Iron-containing micronutrient powder provided to children with

moderate-to-severe malnutrition increases hemoglobin concentrations

but not the risk of infectious morbidity: a randomized, double-blind,
placebo-controlled, noninferiority safety trial13
Mathieu Lemaire, Qazi Shafayetul Islam, Hua Shen, Marufa Aziz Khan, Monira Parveen, Fahmida Abedin, Farhana Haseen,
Ziauddin Hyder, Richard J Cook, and Stanley H Zlotkin

INTRODUCTION

Malnutrition and iron deficiency (ID) are comorbid conditions,

each of which affects large numbers of young children in developing countries (1, 2). For example, .50% of children living
in rural Bangladesh have moderate or severe malnutrition (3)
and 85% have anemia, most of which is likely due to ID (4).
Nutritional interventions (hospital- or community-based) are
recommended for malnourished children (5). However, there is

confusion about the safety of prescribing ID treatment in a

malnourished population.
Because both malnutrition and ID compromise the immune
response (6, 7), malnourished, iron-deficient individuals should
be predisposed to infection. However, reports that iron supplementation paradoxically increased the risk of infection in children (810) triggered intense efforts to investigate this issue: 2
meta-analyses, which summarized the results of these studies,
concluded that iron supplementation is not harmful (11, 12).
However, because malnourished children were either excluded
or absent from most of these studies, the generalizability of this
conclusion is limited. We identified 6 studies that did include
malnourished children, but all have drawbacks limiting their
usefulness (see supplemental Table 1 under Supplemental data
in the online issue). Convincing evidence regarding the causal
link between provision of oral iron and infection susceptibility
in the context of malnutrition is thus lacking.
Apparent contradictions between current World Health Organization guidelines reflect this uncertainty. On the one hand,
the guidelines for malnourished children requiring hospitalization state that iron should never be given during the initial phase
of treatment because it can have toxic effects and may reduce
resistance to infection (13). In contrast, guidelines for ID anemia
recommend population-wide oral iron supplementation when the
prevalence of anemia is .40%, without mention of nutritional
status (14, 15).
1
From the Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada (ML and SHZ); the Research and Evaluation Division, BRAC, Dhaka, Bangladesh (QSI, MAK, MP, FA, FH, and
ZH); the Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Canada (HS and RJC); Health, Nutrition and Population,
Africa Region, The World Bank Health, Washington, DC (ZH); the Department of Nutritional Sciences, University of Toronto, Toronto, Canada (SHZ);
and the Dalla Lana School of Public Health, University of Toronto, Toronto,
Canada (ZH and SHZ).
2
Supported by the Thrasher Research Fund and HJ Heinz Company
Foundation.
3
Address correspondence and reprint requests to SH Zlotkin, The Hospital for Sick Children, 555 University Avenue, Room 1410-Executive Office,
Toronto, ON M5G 1X8, Canada. E-mail: stanley.zlotkin@sickkids.ca.
Received November 29, 2010. Accepted for publication May 23, 2011.
First published online June 29, 2011; doi: 10.3945/ajcn.110.009316.

Am J Clin Nutr 2011;94:58593. Printed in USA. 2011 American Society for Nutrition

585

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ABSTRACT
Background: A link between the provision of iron and infectious
morbidity has been suggested, particularly in children with malnutrition. Two meta-analyses concluded that iron is not harmful, but
malnourished children were underrepresented in most available
studies.
Objective: This study evaluated the effect of iron-containing micronutrient powder (iron MNP) on infectious morbidities when provided to children with moderate-to-severe malnutrition and anemia.
Design: A randomized, double-blind, placebo-controlled, noninferiority
safety trial using a 2-mo course of daily iron MNP or placebo powder
(PP) was conducted in 268 Bangladeshi children aged 1224 mo
with moderate-to-severe malnutrition (weight-for-age z score  22)
and a hemoglobin concentration between 70 and 110 g/L. The primary endpoint was a composite of diarrhea, dysentery, and lower
respiratory tract infection episodes (DDL) recorded through home
visits every 2 d during the intervention and then weekly for 4 mo.
The noninferiority margin was 1.2. Secondary endpoints included
hemoglobin and anthropometric changes at 2 and 6 mo. All deaths
and hospitalizations were documented. To capture seasonal variation, the study was repeated in the winter and summer with 2 distinct groups. An intention-to-treat analysis of recurrent events was
performed by using the univariate Anderson-Gill model.
Results: The baseline characteristics of the subjects were similar.
Analysis of phase-aggregated DDL data showed that iron MNP was
not inferior to PP (relative risk: 0.81; 95% CI: 0.62, 1.04) and
improved hemoglobin concentrations (P , 0.0001). We recorded
no deaths, and hospitalizations were rare.
Conclusion: Iron MNP is safe and efficacious when provided to children aged 1224 mo with moderate-to-severe malnutrition and anemia.
This trial is registered at clinicaltrials.gov as NCT00530374.
Am J
Clin Nutr 2011;94:58593.

