Eichler et al.

BMC Public Health 2012, 12:506

http://www.biomedcentral.com/1471-2458/12/506

RESEARCH ARTICLE Open Access

Effects of micronutrient fortified milk and cereal

food for infants and children: a systematic review
Klaus Eichler*, Simon Wieser, Isabelle Rüthemann† and Urs Brügger†

Abstract
Background: Micronutrient deficiency is a common public health problem in developing countries, especially for
infants and children in the first two years of life. As this is an important time window for child development,
micronutrient fortified complementary feeding after 6 months of age, for example with milk or cereals products, in
combination with continued breastfeeding, is recommended. The overall effect of this approach is unclear.
Methods: We performed a Systematic Review and Meta-analysis to assess the impact of micronutrient fortified milk
and cereal food on the health of infants and little children (aged 6 months to 5 years) compared to non-fortified
food. We reviewed randomized controlled trials using electronic databases (MEDLINE and Cochrane library searches
through FEB 2011), reference list screening and hand searches. Three reviewers assessed 1153 studies for eligibility
and extracted data. One reviewer assessed risk of bias using predefined forms.
Results: We included 18 trials in our analysis (n = 5’468 children; range of mean hemoglobin values: 9.0 to 12.6 g/
dl). Iron plus multi micronutrient fortification is more effective than single iron fortification for hematologic
outcomes. Compared to non-fortified food, iron multi micronutrient fortification increases hemoglobin levels by
0.87 g/dl (95%-CI: 0.57 to 1.16; 8 studies) and reduces risk of anemia by 57% (relative risk 0.43; 95%-CI 0.26 to 0.71;
absolute risk reduction 22%; number needed to treat 5 [95%-CI: 4 to 6]; 6 Studies). Compared to non-fortified food,
fortification increases serum levels of vitamin A but not of zinc. Information about functional health outcomes (e.g.
weight gain) and morbidity was scarce and evidence is inconclusive. Risk of bias is unclear due to underreporting,
but high quality studies lead to similar results in a sensitivity analysis.
Conclusions: Multi micronutrient fortified milk and cereal products can be an effective option to reduce anemia of
children up to three years of age in developing countries. On the basis of our data the evidence for functional
health outcomes is still inconclusive.
Keywords: Micronutrients, Fortification, Milk, Cereals

Background function and motor development, are determined. Even

Micronutrient (MN) deficiency is a common public with optimum breastfeeding, these steps depend on a an
health problem, specifically for infants and children, in adequate quantity and quality of complementary feeding,
many low and middle income countries. For example, leading to an adequate MN supply [2]. Negative health
anemia (caused by iron deficiency) or increased infection consequences resulting from suboptimal feeding, such as
rates and mortality (exacerbated by vitamin A and zinc stunting (i.e. low height-for-age), are associated with
deficiency) are serious threats for child development [1]. higher morbidity and decreased function in later life [3].
The first two years of life represent a narrow time win- Several strategies have been shown to be effective in
dow, which is of outstanding importance for child devel- resolving MN deficiencies for different target groups and
opment [2]. During this time period future growth and are proposed in recommendations and guidelines [4-6]:
vulnerable physiological capacities, such as cognitive Food based approaches (e.g. spreads to increase energy-
density and MN content of food; MN powders for home
* Correspondence: [email protected] fortification with sprinkles) and MN supplementation
†
Equal contributors
Institute of Health Economics, Zurich University of Applied Sciences, St. (e.g. vitamin A capsules administered at defined intervals).
Georgenstrasse, 70 P.O. Box, Winterthur 8401, CH, Switzerland

© 2012 Eichler et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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In addition, fortification of staple food (e.g. fortified salt, Control intervention: Non-fortified food; additional
flour or oil) is widely used to resolve MN deficiencies of other nutritional approaches, if such approaches were
general populations. applied in the intervention and control group. Outcome:
Fortified complementary feeding after 6 months of At least one of the following health related outcomes:
age, in combination with continued breastfeeding [7], surrogate measures (such as MN serum levels,
typically comprises milk or cereals products (e.g. por- hematological parameters), functional outcome (e.g.
ridge or gruel) for infants. This type of food, however, is motor development), measures of morbidity (such as
often not covered by programs that provide fortified disease rates) or mortality. Study designs: Randomized
staple food for the general population. Primary studies controlled trials of any follow-up time.
have assessed the effects of fortified milk or cereals for We excluded studies with infants and toddlers younger
infants and children [8,9] and some countries, such as than 6 months [14] or applying infant formula [15],
Mexico, have introduced country wide food programs, studies addressing adolescents or adult women, inter-
where fortified milk is one component [10]. However, ventions based on supplementation, home fortification,
the overall evidence of the effect of fortified milk and bare food based approaches, fortification with compo-
cereals on children has not been systematically assessed. nents other than micronutrients, and studies testing ab-
Thus, we performed a Systematic Review to specifically sorption of MN. A priori, we also excluded studies with
assess the impact of micronutrient fortified milk and cereal fortification of staple food as provided for larger popula-
food on the health of infants and children compared to tion groups to isolate the effect of fortified milk and
non-fortified food in randomized controlled trials. cereals.
We systematically searched for studies using electronic
Methods databases (Medline [search strategy Table 1], Cochrane
We performed our review in accordance with current library; from 1966 to February 2011; no language restric-
guidelines for performing [11,12] and reporting of sys- tion). As this review was part of a larger project, that
tematic reviews [13] and established a scientific advisory evaluates the economic effects of MN fortification as
board (see Acknowledgments for participating experts). well, we also included search terms such as “cost” and
A review study protocol was developed in advance, “economics”. We screened reference lists of included
though not published. papers and contacted experts in the field for additional
According to our research question we defined the fol- references. In addition, we screened homepages of rele-
lowing inclusion criteria: Population: Infants and chil- vant organizations (e.g. WHO, United Nations [World
dren from 6 months to 5 years of age. While our Food Programme, Unicef, Millennium Development
primary focus was on age groups up to 2 years, we Goals], The World Bank, Pakistan National Nutrition
decided to set an upper age limit at 5 years, in order not Survey; International Clinical Epidemiology Network
to miss suitable studies with mixed age groups. Inter- [16]; Global Alliance for Improved Nutrition, GAIN
vention: Micronutrient fortified milk or cereal food. [17]; The Micronutrient Initiative [18]; Bill & Melinda

