce mild iodine defi-ciency but not enough to reverse advanced iodine defi-ciency and/or to reduce the enlargement of the thyroidgland.
While the positive impact on short-term nutritionaloutcomes was rather consistent (with the exception ofzinc), these improvements did not always translate into ameasurable impact on functional health outcomes ofgrowth, morbidity, and cognitive development. Whilefour of seven studies reported a significant beneficialeffect of the MMN fortification on weight gain, increasedBMI,68–70,73 or MUAC,68,69 only two studies showed aneffect on height.72,73 A possible explanation for a lack of aclear effect may be that the extra energy and macronutri-ents, which were also provided to the control group, con-tributed to the height and weight gains observed in bothgroups and might have masked any additional effect ofthe MMNs. This may be all the more relevant if childrenwere initially undernourished, as was the case in many ofthe reviewed studies. Interventions that positivelyimpacted child growth provided an MMN combinationof at least iron, vitamin A, zinc, iodine, B-vitamins, andvitamin C via fortified beverages (3 studies) or milk por-ridge (1 study). While effects on linear growth wereobserved after intervention periods of 6 and 14months,72,73 effects on weight gain were already reportedafter 8 weeks of intervention.68
The effects of MMN fortification on morbidity out-comes were equivocal, with four of seven studies showingsome beneficial effects on children’s health. The mostcommon effects observed were reduced incidence orduration of diarrhea and respiratory-related diseases afterMMN fortification. Since respiratory and diarrheal dis-eases are probably the most common illnesses in chil-dren, it might have been easier to detect an effect on theseillnesses compared to other less-common diseases. Theeffects of MMN fortification on other diseases or healthoutcomes were assessed only by single studies, and moreevidence is needed to draw conclusions.
Overall, the results of MMN-fortified food interven-tions on children’s cognitive performance were inconsis-tent and differed by cognitive domain. The cognitiveabilities most affected relate to working memory, withfour of six studies reporting some beneficial effect. Thetwo studies that clearly found a beneficial effect of MMN-fortified foods compared to unfortified food on workingmemory performance in the entire sample of participantshad in common a long duration (6 and 12 months) anddelivery of iron and vitamin A in combination withiodine and/or zinc.63,74 Other effects on memory andattention/concentration, as reported by two more studies,might be chance findings given the many outcomesassessed at follow-up and few significant differencesbetween groups.71,75 The consistent positive results on
working memory across studies suggests there may be avalid effect of MMN fortification.
The present review offers a comprehensive andconcise overview of the experimental research on theimpact of MMN food fortification on the nutrition andhealth of school-age children. All of the studies reviewedwere efficacy studies carried out in well-controlled set-tings. The interventions, however, varied with regard tothe combination of micronutrients, the dosage, durationof intervention, and potential confounders and effectmodifiers (e.g., the age and nutritional status of the studypopulation or the macronutrient content of the fortifiedfood). Also, the methods applied to assess health out-comes varied across studies. The cognitive tests and theirpsychometric properties were not always well described.Due to this heterogeneity it is challenging to compareresults across studies.
To our knowledge, this review is the first to show thatprovision of MMNs via fortification consistentlyimproves biochemical indicators of micronutrient statusin schoolchildren. Whereas a previous Cochrane system-atic review that investigated the effectiveness of schoolfeeding without MMN fortification reported mixedresults on Hb or hematocrit,60 this review provides clearevidence of the benefits of MMN fortification for reduc-ing anemia prevalence in school-age children.
The same Cochrane review on the effects of (unfor-tified) school meal interventions reported small improve-ments in height and/or weight gain of schoolchildren.The present review suggests that MMN-fortified foodmight have a beneficial effect on growth, especially weightgain, compared to unfortified food, though the results areequivocal. This review’s findings of a possible positiveeffect of MMN fortification on weight are in line with anearlier meta-analysis that investigated the effects of MMNfortification on child growth.42 The meta-analysisincluded five studies in infants and children above the ageof 5 years and showed an overall weighted effect size ofMMN of 0.28 (95% CI: 0.16–0.41) for height and of 0.28(95% CI: -0.07–0.63) for weight. The present reviewreports on two additional studies that further strengthenthe hypothesis that MMN fortification may cause healthyweight gain in school-age children.