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LEMAIRE ET AL

This trial aimed to determine the safety of providing iron (as an

iron-containing micronutrient powder) to malnourished Bangladeshi children living in the community. Our primary safety
endpoint was the incidence of infectious morbidities, including
diarrhea, dysentery, and lower respiratory tract infections.

SUBJECTS AND METHODS

Study design, sites, and population

Random assignment and masking

The subjects were first stratified by malnutrition level (22 
WAZ , 23 and WAZ  23). Then, the eligible children were
randomly assigned to either daily iron MNP or placebo powder
(PP) by using permuted block assignments (sizes = 4 and 6)
generated with Microsoft Excel (Microsoft, Redmond, WA) and
the algorithm from www.randomization.com.
The iron MNP content was as follows: microencapsulated iron,
12.5 mg (Descote Ferrous Fumarate 60Ultra; Particle Dynamics, St Louis, MO); vitamin A, 400 lg retinol equivalents
(REs) [acetate; US Pharmacopoeia (USP), Rockville, MD
FCC]; zinc gluconate, 5 mg (USP); vitamin C, 30 mg [ascorbic
acid, USP-FCC (Food Chemicals Codex)]; and folic acid, 0.15 mg
(USP-FCC). Maltodextran was used as a vehicle. PP contained
only the vehicle. No texture or taste difference between the powders
was apparent when sprinkled onto complementary foods. Sachets
were similar except for labeling with unique codes. Renata Ltd
(Dhaka, Bangladesh) packaged the powders and confirmed the
content of both sachet types before delivery. All members of the
research team and the family were masked to treatment allocation.

The primary outcome measure was a composite score based on

all distinct episodes of diarrhea, dysentery, and lower respiratory
tract infections (LRTIs). The composite outcome will hereafter be
referred to as DDL. Outcomes were defined as diarrhea, 3 loose
watery stools within 24 h; dysentery, 1 loose hemorrhagic stool
within 24 h; LRTI, cough or difficulty breathing and tachypnea
(.40 breaths/min), with or without chest indrawing (17). Fever
is not required for any of these standard diagnostic definitions.
Episodes were considered to be finished when a child was asymptomatic for .48 h (18).
Infectious morbidity was assessed by using active case detection during the intervention period. More precisely, trained
assessors, supervised by a physician, performed a thorough evaluation of each child at home, every other day for 2 mo. During the
postintervention period, the same thorough evaluation was performed, but this time on a weekly basis (see supplemental Figure
1b under Supplemental data in the online issue). The data set for
this period is therefore not as reliable as that of the first 2 mo
because it relies more on maternal recall for details about each
episode. The protocol was repeated with different subjects over 2
nonoverlapping seasons (winter and summer), hereafter referred
to as phase 1 (12/200706/2008) and phase 2 (07/200801/2009),
respectively (see supplemental Figure 1c under Supplemental
data in the online issue). The trained assessors completed a
standardized questionnaire at each visit to elicit specific symptoms of diarrhea, dysentery, and LRTI. Also, axillary temperature
was measured twice within 30 min with a mercury thermometer,
and the respiratory rate was recorded by counting breaths for 60 s.
Fever was defined as 2 recordings of 37.2C.
One sachet was administered daily to each child for 2 mo. Clear
instructions for storage and use with complementary feeding were
provided to parents before randomization (19). Families were
asked to keep all empty sachets. The trained assessors counted the
sachets every week as a measure of adherence to the intervention.
Details pertaining to all hospital admissions or deaths were
recorded, as were all encounters with local health care workers or
doctors. Episodes of prolonged fever of unknown origin, defined
as fever lasting .10 d with no apparent source, were also noted.
An independent data safety monitoring committee performed
an interim safety analysis after the first phase. The protocol
stipulated that the study would be stopped if 1 of the 2 arms were
associated with significantly more adverse outcomes.
The main secondary efficacy outcomes were the effect of iron
MNP on hemoglobin and growth variables over time. Hemoglobin
was measured at baseline, 2 mo, and 6 mo by using portable
ngelholm, Sweden) per the manuHemoCue photometers (A
facturers recommendations. Anthropometric data were recorded
at the same time: weight (within 0.1 kg) was obtained with a
Salter balance (Salter Scales, Tonbridge, Kent, United Kingdom),
and height (within 0.1 cm) was measured while the subjects were
recumbent. Sociodemographic information about the subjects,
their parents, and their family dwelling was collected at baseline.