Table 1 Medline electronic search strategy

Step Search Medline 1 Search Medline 2 Search Medline 3
1 "Infant Formula"[MeSH]a "economics"[MeSH] nutrition disorders[MeSH]
OR "Milk"[MeSH]
2 fortif*[TIAB]b "micronutrients"[MeSH] child* OR infant* OR toddl*[TIAB]
3 1 AND 2 "Nutrition Disorders"[MeSH] "cost*"[TIAB] OR "economics"[MeSH]
4 "Cereals"[MeSH] 1 AND 2 AND3 1 AND 2 AND 3
5 fortif*[TIAB] "cost*"[TIAB] "india*"[TIAB] OR "pakistan*"[TIAB] OR
"philippine*"[TIAB] OR "asia*"[TIAB] OR "africa*"[TIAB]
6 4 AND 5 "micronutrients"[MeSH] 4 AND 5
7 3 OR 6 "nutrition disorders"[MeSH]
8 child*[TIAB] OR infant*[TIAB] 5 AND 6 AND 7
OR toddler*[TIAB]
9 7 AND 8 4 OR 8
Three Medline searches were performed and retrieved references were cumulated. As this review was part of a larger project that evaluates the economic effects
of micronutrient fortification as well, we included also search terms such as “cost” and “economics”.
a
MeSH: Medical Subject Heading.
b
TIAB: Title/Abstract.
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Gates Foundation [19]). We also contacted a manufac- include those data in the meta-analysis. For binary data,
turer (Nestlé) for further material and performed hand we calculated risk ratios and 95%-CI. Heterogeneity be-
searches in relevant journals with developing countries tween trials was calculated with I2, that is the percentage
issues (such as The Lancet). All references were stored of the total variation in estimated effects that is due to
in an EndNote X4 database (Thomson/ISI ResearchSoft heterogeneity rather than chance (where values of 25%
Berkeley, CA, USA). are assigned low, 50% moderate and 75% high) [23].
Second, we divided our dataset into pre-specified sub-
Study selection and data extraction groups to explore the influence of possible modifying
Three reviewers screened titles and abstracts for rele- factors on the outcome (fortified milk vs. cereal food;
vance and assessed potentially relevant studies for inclu- high vs. low/middle-income countries; single- vs. dual/
sion by full text. Teaching sessions were held in advance multi-micronutrient fortification strategy).
to improve conceptual consistency between reviewers. Third, we performed a meta-regression analysis
Disagreements were resolved by consensus meetings. If weighted for the inverse of the variance of the outcome
data of a specific population were published in several [12]. With this approach we evaluated the unique contri-
papers or if follow-up data were presented, we included bution of other a priori chosen independent factors on
each population only once. Using a predefined form, the most often reported outcome (dependent variable:
data were extracted by one reviewer in an Excel database hemoglobin level; independent variables: hemoglobin
and checked independently by a second reviewer. levels before intervention; daily amount of fortified MN;
We extracted data on general study information (e.g. length of follow-up; completeness of follow-up).
study region; length and completeness of follow up), For parametric and non-parametric tests P-values
study setting (e.g. level of population recruitment), <0.05 were considered significant. Analyses were per-
population details, intervention (e.g. daily amount of for- formed using the STATA SE 9 software package (Stata-
tified MN, determined as daily difference between inter- Corp. 2007. Stata Statistical Software, College Station,
vention and control group; composition of MN; Texas, USA).
comparator food) and outcome (e.g. morbidity rates;
hemoglobin levels [g/dl; conversion to g/L with factor
10]). Results
One reviewer assessed risk of bias in individual studies Description of included studies
with a component approach exploring methodological Our searches retrieved 1153 potentially relevant studies
quality on the study level (adequate generation of ran- (Figure 1). Eighteen RCT[8-10,24-38] (n = 10 fortified
dom sequence, concealment of allocation, blinding) as milk; n = 8 fortified cereals) fulfilled inclusion criteria
well as on the outcome level (incomplete outcome data and were included for our main analysis (Table 2).
due to attrition; selective outcome reporting) [12]. These 18 trials comprised 5468 infants and children
from different regions (2 studies from Asia [8,37], 5
Statistical analysis studies from Africa [9,33-36]; 5 Studies from South- and
First, we calculated pooled estimates. For continuous Middle-America [10,27,29,30,38]; 6 Studies from Europe
variables we computed weighted mean differences [24-26,28,31,32]).
(WMD) and 95%-confidence intervals (CI). For example, Study population sizes varied from n = 33 to n = 1120
for analysis of hemoglobin change we used the mean participants (median 166; IQR 92 to 361). Most partici-
change in the intervention and in the control group and pants belonged to vulnerable groups and had been
their pooled standard deviation (SD). If the sample size recruited from different settings (8 studies: medical or
decreased during the study, we used the lower sample community care centers:, 7 studies: low income risk
size at the end of the study. If mean hemoglobin change groups; 2 studies: general population of peri-urban and
per group and SD were not reported, we calculated rural areas; 1 study: no information given). The most
change as the difference of baseline and final values for frequent exclusion criteria were chronic diseases, severe
intervention and control group and applied the SD of anemia, severe mal-/under-nutrition, and low birth
final values [20]. If 95%-CI of mean values were reported weight. Mean age of participants ranged from 6 to
we converted them to SD assuming normal distribution 23 months at inclusion (upper age limit was 3 years in
[21]. To check results for robustness, we also calculated one study [8]) and the sex ratio was well balanced. Mean
WMD for final hemoglobin values of both study groups, hemoglobin values of children at baseline varied between
as this data was reported more often. Due to consider- studies from 9.0 g/dl to 12.6 g/dl (median of study
able heterogeneity between trials, we applied a random values: 11.1 g/dl). Follow up periods were generally short
effects model [22]. When authors reported only medians and did not exceed one year (mean follow up:
for continuous data (e.g. for ferritin levels), we did not 8.2 months; range: 2.3 to 12).
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Records identified through Additional records identified

identification
database searching through other sources
(n=956) (n=197)