The earlier Cochrane review on (unfortified) schoolfeeding interventions as well as a meta-analysis on theeffects of MMNs on cognitive performance reported ben-eficial effects on fluid intelligence (i.e., reasoning ability)and academic or math performance.55,60 No effect ofMMN fortification was found on these particular cogni-tive domains in the present review. The inconsistency ofthe findings reported here is mostly due to methodologi-cal issues: few of the studies in the present review usedbatteries designed to assess fluid intelligence63,75 and aca-demic performance as a separate outcome74,75 (none of
Nutrition Reviews® Vol. 69(4):186–204200
them showing any significant effect of the intervention),whereas the Cochrane review60 and the meta-analyses55
involved many more trials (up to 12) measuring theseabilities instead. In contrast, most of the studies reviewedhere measured some aspects of working memory andlearning, making it more likely that some effects would bedetected. It is supposed that the absence of findings onfluid intelligence and academic performance are atpresent explained by the lack of available data. Futureresearch should continue to investigate the cognitivefunctions of fluid intelligence, memory, and academicperformance (mostly mathematics and reading).
MMN interventions might improve children’sgrowth more than interventions with single nutrients, asshown by a meta-analysis of Ramakrishnan et al.42
Furthermore, a study investigating the effects of amicronutrient intervention in 6–9-year-old Chineseschoolchildren reported that cognitive performance andgrowth improved significantly more after treatmentwith zinc plus a combination of MMNs compared totreatment with zinc alone.80,81 These findings suggestthat multiple growth-limiting nutrient deficiencies mayexist simultaneously and can be relieved by MMN inter-ventions rather than by single-micronutrient supple-mentation. Another possible explanation for why theprovision of MMNs can be more effective than singlemicronutrients may be related to the interaction ofmicronutrients. Micronutrients such as vitamin A, zinc,and iron interact with each other in such a way thatinadequate intake of one micronutrient can negativelyinfluence the absorption, metabolism, or depletion ofother micronutrients.82,83
School feeding programs are widely popular in mostof the world and, by virtue of the fact that they providefood for direct consumption to the child, offer a readyvehicle for delivering missing micronutrients to school-children through fortification. With MMN fortification,school meals can provide a safe and effective nutritionalintervention and make a valuable contribution to thenutritional needs of schoolchildren.84–87 MMN fortifica-tion may offer logistical advantages to supplementationwith single micronutrients in the context of school feedingprograms. Fortified foods and on-site fortificants such aspowder and salt may be more acceptable to children com-pared to liquids or tablets, and the provision of multiplemicronutrients at physiologic doses reduces the risk ofoverdose, thereby eliminating the need for precise target-ing and routine monitoring of costly biochemical indica-tors.There are trade-offs,however,and MMN fortificationat lower doses may not result in as great an impact onchildren’s health as supplementation with higher doses ofa single nutrient. At present, micronutrient supplementa-tion is not commonly recommended for school-age chil-dren. The only guidance from the WHO that pertains to
school-age children calls for supplementation with ironwhen anemia prevalence is >40% in this age group andthere is no food-based strategy, such as dietary modifica-tion or fortification, in place to improve iron status.88 Thefindings reported here that MMN fortification of foodsmay be useful for school feeding should not be consideredto override any WHO-recommended micronutrientsupplementation interventions for preschool or school-age children. The decision to implement targeted micro-nutrient supplementation,MMN-fortified food,or on-sitefortificants will always need to be context specific.