Noninferiority margin
The noninferiority margin on the relative risk scale (MNP
compared with PP) was denoted by D and is a threshold that is
defined as an acceptable difference in the value of the response

Downloaded from ajcn.nutrition.org by guest on December 15, 2014

This study was a randomized, double-blind, prospective,

placebo-controlled, noninferiority trial aimed at assessing the
safety of daily oral iron when provided as a micronutrient powder
(iron MNP) to children with moderate-to-severe malnutrition.
The powder is used to fortify homemade complementary food.
Subjects were selected from 29 villages located in 5 Unions in
Mymensingh district (see supplemental Figure 1A and supplemental Table 2 under Supplemental data in the online issue).
This area has a low prevalence of malaria (0.4%) (16).
To identify potential study subjects, selected villages were
screened for children aged 1224 mo with moderate-to-severe
malnutrition, defined as a weight-for-age z score (WAZ)  22
based on the National Center for Health Statistics standards.
Only one child per household was included to prevent crosscontamination. Exclusion criteria included a hemoglobin concentration ,70 or .110 g/L, weight-for-height z score (WHZ) ,
23, kwashiorkor (defined as evidence of edema), congenital abnormalities, iron supplementation in the previous 6 mo,
prior inclusion in a nutrition program, or any chronic illness
other than malnutrition. Children excluded because of severe
chronic medical conditions were referred to local physicians for
treatment.
Ethics review boards at the Hospital for Sick Children (Toronto, Canada), the Bangladesh Medical Research Council
(Dhaka, Bangladesh), and the University of Waterloo (Waterloo,
Canada) approved the research protocol. A consent form in
Bangla was read aloud to parents. A signed consent form was
required for inclusion of a subject in the study.

Procedures

SAFETY OF IRON MNP IN MALNOURISHED CHILDREN

587

Statistical analyses

RESULTS

The main analysis examined the primary outcome (DDL)

recorded during the intervention and postintervention periods,
from both phases (phase-aggregated data). Other exploratory
analyses were similarly performed on phase- and period-specific
data. Recurrent events analyses were used to estimate the relative
risk (RR) of DDL when the iron MNP group was compared with

In phases 1 and 2, nearly 4000 households were screened: 81%

of eligible children were assessed, and 34% met the entry criteria
(Figure 1). No between-group differences in baseline characteristics
were noted whether phases were analyzed separately or together
(Table 1). The only between-phase differences noted were
more prevalent stunting in phase 1 (defined as a height-for-age

Sample size calculation

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Sample size calculation was based on annual data from 2

studies conducted in Bangladesh that included few malnourished
children (17, 24). Our conservative estimate was that Bangladeshi
children would have 7 episodes of diarrhea, dysentery, or
LRTIs in any 6-mo period. We calculated the SD for each infection category from Mitra (17), and these were then combined
to generate a composite SD for the composite primary outcome.
The sample size was calculated with National Council for Social
Studies-Power Analysis and Sample Size (NCSS-PASS, 2006;
Kaysville, UT) by using a D value of 1.2; 168 subjects would
achieve 80% power to detect noninferiority by using a onesided, 2-sample t test. The actual difference between means was
assumed to be 0.05 (ie, the expected effect sizes for both groups
would be within 5% of each other), and a was set at 0.05. After
adding 10% for loss to follow-up and dropouts, and another 30%
to account for seasonal differences between phases 1 and 2, the
target sample size was 240 children (ie, 60 per group per
season).