Records after duplicates removed

Screening (n=1018)

Records screened Records excluded

(n=1018) (n= 960)

Full text articles Full text articles

assessed for eligibility excluded, with reasons
(n=58) (n=40)
Eligibility

Studies included
in qualitative synthesis
(n= 18)

Studies included
Included

in quantitative synthesis
(meta-analysis)
(n= 18)

Figure 1 Study flow of the systematic review.

Fortified milk was prepared with centrally processed compared to the iron single-fortification strategy (n = 5
fortified milk powder in most of the studies. Fortified studies; hemoglobin increase 0.20 g/dl (95%-CI: -0.05 to
cereals comprised centrally processed weaning or com- 0.45; I2 = 43%). The daily applied iron dosage was similar
plementary food, such as fortified porridge, gruel or for the single-iron approach (median: 6.5 mg) and the
weaning rusk to prepare a pap. Iron was the most fre- MMN-approach (median 6.7 mg).
quently used MN for fortification (15 of 18 trials), fol-
lowed by zinc (9 trials) and vitamin A (6 trials). Seven
studies used a single-MN fortification strategy (6 studies Effect on anemia prevalence
with iron only; 1 study with zinc only), two studies a Eleven trials provided data for anemia rates, all of them
dual- and 9 studies a multi-micronutrient (MMN) strat- using iron as a single- or a MMN-fortification strategy.
egy (i.e. 3 or more MN, for example additional fortifica- Applied thresholds for anemia varied between 10.5 g/dl
tion with vitamin C and E, selenium, copper). and 11 g/dl and the median of anemia rates at baseline
was 36% (IQR: 15% to 40%; 9 studies with data). Forti-
fied milk or cereals reduced the risk of suffering from
Effect on hemoglobin levels anemia by 50% (risk ratio 0.50, 95%-CI: 0.33 to 0.75;
Hemoglobin blood level was the most frequently I2 = 71%; Figure 3). Again, a stronger effect of the MMN
reported outcome parameter. Across 13 studies that fortification approach emerged (n = 7 studies; risk ratio
tested iron fortification irrespective of other added MN, 0.43 (95%-CI: 0.26 to 0.71; I2 = 81%) compared to the
the mean increase of hemoglobin compared to the con- iron single-fortification strategy (n = 4 studies; risk ratio
trol group was 0.62 g/dl (95%-CI: 0.34 to 0.89) for chil- 0.76 (95%-CI: 0.45 to 1.28; I2 = 0%). Overall, the absolute
dren fed with fortified milk or cereals (Figure 2). risk reduction (ARR) of suffering from anemia was 14%
Heterogeneity was high (I2 = 86%). Comparison of differ- (un-weighted data of 11 trials), translating into a number
ent subgroups showed a stronger effect of the iron needed to treat (NNT) with fortified milk or cereals of 7
MMN fortification approach (n = 8 studies; hemoglobin (95%-CI: 6 to 9) participants over a period of 8 months
increase 0.87 g/dl (95%-CI: 0.57 to 1.16; I2 = 82%) (i.e. the mean follow-up time) to avoid one case of
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Eichler et al. BMC Public Health 2012, 12:506
Table 2 Details of included studies for fortification of milk and cereal food
Study Population Intervention Control food Outcome Comment
Author, year: Brown, Country: Peru Target population: Cereals, fortified (porridge); single porridge, After 0.5 year: plasma zinc; Both groups recieved iron
2007 [29] Design: RCT periurban area; Age (mean; range): MN strategy MN applied a: Zn unfortified anthropometry; infections fortification and vitamin
0.6; 0.5 to 0.7 years Males (%): 46 Iron dosage b: n.a.c mg/day; Iron for zink supplements, thus net
Exclusion criteria: risk of acute compound d: n.a. intervention was zinc
malnutrition; chronic diseases fortification.
Author, year: Daly, Country: UK (74% white; 24% Milk, fortified; multi MN strategy milk, After 1 year: hematological Functional outcome was
1996 [31] Design: RCT Afro-Caribbean; 2% Asian) Target MN applied: Fe, VitA, other unfortified parameters; anthropometry extracted from related paper
population: poor innerurban Age Vitamins, other MN Iron dosage: Williams_1999 [39].
(mean; range): 0.65; 0.5 to 0.7 5.47 mg/day; Iron compound:
years Males (%): 47 Exclusion no info
criteria: preterm at birth
Author, year: Faber, Country: South Africa Target Cereals, fortified (porridge); multi porridge, After 0.5 year: hematological Population baseline
2005 [33] Design: RCT population: rural area, low MN strategy MN applied: Fe, Zn, unfortified parameters, serum retinol, characteristics only for
socio-economic status, Age (mean; other Vitamins Iron dosage: 27.5 zinc; growth; motor infants who completed
range): 0.7; 0.6 to 0.9 years Males mg/day; Iron compound: FeFu development the study.
(%): 51 Exclusion criteria: birth
weight <2500 g, severe anemia
Author, year: Gibson, Country: Zambia Target population: Cereals, fortified (porridge); multi porridge, After 1 year: hematological All children received VitA and
2011 [35] Design: RCT middle income class Age (mean; MN strategy MN applied: Fe, Zn, unfortified parameters; serum zink, Iodine by a public
range): 0.5; 0.5 to 0.5 years Males other Vitamins, other MN Iron anthropometry; hospital supplementation program.
(%): 48 Exclusion criteria: "not in dosage: 5.36 mg/day; Iron referral; death; diarrhea; Some outcomes extracted
good health" compound: no info pneumonia; mental and from related paper
motor development (Chilenje_2010) [40] and
(Manno_2011) [41].
Author, year: Gill, Country: Ireland Target population: Milk, fortified; single MN strategy formula milk, After 0.75 year:
1997 [24] Design: RCT no info Age (mean; range): 0.5; 0.5 MN applied: Fe Iron dosage: 6.54 unfortified hematological parameters,
to 0.5 years Males (%): 51 Exclusion mg/day; Iron compound: FeSu for iron anthropometry
criteria: severe or chronic disaese,
malnutrition; congenital anomalies
Author, year: Lartey, Country: Ghana Target population: Cereals, fortified (porridge); multi porridge, After 0.5 year: hematological Intervention cereal with 2
1999 [34] Design: RCT urban area Age (mean; range): 0.5; 0.5 MN strategy MN applied: Fe, Zn, unfortified parameters; anthropometry; formulations of fortification
to 0.5 years Males (%): 48 Exclusion VitA, other Vitamins, other MN diarrhea; fever; respiratory depending on daily cereal
criteria: congenital abnormalities Iron dosage: 14.25 mg/day; Iron illness intake of infant to avoid
compound: electrFe potential toxicity problems.
Author, year: Liu, 1993 Country: China Target population: all Cereals, fortified (rusk); multi MN rusk, After 0.25 year: hematological
[37] Design: RCT population classes (90% of all strategy MN applied: Fe, Zn, VitA, unfortified paramters; MN-serum levels,
children) Age (mean; range): 0.8; 0.5 other Vitamins, other MN Iron anthropometry
to 1.1 years Males (%): 55 Exclusion dosage: 5 mg/day; Iron
criteria: no info compound: FeAmCi
Author, year: Maldonado Country: Spain Target population: no Milk, fortified; multi MN strategy milk, unfortified After 0.33 year: hematological No child with anemia
Lonzano, 2007 [25] info Age (mean; range): 1.9; (range: MN applied: Fe, other Vitamins, (cows whole parameters at baseline.
Design: RCT no info) years Males (%): 58 Exclusion other MN Iron dosage: 5.9 milk formula)