CONCLUSION
The findings of this review show that MMN food fortifi-cation can improve micronutrient status and reduceanemia in schoolchildren. MMN fortification also seemsto be effective for reducing morbidity from diarrhea andrespiratory infections and might have positive effects onchild growth and cognitive domains, particularly thoserelated to memory. Future research on the impact of for-tification on health and developmental outcomes shouldtest the efficacy of MMN-fortified-food-based interven-tions in a two-by-two design (testing MMN fortificationof food against an unfortified food, a MMN tablet, and nointervention at all) in order to be able to assess the sepa-rate effects of energy and macronutrients versus MMNsas well as their interactions. Field studies should strive toensure rigorous assessment of outcomes based on stan-dardized methods that are appropriate for the targetpopulation and apply valid statistical procedures.Researchers should consider comparing the cost-effectiveness of providing MMN-fortified foods to that ofmicronutrient supplements through schools in futurestudies. The results of this review show that MMN forti-fication of food can have an impact on various aspects ofthe health and development of schoolchildren. Consider-ing the vast number of school-age children suffering fromMMN deficiencies and the consequences, the overallimpact of MMN interventions in school-age children canbe an investment in future generations by helping thesechildren to achieve optimal health and increase theirpotential to learn.
Acknowledgments
The authors would like to thank Danielle Wolvers for herexpert consultation on the research investigating childmorbidity.
Declaration of interests. While preparing this manu-script, Cora Best and Tina van den Briel were employedby the United Nations World Food Programme; Nicole
Nutrition Reviews® Vol. 69(4):186–204 201
Neufingerl, Catherine Transler, Saskia Osendarp, andDanielle Wolvers are employed by Unilever Research &Development. Joy Miller del Rosso is employed by theManoff Group.
REFERENCES
1. World Health Organization. Physical Status: The Use and Inter-pretation of Anthropometry. Report of a WHO Expert Commit-tee. Technical Report Series No. 854. Geneva: World HealthOrganization; 1995.
2. De Benoist B, McLean E, Egli I, Cogswell M. Worldwide Preva-lence of Anaemia 1993–2005: WHO Global Database onAnemia. Geneva: World Health Organization and Centers forDisease Control and Prevention; 2008.
3. Sommer A, Davidson FR. Assessment and control of vitamin Adeficiency: the Annecy Accords. J Nutr. 2002;132(Suppl):S2845–S2850.
4. Allen L, de Benoist B, Dary O, et al. Guidelines on Food Fortifi-cation with Micronutrients. Geneva: World Health Organiza-tion and Food and Agricultural Organization of the UnitedNations; 2006.
5. Golub MS, Keen CL, Gershwin ME, Hendrickx AG. Develop-mental zinc deficiency and behavior. J Nutr. 1995;125(Suppl):S2263–S2271.
6. del Rosso JM, Marek T. Class Action: Improving School Perfor-mance in the Developing World through Better Health andNutrition. Washington, DC: The World Bank; 1996.
7. Ministry of Public Health, Thailand. The Fifth National Nutri-tion Survey, 2003. Bangkok, Thailand: Department of Health,Ministry of Public Health; 2003.
8. Pedro MRA, Cerdeña CM, Constantino MAS, et al. 6th NationalNutrition Survey: Philippines, 2003. Manila, Philippines: Foodand Nutrition Research Institute, Department of Science andTechnology; 2005.
9. Government of Nicaragua, Ministry of Education, Culture,and Sports. Evaluación Nutricional en preescolares y escolaresbeneficiados por el Programa Integral de Nutrición Escolar PINEMECD. Managua, Nicaragua: Gobierno de Nicaragua, Ministe-rio de Educación Cultura y Deportes; 2005.
10. Instituto Colombiano de Bienestar Familiar. Encuesta Nacio-nal de la Situacion Nutricional en Colombia, 2005. Bogota,Colombia: Instituto Colombiano de Bienestar Familiar; 2005.
11. UNICEF, WHO, and Ministry of Health Mozambique. Estudonacional sobre a deficiência em iodo na crianças dos 6 aos 12aos de idade. Maputo, República de Moçambique: DirecçãoNacional de Saúde, UNICEF, World Health Organization, Min-isterio de Saude; 2006.
12. Institute of Development Economics, Micronutrient Labora-tories Aga Khan University Medical Centre, and Governmentof Pakistan Planning Commission. National Nutrition Survey2001–2002. Islamabad: Pakistan Institute of DevelopmentEconomics, Micronutrient Laboratories Aga Khan UniversityMedical Centre, Government of Pakistan, Planning Commis-sion; 2003.
13. Abuye C, Berhane Y, Akalu G, Getahun Z, Ersumo T. Preva-lence of goiter in children 6 to 12 years of age in Ethiopia.Food Nutr Bull. 2007;28:391–398.