the PP group. The expected number of DDL episodes was

evaluated by using the Nelson-Aalen estimate, a nonparametric
estimate of the average (or equivalently the mean, or expected)
cumulative number of events over time. This method is used
routinely to analyze recurrent infections because it effectively
deals with subjects followed for different lengths of time. By
taking into account the at-risk period for each subject, the calculation of the number of observed events is more meaningful. It
is important to note that the term RR is used here in its generic
sense, as was done by some of the pioneers in the field of timeto-event analysis (25). Indeed, our estimates are not true hazard
ratios given that subjects have multiple recorded events.
Two types of regression analyses were conducted to estimate
treatment effects, reported as the RR of DDL (iron MNP relative to PP) along with its corresponding 95% CIs (26). The first
regression analysis was based on the Andersen-Gill model, with
robust variance estimates. The Andersen-Gill model is an extension of the Cox regression model used to analyze recurrent
event data (ie, it deals with the fact that each patient may experience more than one event over time) (27). It makes use of the
number and times of events. The robust variance estimate is used
to ensure tests and CIs are valid even if there is a strong association between event times within patients (28). It is therefore
analogous to a generalized estimating equation type of analyses
used routinely in dealing with longitudinal or clustered data. The
second regression analysis involved a semiparametric negative
binomial model (mixed Poisson), which provides an estimate of
the association within patients, or equivalently the heterogeneity
in event rates between patients (29). It does this by introducing
random effects that are patient-specific. Note that subjects recurrent event processes are censored at the time of loss to follow-up,
as is customarily done in survival analysis. Both the NelsonAalen and Andersen-Gill methods allow patients to drop out of
the risk set and back in again over the course of observations.
Details pertaining to any hospitalizations were included in the
analysis only if caused by DDL, without weighting. Because the
results for both regression analyses agreed very closely with each
other, only the former is reported. A conclusion of noninferiority
was possible only if the upper bound of the 95% CI fell entirely
below the D value of 1.2. Only the intention-to-treat analysis is
presented. Initial hemoglobin concentrations (90 or .90 g/L)
and the number of live children (as a continuous variable) were
also included in the model. The software used for these analyses is R (version 2.11.10), with the Survival package (version
2.364), both of which are available at http://CRAN.R-project.
org).
Changes in hemoglobin and anthropometric variables were
analyzed by using Wilcoxons test between the iron MNP and PP
groups. These analyses were done by using JMP software (version
9.0, 19892010; SAS Institute Inc, Cary, NC). Test results were
considered significant if P , 0.05.

parameter between the tested treatment and a standard agent

(20) The margin D should be chosen as the largest relative risk
(RR) that one would be willing to accept with the use of the new
treatment. Ideally, D should be derived from both statistical
reasoning by using information available from the relevant literature, but also primarily from clinical judgment (21). Investigators must rely on the latter when no historical data are
available to provide a reliable effect estimate. Because this was
the first trial to systematically investigate the problem of iron
safety in malnourished and anemic children, no prior clinical
trial or historical data were available.
For this study, a D value of 1.2 was used for 2 reasons: 1) as
clinicians, we believed that it was reasonable to accept an increase of up to 20% in infections above and beyond what is
observed in the community (or with placebo) to maximize the
opportunity for infants to benefit from iron MNP, and 2) a D
value of 1.2 fitted within the range of what is considered an
acceptable margin (typically between 10% and 20%) (22). What
does this mean concretely for the children? It would mean that
if a child were expected to have 5 infectious episodes within a
6-mo period, only an average of 1 additional infection would
be tolerated during that time frame for children in the iron
MNP group. As a result of the uncertainty associated with ascertaining D, we decided to use active-case detection to minimize as much as possible the likelihood of missing any
significant infections associated with the use of iron MNP (when
compared with PP). It is important to note that, for this trial,
noninferiority between the treatment arms would be concluded
only if the value of the upper bound of the RR (95% CI) is ,1.2.
We refer interested readers to a recent review on the topic for
more details (23).