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criteria: iron supplementation mg/day; Iron compound: no info
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Table 2 Details of included studies for fortification of milk and cereal food (Continued)
Author, year: Morley, Country: UK (Indian ethnicity) Target Milk, fortified; single MN strategy formula, After 0.75 year: hematological Only data from Norwich cohort
1999 [26] Design: RCT population: mother with higher MN applied: Fe Iron dosage: 1.8 unfortified parameters, antropometry, blood samples could be taken at
eduction, non-manual social class Age mg/day; Iron compound: FeSu motor and mental baseline and were extracted for
(mean; range): 0.78; (range: no info) development Hb outcome.
years Males (%): 50 Exclusion criteria:
relevant disease; iron supplementation
Author, year: Nesamvuni, Country: South Africa Target Cereals, fortified (maize porridge); maize meal, After 1 year: hematological Children and family members
2005 [36] Design: RCT population: poor socio-economic dual MN strategy MN applied: VitA, unfortified parameters, retinol level, received the food.
status, undernourished children Age other Vitamins Iron dosage: n.a. anthropometry
(mean; range): no info; 1 to 3 years mg/day; Iron compound: n.a.
Males (%): 0 Exclusion criteria: physical
or mental disability, severe
undernutrition
Author, year: Oelofse, Country: South Africa Target population: Cereals, fortified (porridge); dual normal diet After 0.5 year: hematological 90% of control group already
2003 [9] Design: RCT urban disadvantaged black community MN strategy MN applied: Zn, other parameters, zinc level, retinol recieved commercially prepared
(low socioeconomic status) Age (mean; Vitamins Iron dosage: -0.8 mg/day; level, anthropometry, complementatry food. The food
range): 0.5; (range: no info) years Males Iron compound: FePP psychomotor development concentration of iron did not
(%): 0 Exclusion criteria: birth weight relevanlty differ between groups,
< 2.5 kg; congenital abnormalities but of Zinc and of VitA.
Author, year: Rivera, 2010 Country: Mexico Target population: Milk, fortified; multi MN strategy milk, After 1 year: hematological Study results are adjusted for
[10] Design: RCT (accounted households living in poverty Age MN applied: Fe, Zn, other Vitamins, non-fortified parameters cluster effect. Evaluation of a
for cluster randomisation) (mean; range): no info; 1 to 2.5 years other MN Iron dosage: 7.82 large scale program (Leche
Males (%): 50 Exclusion criteria: no info mg/day; Iron compound: FeGlu Lincosa) in Mexico.
Author, year: Sazawal, 2010 Country: India Target population: Milk, fortified; multi MN strategy milk, After 1 year: hematological Some data extracted from
[8] Design: RCT periurban area; illiteracy of parents Age MN applied: Fe, Zn, VitA, other unfortified parameters, anthropometry, relating paper: Sazawal_2006
(mean; range): 1.9; 1 to 3 years Males Vitamins, other MN Iron dosage: severe illnesses, diarrhoea, [42] Completeness relates to
(%): 50 Exclusion criteria: severe 8.3 mg/day; Iron compound: FeSu lower respiratory tract hematologic parameters.
malnutrition; severe illness infections, pneumonia
Author, year: Schümann, Country: Guatemala Target population: Cereals, fortified (bean paste); beans, After 0.19 year: All children recieved anthelmintic
2005 [38] Design: RCT low income; periurban settlement Age single MN strategy MN applied: unfortified hematological parameters treatment; all families were
(mean; range): 1.7; 1 to 2 years Males Fe Iron dosage: 17.1 mg/day; compensated. Three arm trial: Only
(%): 52 Exclusion criteria: gastric or Iron compound: FeSu data for FeSu group (n = 31) vs.
intestinal diseases; infections control group (n = 30) extracted.
Author, year: Stevens, 1998 Country: UK (mostly caucasian) Target Milk, fortified; single MN strategy milk, unfortified After 1 year:
[32] Design: RCT population: lower social classes were MN applied: Fe Iron dosage: 6.87 hematological parameters
overrepresented Age (mean; range): mg/day; Iron compound: FeSu
0.5; 0 to 0 years Males (%): 0 Exclusion
criteria: illness, major congenital
malformation
Author, year: Villalpando, Country: Mexico Target population: Milk, fortified; multi MN strategy milk, unfortified After 0.5 year: The results of the study lead to
2006 [27] Design: RCT poor periurban community Age (mean; MN applied: Fe, Zn, other hematological parameters broadening of a fortified milk
range): 1.8; 0.8 to 2.5 years Males (%): Vitamins Iron dosage: 6.74 distribution program in Mexico.