14. Sebotsa ML, Dannhauser A, Jooste PL, Joubert G. Prevalenceof goitre and urinary iodine status of primary-school childrenin Lesotho. Bull World Health Organ. 2003;81:28–34.
15. Ministere de la Sante Publique. Rapport de l'enquete nationalede nutrition de la population, 2005. Bujumbura, Burundi: Min-istere de la Sante Publique; 2006.
16. Ministry of Public Health Afghanistan, UNICEF, U.S. Centersfor Disease Control and Prevention, National Institute of Foodand Nutrition Italy, Tufts University. Summary Report of theNational Nutrition Survey, Afghanistan, 2004. Kabul, IslamicRepublic of Afghanistan: Ministry of Public Health (Afghani-stan), UNICEF, Centers for Disease Control and Prevention,National Institute for Research on Food and Nutrition Italy,Tufts University; 2005.
17. De Benoist B, Andersson M, Egli I, Takkouche B, Allen H. IodineStatus Worldwide. WHO Global Database on Iodine Deficiency.Geneva: World Health Organization; 2004.
18. Serge Hercberg S, Preziosi P, Galan P. Iron deficiency inEurope. Public Health Nutr. 2001;4:537–545.
19. Elmadfa I. European nutrition and health report 2009. ForumNutr. 2009;62:68–156.
20. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL.Prevalence of iron deficiency in the United States. JAMA.1997;277:973–976.
21. Centers for Disease Control and Prevention. Iron deficiency,United States, 1999–2000. Morb Mortal Wkly Rep.2002;51:897–899.
22. Halterman JS, Kaczorowski JM, Aligne CA, Auinger P,Szilagyi PG. Iron deficiency and cognitive achievementamong school-aged children and adolescents in the UnitedStates. Paediatrics. 2001;107:1381–1386.
23. Cardenas VM, Zyber DM, Ortiz M, Graham DY. Iron deficiencyand Helicobacter pylori infection in the United States. Am JEpidemiol. 2006;163:127–134.
24. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Ran-domised study of cognitive effects of iron supplementationin non-anaemic iron-deficient adolescent girls. Lancet.1996;348:992–996.
25. Schurch B. Malnutrition and behavioural development: thenutrition variable. J Nutr. 1995;125(Suppl):S2255–S2262.
26. Ramakrishnan U, Huffman SL. Multiple micronutrient malnu-trition: what can be done? In: Semba RD, Bloem MW, eds.Nutrition and Health in Developing Countries, 2nd ed. Totowa,NJ: Humana Press, Inc; 2008:365–391.
27. Hambridge KM. Zinc and diarrhea. Acta Paediatr.1992;81(Suppl s383):82–86.
28. Jalal F, Nesheim MC, Agus Z, Sanjur D, Habicht JP. Serumretinol concentrations in children are affected by foodsources of beta-carotene, fat intake, and anthelmintic drugtreatment. Am J Clin Nutr. 1998;68:623–629.
29. Lo YT, Chang YH, Lee MS, Wahlgyist ML. Health and nutritioneconomics: diet costs are associated with diet quality. AsiaPac J Clin Nutr. 2009;18:598–604.
30. Poskitt EME, Morgan B. Infancy, childhood and adolescence.In: Geissler C, Powers H, eds. Human Nutrition, 11th ed. NewYork, NY: Elsevier Churchill Livingstone; 2005:257–298.
31. Schmidt M, Affenito SG, Striegel-Moore R, et al. Fast-foodintake and diet quality in black and white girls: the NationalHeart, Lung, and Blood Institute Growth and Health Study.Arch Pediatr Adolesc Med. 2005;159:626–631.
32. Rajeshswari R, Yang SJ, Nicklas TA, Berenson GS. Seculartrends in children’s sweetened-beverage consumption (1973to 1994): the Bogalusa Heart Study. J Am Diet Assoc.2005;105(2):208–214.
33. Gogtay N, Giedd JN, Lusk L, et al. Dynamic mapping of humancortical development during childhood through early adult-hood. Proc Natl Acad Sci USA. 2004;101:8174–8179.