588

LEMAIRE ET AL

z score  22; P = 0.006) and more prevalent wasting in phase

2 (defined as weight-for-height z score  22, P = 0.009; see
supplemental Table 3 under Supplemental data in the online
issue). We surmised that the higher prevalence of wasting in
phase 2 was attributable to the greater height of the children in
this phase (P = 0.09). To answer this question, we tested the
effects of adding the categorical WHZ  22 and HAZ  22
data to a logistic regression model (see supplemental Table 4 under
Supplemental data in the online issue): the observed betweenphase variability is entirely explained by the presence of taller
children in phase 2. Parental and family-dwelling characteristics
were comparable between groups (Table 2), except for higher
maternal weight in phase 2 (P = 0.02). Importantly, betweenphase analysis of nonsubject characteristics yielded many differences, all favoring phase 2, independent of intervention groups
(see supplemental Table 5 under Supplemental data in the online issue). These included higher maternal age, maternal literacy,
and family monthly income; larger size of main room in family
dwelling; and increased access to a tube well (all in phase 2
families; P , 0.05 for all).
Early dropouts after randomization but before the intervention
started were rare (5/268; 1.9%; Figure 1). Of the subjects who

started the intervention, loss to follow-up was documented in 7 of

134 (5.2%) children from the iron MNP group and 11 of 129
(8.5%) children from the PP group. The baseline characteristics
of these subjects were similar to those who finished the trial (see
supplemental Table 6 under Supplemental data in the online
issue). The 2-mo intervention was completed by .92% of subjects, and data were obtained for the entire 6 mo for .90%. The
number of successful planned home visits was .95% for both
groups. No statistically significant between-group differences were
identified for all of the above variables (Table 3). Weekly counting
of empty sachets by the trained assessors yielded an estimate of
100% adherence.
A trend toward lower infectious morbidity was noted when
data from the full 6-mo period was compiled (primary outcome),
favoring iron MNP (RR: 0.80; 95% CI: 0.62, 1.04; Figure 2).
This result, consistent with a conclusion of noninferiority with
a prespecified D of 1.2 (Figure 3), was unchanged when hemoglobin status (90 or .90 g/L) or number of children per
family (as a continuous variable) was included in the analytic
model: hemoglobin status (RR: 0.83; 95% CI: 0.65, 1.08) and
number of children per family (RR: 0.81; 95% CI: 0.63, 1.04).
The incidence rates of infections were lower than expected in

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FIGURE 1. Flow diagram illustrating the number of children screened, excluded, and randomly assigned and the temporal pattern of dropouts for each
group. Combined data from both phases are presented; for phase-specific details, see supplemental Figure 2 under Supplemental data in the online issue. The
numbers in parentheses indicate the number of sachets consumed before loss to follow-up; the underlined numbers indicate data from phase 1 subjects. Iron
MNP, iron-containing micronutrient powder; PP, placebo powder.

589

SAFETY OF IRON MNP IN MALNOURISHED CHILDREN

TABLE 1
Sociodemographic, anthropometric, and laboratory characteristics of the
study participants1

TABLE 1 (Continued )
Comparison group

Comparison group
Characteristic and phase no.
Characteristic and phase no.