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50 Exclusion criteria: no info mg/day; Iron compound: FeGlu
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Table 2 Details of included studies for fortification of milk and cereal food (Continued)
Author, year: Virtanen, 2001 Country: Sweden Target population: Milk, fortified; single MN strategy milk, unfortified After 0.5 year:
[28] Design: RCT urban area Age (mean; range): 1; 1 to MN applied: Fe Iron dosage: 4.53 hematological parameters
1 years Males (%): 39 Exclusion criteria: mg/day; Iron compound: FeGlu,
milk intolerance; poor health FeLac
Author, year: Walter, 1998 Country: Chile Target population: From Milk, fortified; single MN strategy formula, low After 1 year:
[30] Design: RCT four contiguos urban communities Age MN applied: Fe Iron dosage: 6.5 iron fortifed hematological parameters,
(mean; range): 0.5; 0 to 0 years Males mg/day; Iron compound: FeSu anthropometry
(%): 52 Exclusion criteria: major birth or
neonatal complications, chronic illness
a
MN (micronutrient) applied: Fe: iron; Zn: zinc; VitA: Vitamin A; other Vitamins: e.g. Vitamin C; other MN (micronutirents): e.g. selen, copper.
b
Iron dosage: Determined as daily difference between intervention and control group.
c
n.a.: not applicable
d
Iron compound: FeSu: iron-sulfate; FePP: iron-pyrophosphate; NaFeEDTA: natrium-iron-EDTA; FeFu: iron-fumarate; FeGlu: iron-gluconate; FeAmCi: ferric-ammonium-citrate; FeLa: Ferrous lactate; electrFe: electrolytic
iron.

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Study mean difference N, mean (SD); N, mean %

ID Hb [g/dl] (95% CI) Fortification (SD); Control Weight

Schümann (2005) 0.10 (-0.44, 0.64) 31, .83 (.93) 30, .73 (1.2) 6.92

Virtanen (2001) -0.12 (-0.51, 0.27) 20, .14 (.67) 16, .26 (.52) 7.91

Stevens (1998) 0.67 (0.21, 1.13) 24, .84 (.61) 26, .17 (1) 7.48

Gill (1997) 0.15 (-0.13, 0.43) 192, .26 (.92) 60, .11 (.99) 8.53

Morley (1999) 0.30 (-0.21, 0.81) 40, 2.7 (1.1) 32, 2.4 (1.1) 7.11

Subtotal (I-squared = 43.4%, p = 0.132) 0.20 (-0.05, 0.45) 307 164 37.94

Daly (1996) 0.90 (0.46, 1.34) 41, .4 (.7) 43, -.5 (1.3) 7.55

Villalpando (2006) 0.92 (0.48, 1.36) 58, .91 (1.15) 57, -.01 (1.24) 7.60

Liu (1993) 0.71 (0.35, 1.07) 77, -.08 (1.23) 85, -.79 (1.11) 8.07

Lartey (1999) 0.50 (-0.17, 1.17) 47, 0 (1.4) 48, -.5 (1.9) 6.06

Faber (2005) 0.90 (0.45, 1.35) 144, .8 (1.22) 142, -.1 (2.43) 7.54

Sazawal (2010) 1.54 (1.29, 1.79) 233, 1.98 (1.14) 232, .44 (1.54) 8.71

Maldonado Lonzano (2007) 0.70 (0.26, 1.14) 16, .3 (.4) 17, -.4 (.82) 7.60

Gibson (2011) 0.60 (0.40, 0.80) 278, .5 (1.1) 285, -.1 (1.3) 8.92

Subtotal (I-squared = 81.5%, p = 0.000) 0.87 (0.57, 1.16) 894 909 62.06

Overall (I-squared = 86.2%, p = 0.000) 0.62 (0.34, 0.89) 1201 1073 100.00

-.5 0 .5 1 1.5
Fortification decreases Hb Fortification increases Hb

Figure 2 Effect of iron fortification of milk and cereals on hemoglobin (Hb) levels compared to non-fortified food. Only studies with iron
fortification included (n = 13 RCT). Results are provided as weighted mean difference in hemoglobin (WMD: g/dl with 95%-CI; conversion to g/L
with factor 10) between intervention and control group (iron single-fortification (1); iron multi micronutrient fortification (3); overall effect).