Nutrition Reviews® Vol. 69(4):186–204202
34. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E,Toga AW. Longitudinal mapping of cortical thickness andbrain growth in normal children. J Neurosci. 2004;24:8223–8231.
35. Toga AW, Thompson PM, Sowell ER. Mapping brain matura-tion. Trends Neurosci. 2006;29:148–159.
36. Shetty PS, James WPT. Body Mass Index – A Measure of ChronicEnergy Deficiency in Adults. FAO Food and Nutrition paper 56.Rome: Food and Agriculture Organization; 1994.
37. Sharp P. Minerals and trace elements. In: Geissler C, Powers H,eds. Human Nutrition and Dietetics, 11th ed. New York, NY:Elsevier Churchill Livingstone; 2005:241–244.
38. Bender DA. Fat-soluable vitamins. In: Geissler C, Powers H,eds. Human Nutrition and Dietetics, 11th ed. New York, NY:Elsevier Churchill Livingstone; 2005:212–217.
39. De Onis M. Child growth and development. In: Semba RD,Bloem MW, eds. Nutrition & Health in Developing Countries,2nd ed. Totowa, NJ: Humana Press Inc; 2008:71–91.
40. Levitsky DA, Strupp BJ. Malnutrition and the brain: changingconcepts, changing concerns. J Nutr. 1995;125(Suppl):S2212–S2220.
41. Levitsky DA. Malnutrition and hunger to learn. In: Levitsky D,ed. Malnutrition, Environment and Behaviour: New Perspec-tives. Ithaca, NY: Cornell University Press; 1979:161–179.
42. Ramakrishnan U, Aburto N, McCabe G, Martorell R. Multimi-cronutrient interventions but not vitamin A or iron interven-tions alone improve child growth: results of 3 meta-analyses.J Nutr. 2004;134:2592–2602.
43. Ramakrishnan U, Nguyen P, Martorell R. Effects of micronu-trients on growth of children under 5 y of age: meta-analysesof single and multiple nutrient interventions. Am J Clin Nutr.2009;89:191–203.
44. Beaton GH, Martorell R, Aronson KA, et al. Vitamin A supple-mentation and child morbidity and mortality in developingcountries. Food Nutr Bull. 1994;15.
45. Glasziou PP, Mackerras DE. Vitamin A supplementation ininfectious diseases: a meta-analysis. BMJ. 1993;306:366–370.
46. Tonascia JA. Meta-analysis of Published Community Trials:Impact of Vitamin A on Mortality. Helen Keller International.Proceedings of the Bellagio Meeting on Vitamin A Deficiencyand Childhood Mortality. New York, NJ: Helen Keller Interna-tional; 1993:49–51.
47. Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrheaand pneumonia by zinc supplementation in children indeveloping countries: pooled analysis of randomized con-trolled trials. Zinc Investigators’ Collaborative Group. JPediatr. 1999;135:689–697.
48. Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oralzinc in acute and persistent diarrhea in children in develop-ing countries: pooled analysis of randomized controlledtrials. Am J Clin Nutr. 2000;72:1516–1522.
49. Baqui AH, Black RE, El AS, et al. Effect of zinc supplementationstarted during diarrhoea on morbidity and mortality inBangladeshi children: community randomised trial. BMJ.2002;325:1059.
50. Sachdev H, Gera T, Nestel P. Effect of iron supplementationon mental and motor development in children: systematicreview of randomised controlled trials. Public Health Nutr.2005;8:117–132.
51. Grantham-McGregor S, Ani C. A review of studies on theeffect of iron deficiency on cognitive development in chil-dren. J Nutr. 2001;131(Suppl):S649–S666.
52. Zimmermann MB, Connolly K, Bozo M, Bridson J, Rohner F,Grimci L. Iodine supplementation improves cognition iniodine-deficient schoolchildren in Albania: a randomized,controlled, double-blind study. Am J Clin Nutr. 2006;83:108–114.
53. Van den Briel T, West CE, Bleichrodt N, van de Vijver FJ,Ategbo EA, Hautvast JG. Improved iodine status is associatedwith improved mental performance of schoolchildren inBenin. Am J Clin Nutr. 2000;72:1179–1185.