PP

65
71

64
68

34 (52.3)
33 (46.5)

36 (56.3)
30 (44.1)

17.7 6 3.94
17.9 6 2.9

17.6 6 3.9
17.3 6 2.8

7.7 6 0.7
7.8 6 0.7

7.7 6 0.8
7.7 6 0.7

73.4 6 3.5
74.1 6 3.2

73.3 6 4.1
74.0 6 3.2

22.8 (23.1, 22.6) 22.9 (23.3, 22.6)

22.8 (23.2, 22.5) 22.7 (23.0, 22.5)
24 (36.9)
21 (29.6)

23 (35.9)
19 (27.5)

22.5 (23.0, 22.2) 22.6 (23.0, 22.0)

22.4 (23.0, 21.9) 22.2 (22.9, 21.7)
56 (86.2)
48 (67.6)

48 (75.0)
37 (54.4)

22.0 (22.3, 21.6) 22.0 (22.3, 21.6)

22.1 (22.4, 21,8) 22.2 (22.4, 21.9)
31 (47.7)
44 (62.0)

33 (51.6)
44 (64.7)

96.3 6 9.7
94.2 6 10.5

95.0 6 10.2
96.0 6 9.3

16 (24.6)
21 (29.6)

18 (28.1)
19 (27.9)
(Continued)

both groups (see supplemental Table 7 under Supplemental

data in the online issue). When the 6-mo data were analyzed
independently for each phase (subgroup analysis), the composite
primary outcome was lower for the iron MNP group in phase 1
(RR: 0.60; 95% CI: 0.43, 0.85), but not in phase 2 (RR: 0.98;
95% CI: 0.69, 1.39).
The phase-aggregated analysis, which focused on the intervention periods (the first 2 mo of the each phase), showed no
between-group difference in infectious morbidity risk (RR: 0.98;
95% CI: 0.71, 1.37; see supplemental Figure 3a under Supplemental data in the online issue). Separate examinations of
phase 1 (RR: 0.72; 95% CI: 0.46, 1.12) and phase 2 (RR: 1.35;
95% CI: 0.84, 2.13) indicated trends in opposite directions. A
similar analysis focused on the postintervention intervals of both

Iron MNP

PP

3 (28)
3 (28)

3 (17)
3 (27)

21 (32.3)
22 (30.9)

17 (26.6)
16 (23.5)

61 (93.9)
63 (88.7)

64 (100)
63 (92.7)

30 (46.2)
32 (45.1)

27 (42.2)
25 (36.8)

2,9

No. of live children per family (n)

1
2
First-born child [n (%)]2
1
2
Polio vaccine and vitamin A
at last immunization [n (%)]2
1
2
Antihelminthic treatment in
the past 3 mo [n (%)]2
1
2
1

Iron MNP, iron-containing micronutrient powder; PP, placebo powder;

WAZ, weight-for-age z score; HAZ, height-for-age z score; WHZ, weight-forheight z score. None of the between-group comparisons were significant (for
all exact P values, see Supplemental Table 3 under Supplemental data in the
online issue).
2
P values assessed with Fishers exact test (2-tailed).
3
P values assessed with t test.
4
Mean 6 SD (all such values).
5
P values assessed with Wilcoxons rank sum test.
6
Values are medians; 25th, 75th quartiles in parentheses.
7,8
Between-phase P value: 70.006, 80.009.
9
Range in parentheses.

phases and showed a statistically significant reduction in infectious morbidity risk (RR: 0.66; 95% CI: 0.46, 0.93; see
supplemental Figure 3b under Supplemental data in the online
issue). In this case, iron MNP was protective in phase 1 (RR:
0.45; 95% CI: 0.26, 0.77), and a similar trend was observed in
phase 2 (RR: 0.77; 95% CI: 0.50, 1.20).
There were no episodes of prolonged fever, no deaths, and short
hospital admissions for 2 infants in each group (see supplemental
Table 8 under Supplemental data in the online issue). No diagnosis of malaria was recorded. No between-group differences
were found in the incidence of febrile episodes (P = 0.50; data
not shown) or in the mean axillary temperature trends (P = 0.08;
supplemental Figure 5 under Supplemental data in the online
issue). Additional data on patterns of health care utilization are
also available (see supplemental Tables 9 and 10 under Supplemental data in the online issue).
Whereas baseline hemoglobin was similar between groups
(Table 1), hemoglobin was higher for subjects randomly assigned
to iron MNP (P , 0.0001) at 2 mo (Table 4). The same trend
was observed after 6 mo (P = 0.03, both phases combined).
Importantly, an increase in hemoglobin over baseline was noted
at 2 and 6 mo in subjects who received PP (P , 0.0001).
Measured heights and weights were comparable between groups
at all time points (see supplemental Figure 4 under Supplemental
data in the online issue). The only exception was higher weights
at 60 d for subjects from phase 2 randomly assigned to iron MNP
(P = 0.026)an effect that did not persist to the end of the trial
(P = 0.458). A difference in daily weight gain was observed when
both phases were combined, which favored the iron MNP group