anemia. For the MMN approach these results are even Effects on serum zinc and vitamin A levels
more favorable (un-weighted data of 7 trials: ARR 22%; Five studies provided data for change in serum zinc
NNT 5 [95%-CI: 4 to 6]). levels. MN fortification with zinc led to no relevant
change in zinc serum levels (0.4 micro-g/dl (95%-CI: -1
.7 to 2.6; I2 = 0%) compared to control groups. However,
Effect on ferritin levels fortification increased vitamin A serum levels compared
Ferritin is the most direct measure to conclude if iron to control groups (four studies with data: Retinol in-
stores increase by iron-fortified food consumption. crease by 3.7 micro-g/dl [95%-CI: 1.3 to 6.1; I2 = 37%]).
Eleven trials provided data for ferritin serum levels. Fer-
ritin levels were not adjusted for subclinical infections. Effects on growth, functional measures and morbidity
Given the skewed distribution of ferritin values, authors For three European studies, no relevant effect of fortifi-
often reported median estimates. Medians were signifi- cation on height and weight was seen and morbidities
cantly higher in the intervention groups (ranges of fer- were not an issue in this population.
ritin medians at end of study [micro-g/l]: intervention: All other results relate to non-European low-/middle
15.8 to 44.6; control: 6.5 to 28; P < 0.01). Only three income countries. Due to the short follow-up period in
studies provided mean values to be included in a meta- most of the studies, no meaningful conclusion can be
analysis, which showed an effect in the same direction. drawn for possible effects of fortification on height or
The mean ferritin increase with iron fortification was weight gain or z-scores (weight-for-age; height-for-age;
11.3 micro-g/l (95%-CI: 3.3 to 19.2; I2 = 79%) compared weight-for-height). Of 9 studies with data, 7 trials
to control groups. reported no relevant differences between intervention
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Study Risk Ratio for Events, Events, %

ID anemia (95% CI) Fortification Control Weight

Virtanen (2001) 2.43 (0.11, 55.89) 1/20 0/16 1.54

Stevens (1998) 0.12 (0.01, 2.12) 0/24 4/26 1.81

Gill (1997) 0.82 (0.38, 1.76) 21/192 8/60 11.25

Walter (1998) 0.75 (0.36, 1.59) 12/430 15/405 11.42

Subtotal (I-squared = 0.0%, p = 0.533) 0.76 (0.45, 1.28) 34/666 27/507 26.02

Daly (1996) 0.07 (0.01, 0.54) 1/41 14/43 3.43

Villalpando (2006) 0.49 (0.21, 1.13) 7/58 14/57 10.47

Lartey (1999) 0.91 (0.53, 1.56) 16/47 18/48 13.99

Rivera (2010) 0.41 (0.21, 0.80) 14/357 20/210 12.46

Sazawal (2010) 0.24 (0.17, 0.34) 31/233 128/232 16.36

Gibson (2011) 0.56 (0.43, 0.73) 63/282 114/286 17.27

Maldonado Lonzano (2007) (Excluded) 0/16 0/17 0.00

Subtotal (I-squared = 80.5%, p = 0.000) 0.43 (0.26, 0.71) 132/1034 308/893 73.98

Overall (I-squared = 71.2%, p = 0.000) 0.50 (0.33, 0.75) 166/1700 335/1400 100.00

.02 .05 .1 .2 .5 1 2
Fortification reduces risk Fortification increases risk

Figure 3 Effect of iron fortification of milk and cereals on anemia compared to non-fortified food. Only studies with iron fortification
included (n = 11 RCT). Results are provided as risk ratio (RR, 95%-CI) of suffering from anemia in the intervention group compared to the control
group (iron single-fortification (1); iron multi micronutrient fortification (3); overall effect).

and control group at the end of the study. In one study milk significantly reduced the probability of days with
[36], more weight gain was seen in the intervention severe illness (by 15%), and the relative risk of diarrhea
group after one year (4.6 kg vs. 2.0 kg; P < 0.05), in an- (by 18%) and lower respiratory illness (by 26%).
other study [8] children consuming fortified milk
showed improvement in weight gain compared to con-
trol group (difference 0.21 kg/year [95%-CI 0.12 to 0.31) Exploring heterogeneity
and height gain (difference 0.51 cm/year [95%-CI 0.27 to In our pre-specified subgroup analyses no relevant influ-
0.75). ence on the outcome was detected for the mode of forti-
Of three studies with data for psychomotor develop- fied food (fortified milk vs. cereals). Hemoglobin change
ment of children, two trials reported no relevant differ- was somewhat higher in studies from low/middle in-
ence between groups [9,35] and one study [33] found come countries (0.78 g/dl (95%-CI: 0.41 to 1.15) com-
slight improvements compared to the control group. pared to high income countries (0.42 g/dl (95%-CI: 0.10
Of four studies with morbidity data of children, three to 0.73), but the difference was not statistically signifi-
trials reported no relevant differences between groups cant. The dual-/multi-micronutrient approach led to a
for infections [29], for diarrhea, fever and respiratory ill- significantly stronger effect of iron fortification on
ness [34] and for referral to hospital or death in partly hemoglobin increase than the iron single-fortification
HIV exposed children [35]. In one study [8] fortified strategy (Figure 3).
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Table 3 Risk of bias summary table

EN Author Year Adequate Allocation Blinding? Incomplete Are typical outcomers
sequence concealment? outcome reported? (Selective
generation? data addressed outcome reporting)
675 Brown 2007 ? ? YES YES YES
818 Daly 1996 ? ? ? YES YES
951 Faber 2005 NO NO` YES NO YES
1058 Gibson 2011 ? ? YES NO YES
153 Gill 1997 ? YES NO NO YES
1051 Lartey 1999 ? YES NO YES YES
1154 Liu 1993 ? ? ? NO YES
257 Maldonado Lonzano 2007 YES YES YES YES NO
282 Morley 1999 ? YES YES YES YES
1149 Nesamvuni 2005 NO NO YES YES YES
297 Oelofse 2003 NO NO NO NO YES
333 Rivera 2010 ? ? YES NO NO
1 Sazawal 2010 YES YES YES NO YES
1172.2 Schumann 2005 NO NO YES YES NO
838 Stevens 1998 ? ? YES NO NO
403 Villalpando 2006 ? ? YES YES NO
404 Virtanen 2001 ? ? YES NO NO
797 Walter 1998 NO YES YES NO YES
The table presents each study by assessed methodological criterion in a cross-tabulation a. Studies are sorted for author name.
a
Assessment categories: YES: criterion fulfilled; NO: criterion not fulfilled; “?”: unclear, as no information given.