54. Bautista A, Barker PA, Dunn JT, Sanchez M, Kaiser DL. Theeffects of oral iodized oil on intelligence, thyroid status, andsomatic growth in school-age children from an area ofendemic goiter. Am J Clin Nutr. 1982;35:127–134.
55. Eilander A, Gera T, Sachdev HS, et al. Multiple micronutrientsupplementation for improving cognitive performance inchildren: systematic review of randomized controlled trials.Am J Clin Nutr. 2010;91:115–130.
56. Fleischer Michaelson K. Child Growth. In: Koletzko B,Cooper P, Makrides M, Garza C, Uauy R, Wang W, eds. Pediat-ric Nutrition in Practice. Basel, Switzerland: Karger AG;2008:1–5.
57. Brown KH. Diarrhea and malnutrition. J Nutr. 2003;133(Suppl):S328–S332.
58. Calder PC, Jackson AA. Undernutrition, infection and immunefunction. Nutr Res Rev. 2000;13:3–29.
59. Shrestha RM. Effect of iodine and iron supplementation onphysical, psychomotor and mental development in primaryschool children in Malawi. PhD Thesis. Wageningen Univer-sity; 1994.
60. Kristjansson EA, Robinson V, Petticrew M, et al. Schoolfeeding for improving the physical and psychosocial health ofdisadvantaged students. Cochrane Database Syst Rev.2007;(1). Art. No.: CD004676. DOI: 10.1002/14651858.CD004676.pub2.
61. Rivera JA, Hotz C, González-Cossío T, Neufeld L,García-Guerra A. The effect of micronutrient deficiencies onchild growth: a review of results from community-basedsupplementation trials. J Nutr. 2003;133(Suppl):S4010–S4020.
62. Lien do TK, Nhung BT, Khan NC. Impact of milk consumptionon performance and health of primary school children inrural Vietnam. Asia Pac J Clin Nutr. 2009;18:326–334.
63. Osendarp SJ, Baghurst KI, Bryan J, et al. Effect of a 12-momicronutrient intervention on learning and memory in well-nourished and marginally nourished school-aged children: 2parallel, randomized, placebo-controlled studies in Australiaand Indonesia. Am J Clin Nutr. 2007;86:1082–1093.
64. Solon FS, Sarol JN, Jr, Bernardo AB, et al. Effect of a multiple-micronutrient-fortified fruit powder beverage on the nutri-tion status, physical fitness, and cognitive performanceof schoolchildren in the Philippines. Food Nutr Bull.2003;24(Suppl):S129–S140.
65. Sivakumar B, Vijayaraghavan K, Vazir S, et al. Effect of micro-nutrient supplement on health and nutritional status ofschoolchildren: study design. Nutrition. 2006;22(Suppl):S1–S7.
66. Winichagoon P, McKenzie JE, Chavasit V, et al. Amultimicronutrient-fortified seasoning powder enhances thehemoglobin, zinc, and iodine status of primary school chil-dren in North East Thailand: a randomized controlled trial ofefficacy. J Nutr. 2006;136:1617–1623.
67. Nga TT, Winichagoon P, Dijkhuizen MA, et al. Multi-micronutrient-fortified biscuits decreased prevalence of
Nutrition Reviews® Vol. 69(4):186–204 203
anemia and improved micronutrient status and effectivenessof deworming in rural Vietnamese school children. J Nutr.2009;139:1013–1021.
68. Abrams SA, Mushi A, Hilmers DC, Griffin IJ, Davila P, Allen L. Amultinutrient-fortified beverage enhances the nutritionalstatus of children in Botswana. J Nutr. 2003;133:1834–1840.
69. Hyder SM, Haseen F, Khan M, et al. A multiple-micronutrient-fortified beverage affects hemoglobin, iron, and vitamin Astatus and growth in adolescent girls in rural Bangladesh. JNutr. 2007;137:2147–2153.
70. Sarma KV, Udaykumar P, Balakrishna N, Vijayaraghavan K,Sivakumar B. Effect of micronutrient supplementation onhealth and nutritional status of schoolchildren: growth andmorbidity. Nutrition. 2006;22(Suppl):S8–S14.