In our multivariable meta-regression analysis, none of performing analyses using mean values of groups at the
the tested independent variables (mean hemoglobin level end of the study, instead of mean changes of groups.
before intervention; daily amount of consumed iron,
length of follow-up, completeness of follow up) was sig- Discussion
nificantly associated with the change in hemoglobin. To our knowledge, this is the first systematic review,
that has applied a meta-analysis to specifically weigh the
overall evidence for the effects of fortified milk and
Summary assessment of risk of bias cereal food suitable for complementary feeding of chil-
Only two [8,25] of 18 trials provided enough information dren. The evidence relates to study populations between
to conclude that both random sequence generation and 6 month and three years of age. Iron fortification leads
allocation concealment was adequately performed to a clinically relevant increase in hemoglobin levels and
(Table 3). For 11 trials this was unclear and inadequate reduction of anemia rates. For zinc and vitamin A fortifi-
procedures had been applied in 5 trials. Other criteria cation only surrogate parameters are reported, but the
were fulfilled more often: Blinding was reported in 13 of combination with iron (MMN approach) leads to a more
18 studies, incomplete outcome data were addressed in pronounced effect on hemoglobin levels compared to an
8 of 18 trials and 12 of 18 studies showed no selective iron single-fortification strategy. The evidence for func-
outcome reporting (i.e. besides serum markers also tional health outcomes is inconclusive.
height/weight, functional measures or morbidities were
reported). Strengths and limitations
In summary, the risk of bias for the most often We applied a thorough search strategy with a stepwise
reported outcomes hemoglobin change and anemia rates retrieval of studies using electronic databases and add-
is unclear. However, a sensitivity analysis including only itional sources. We cannot exclude having missed refer-
studies with low risk of bias led to similar results (three ences but we believe that we found a near complete
studies that fulfilled 4 of 5 quality criteria [8,25,26]: sample of relevant papers for our specific research
hemoglobin increase 0.87 g/dl (95%-CI: 0.09 to 1.65; question.
I2 = 92%). Another sensitivity analysis showed that the Some limitations have to be mentioned. First, included
result pattern remained basically unchanged after studies showed short follow-up periods, thus the impact
Eichler et al. BMC Public Health 2012, 12:506 Page 11 of 13
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of fortified milk or cereal food on functional health out- to reduce mortality and morbidity via improved nutri-
comes (such as sustainable height and weight gain or tional status [47,48], even though serum level increases
mental and motor development) could not be assessed were small [53], similar to our review. Thus, some
thoroughly. Second, for zinc and vitamin A fortification authors conclude that fortification would also have an
only surrogate outcomes as serum levels are available. impact on morbidity and mortality, although a conclu-
However, the presence of additional fortified micronutri- sive answer cannot yet be given [52]. On the other hand,
ents seems to be important for the effects of iron on negative aspects of iron supplementation have been
hemoglobin levels. The MMN approach is more effective reported, such as increased morbidity and mortality in
than iron single fortification in our review, reflecting regions where malaria transmission is intense. [54] Thus,
that complex micronutrient deficiencies are responsible recommendations concerning iron supplementation
for health problems [20]. Third, risk of bias is unclear have been formulated. [55] These adverse effects, how-
mainly due to underreporting of the randomization pro- ever, may not be that relevant for fortified foods. Daily
cedure and incomplete outcome data. Finally, pooled micronutrient dosages of fortified foods are much lower
estimates have to be interpreted cautiously as statistical as compared to supplementation. Furthermore, children
heterogeneity between studies was considerable and stop eating once they get saturated, which may also not
meta-regression did not reveal significant associations of be the case for high dosage sprinkles, that can be seen as
pre-specified study characteristics with study results. a specific application of supplementation. Nevertheless,
Possible sources for unexplained heterogeneity might be long term data concerning negative effects of iron forti-
underreporting for co-interventions (e.g. public supple- fied foods in regions with high prevalence of malaria and
mentation or food programs) or the diversity of applied infectious diseases are lacking.
MN preparations that have influence on MN absorption. Further compiled evidence is needed to agree on the
For example, five different iron compounds were used optimal MN preparation for fortified milk and cereals
(12 studies with data: six times FeSulfate; twice FeGluco- (such as composition of MN; suitable compounds; molar
nate; one time, each, FePyrophosphate; FeFumarate; Fer- ratios for additives) to fully exhaust the potential of this
ric ammonium citrate; electrolytic iron). In addition, the approach. Future studies should also focus on health
difference in daily consumed iron between intervention outcomes of MN fortification beyond the effect of iron
and control group varied between 1.8 mg and 14.3 mg. on hematological results, for example via long-term
Furthermore, molar ratios, a determinant for MN ab- follow-up of study populations.
sorption, also showed variation (ranges of molar ratios:
ascorbic acid/iron: 0.68 to 30; phytic acid/iron: 1.7 to Implications for decision makers
2.2; calcium/iron: 40 to 134). There are multiple delivery mechanisms for fortified
milk and cereal food. Production and distribution via
Existing systematic reviews and research needs government programs and local public agencies would
Important contributions have been made in the recent be an obvious option to strengthen local structures. Im-
years with other systematic reviews to evaluate the plementation of effective strategies, however, does not