71. van Stuijvenberg ME, Kvalsvig JD, Faber M, Kruger M,Kenoyer DG, Benadé AJ. Effect of iron-, iodine-, and beta-carotene-fortified biscuits on the micronutrient status ofprimary school children: a randomized controlled trial. Am JClin Nutr. 1999;69:497–503.
72. Ash D, Tatala SR, Frongillo E, Ndossi GD, Mehansho H,Latham MC. Trial of a micronutrient dietary supplement tocontrol vitamin A, iron and iodine deficiencies in Tanzania.FASEB J. 1999;13:190.
73. Shatrugna V, Balakrishna N, Krishnaswamy K. Effect of micro-nutrient supplement on health and nutritional status ofschoolchildren: bone health and body composition. Nutri-tion. 2006;22( Suppl):S33–S39.
74. Manger MS, McKenzie JE, Winichagoon P, et al. Amicronutrient-fortified seasoning powder reduces morbidityand improves short-term cognitive function, but has noeffect on anthropometric measures in primary school chil-dren in northeast Thailand: a randomized controlled trial. AmJ Clin Nutr. 2008;87:1715–1722.
75. Vazir S, Nagalla B, Thangiah V, Kamasamudram V,Bhattiprolu S. Effect of micronutrient supplement on healthand nutritional status of schoolchildren: mental function.Nutrition. 2006;22(Suppl):S26–S32.
76. Zimmermann MB, Wegmueller R, Zeder C, et al. Triple fortifi-cation of salt with microcapsules of iodine, iron, and vitaminA. Am J Clin Nutr. 2004;80:1283–1290.
77. United Nations Development Programme. Human Develop-ment Index 2009. Overcoming Barriers: Human Mobility and
Development. New York, NY: United Nations DevelopmentProgramme; 2009.
78. Food and Agriculture Organization/World Health Organiza-tion. Human Vitamin and Mineral Requirements. Report of ajoint FAO/WHO Expert Consultation in Bangkok, Thailand.Rome: Food and Agricultural Organization; 2001.
79. Fischer Walker C, Kordas K, Stoltzfus RJ, Black RE. Interactiveeffects of iron and zinc on biochemical and functionaloutcomes in supplementation trials. Am J Clin Nutr.2005;82:5–12.
80. Sandstead HH, Penland JG, Alcock NW, et al. Effects of reple-tion with zinc and other micronutrients on neuropsychologicperformance and growth of Chinese children. Am J Clin Nutr.1998;68(Suppl):S470–S475.
81. Penland JG, Sandstead HH, Alcock NW, et al. A preliminaryreport: effects of zinc and micronutrient repletion on growthand neuropsychological function of urban Chinese children. JAm Coll Nutr. 1997;16:268–272.
82. Underwood BA, Arthur P. The contribution of vitamin A topublic health. FASEB J. 1996;10:1040–1048.
83. Christian P, West KP, Jr. Interactions between zinc andvitamin A: an update. Am J Clin Nutr. 1998;68(Suppl):S435–S441.
84. Bundy D, Burbano C, Grosh ME, Gelli A, Jukes M, Drake L.Rethinking School Feeding: Social Safety Nets, Child Develop-ment, and the Education Sector (Directions in Development).Washington, DC: World Bank; 2009.
85. Gelli A. Food for Education Works: A Review of WFP ProgrammeMonitoring and Evaluation 2002–2006. Rome: World FoodProgram; 2006.
86. Ahmed AU. The Impact of Feeding Children in School: Evidencefrom Bangladesh. Washington, DC: International Food PolicyResearch Institute; 2004.
87. Ahmed AU, Del Ninno C. The Food for Education Program inBangladesh: An Evaluation of its Impact on Educational Attain-ment and Food Security. Food Consumption and NutritionDivision, Discussion Paper 138. Washington, DC: Interna-tional Food Policy Research Institute; 2002.
88. World Health Organization. Iron Deficiency Anaemia, Assess-ment, Prevention, and Control: A Guide for Programme Manag-ers. WHO/NHD/01.3. Geneva: World Health Organization;2001.
Nutrition Reviews® Vol. 69(4):186–204204