health effects of MN interventions. These reviews differ always work well in the field due to logistical problems
from ours: Dewey and Adu-Afarwuah gave a broad sys- or inappropriate priority setting [56]. Thus, some have
tematic overview of studies and programs aimed at im- discussed the role of the business community in improv-
proving biochemical and functional outcomes with ing nutrition in developing countries [56-58]. Commer-
complementary foods. [43] However, they did not per- cially distributed fortified foods (e.g. with iron) are
form a meta-analysis and presented results in a tabulated already available in many markets, even in low-income
form or as averaged effect sizes. Some reviews have con- countries. In a public private partnership, business part-
centrated on MN supplementation only [44-48] or home ners can provide their professional knowledge and ex-
fortification [49], other reviews have combined supple- perience concerning technical problems with processing
mentation and fortification strategies for analysis [20,50], and fortification, supply and transport, or refrigeration
included children as well as adolescents or adult women and conservation issues (specifically important for milk)
[6,51,52], or included fortified staple food interventions to get interventions more efficient.
[6,52]. A limitation of the market approach is that it may not
The health effects found in our review are in line with reach the poorest of the poor. Thus, a combination of dif-
effect sizes shown in some similar reviews above ferent delivery channels, as well as affordable prices, may
[20,47,52]. This underpins the validity of our findings be needed. Children with severe anemia, who may be
and supports a strategy to intervene with fortified milk overrepresented in very poor groups, are often excluded
and cereal food for infants and children. Supplementa- from trials due to ethical reasons. One may assume, that
tion trials, for example with vitamin A, have been shown the positive effects on the hemoglobin levels may be even
Eichler et al. BMC Public Health 2012, 12:506 Page 12 of 13
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stronger for such children. Additional economic analyses 8. Sazawal S, Dhingra U, Dhingra P, Hiremath G, Sarkar A, Dutta A, Menon VP,
are necessary to contribute to a deeper understanding of Black RE: Micronutrient fortified milk improves iron status, anemia and
growth among children 1–4 years: a double masked, randomized,
the health economic effects of such a strategy and to in- controlled trial. PLoS One 2010, 5(8):e12167.
form the priority setting of decision makers. 9. Oelofse A, Van Raaij JM, Benade AJ, Dhansay MA, Tolboom JJ, Hautvast JG:
The effect of a micronutrient-fortified complementary food on
micronutrient status, growth and development of 6- to 12-month-old
Conclusions disadvantaged urban South African infants. Int J Food Sci Nutr 2003,
Multi micronutrient fortified milk and cereal products 54(5):399–407.
can be an effective option to reduce anemia of children 10. Rivera JA, Shamah T, Villalpando S, Monterrubio E: Effectiveness of a large-
scale iron-fortified milk distribution program on anemia and iron
up to three years of age in developing countries. On the deficiency in low-income young children in Mexico. Am J Clin Nutr 2010,
basis of our data the evidence for functional health out- 91(2):431–439.
comes is still inconclusive. 11. NHS Centre for Reviews and Dissemination: CRD’s guidance for undertaking
reviews in health care. York: University of York; 2008.
Abbreviations 12. Higgins JP, Green S: Cochrane Handbook for Systematic Reviews of
Fe: Iron; MN: Micro nutrients; MMN: Multi micro nutrients; RCT: Randomized Interventions Version 5.1.0 [updated March 2011]. The Cochrane
controlled trial; WMD: Weighted mean difference. Collaboration 2011.
13. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for
Competing interests systematic reviews and meta-analyses: the PRISMA statement. Ann Intern
The authors declare that they have no competing interests. Med 2009, 151(4):264–269.
14. Heird WC: Progress in promoting breast-feeding, combating
Authors’ contributions malnutrition, and composition and use of infant formula, 1981–2006.
KE designed and conducted research, analyzed data and drafted the J Nutr 2007, 137(2):499S–502S.
manuscript. SW helped to design research, conducted research, helped to 15. Food and Agricultural Organization of the United Nations: Standard for
draft the manuscript. IR conducted research, helped to draft the manuscript. infant formula and formulas for special medical purposes intended for
UB helped to design research, helped to draft the manuscript. All authors infants. In CODEX STAN 2007, :72–1981.
read and approved the final manuscript. 16. International Clinical Epidemiology Network: http://www.inclentrust.org/.
17. Global Alliance for Improved Nutrition; http://www.gainhealth.org/.
Expert and Affiliation 18. The Micronutrient Initiative; http://www.micronutrient.org/english/view.asp?
Lindsay H. Allen - Western Human Nutrition Research Center, USA; Narendra x=1.
K. Arora - International Clinical Epidemiology Network, INCLEN, India; Zulfiqar 19. Bill & Melinda Gates Foundation; http://www.gatesfoundation.org/Pages/
A. Bhutta - Aga Khan University, Pakistan; Rodolfo F. Florentino - Nutrition home.aspx.
Foundation of the Philippines; Guillermo Meléndez - Mexican Health 20. Allen LH, Peerson JM, Olney DK: Provision of multiple rather than two or
Foundation, Mexico; Noel W. Solomons - Program Director for Central fewer micronutrients more effectively improves growth and other
America, International Nutrition Foundation, Guatemala; Edgar Vasquez- outcomes in micronutrient-deficient children and adults. J Nutr 2009,
Garibay - University of Guadalajara, Mexico. 139(5):1022–1030.
21. Altman DG, Machin D, Bryant TN, Gardner JM: Statistics with confidence.
Acknowledgements Bristol: BMJ Books; 2001.
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source had no influence on study design; in the collection, analysis, and 24. Gill DG, Vincent S, Segal DS: Follow-on formula in the prevention of iron
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