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Total no. of subjects

1
2
Male sex [n (%)]2
1
2
Age (mo)3
1
2
Weight (kg)3
1
2
Height (cm)3
1
2
WAZ5,6
1
2
WAZ  23 [n (%)]2
1
2
HAZ5,6
17
27
Stunting, HAZ  22 [n (%)]2
1
2
WHZ5,6
18
28
Wasting, WHZ  22 [n (%)]2
1
2
Baseline hemoglobin
concentration (g/L)3
1
2
Baseline hemoglobin
concentration 90 g/L [n (%)]
1
2

Iron MNP

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LEMAIRE ET AL

TABLE 2
Maternal sociodemographic and family-dwelling characteristics1
Comparison group
Characteristic and phase no.

PP

65 (100.0)
67 (94.4)

64 (100.0)
62 (91.2)

24.8 6 6.02
26.5 6 5.5

25.1 6 5.2
27.3 6 5.8

40.3 6 5.2
40.7 6 4.7

39.5 6 5.2
42.8 6 5.14

2 (010)
3 (011)

0 (09)
4 (010)

28 (43.1)
35 (52.2)

27 (42.2)
38 (61.3)

45 (18179)
67 (37149)

45 (18149)
75 (30448)

15 (11, 20)
18 (12, 23)

15 (12, 20)
17 (13, 24)

44 (67.7)
59 (88.1)

45 (70.3)
59 (95.2)

15 (23.1)
16 (23.9)

15 (23.4)
20 (33.3)

TABLE 3
Retention patterns and adherence to study protocol1
Comparison groups

Iron MNP, iron-containing micronutrient powder; PP, placebo powder.

None of the other between-group comparisons were significant unless noted
otherwise (for all exact P values and details on paternal data, see Supplemental Table 4 under Supplemental data in the online issue).
2
Mean 6 SD (all such values).
3
P = 0.02 (t test).
4
Data are from 61 mothers.
5
Values are medians; ranges in parentheses.
6
The monetary exchange calculation used to normalize US dollars was
1 US$ = 67 Takas.
7
Values are medians; 25th, 75th quartiles in parentheses.

(P = 0.002; see supplemental Table 11 under Supplemental data

in the online issue), but this effect was no longer noticeable at the
end of the trial (P = 0.22). Monthly gain in length and daily weight
gain were near normal values for children aged 1224 mo in both
groups during the intervention period (1020 mm/mo and 79 g/d,
respectively; see supplemental Table 11 under Supplemental
data in the online issue). However, these benefits were again
short-lived because both rates slowed down considerably in the
postintervention period (P = 0.01).

DISCUSSION

This is the first trial specifically designed to address the safety of

providing iron-containing MNP to anemic children with moderateto-severe malnutrition. The results show that iron MNP provided
daily for 2 mo is efficacious in terms of the hemoglobin response
and noninferior to placebo in terms of infectious morbidity
(composite of DDL) over a 6-mo period. In fact, a trend toward

Characteristic and phase no.

Iron MNP

PP

n/total n (%)
Early dropouts, loss to follow-up
and retention
Early dropouts, after random
assignment, before intervention
1
2/65 (3.1)
1/64 (1.6)
2
0/71 (0)
2/68 (2.9)
Retention to end of intervention,
2 mo
1
62/63 (98.4)
60/63 (95.2)
2
68/71 (95.8)
61/66 (92.4)
Retention to end of trial, 6 mo
1
60/63 (95.2)
58/63 (92.1)
2
67/71 (94.4)
60/66 (90.9)
Planned home visits
Number of successful home visits
1
2839/2898 (98.0) 2819/2898 (97.3)
2
3120/3266 (95.5) 2882/3036 (94.9)
Number of subjects who missed
1/30 home visits during the
intervention period
1
59/62 (95.2)
54/60 (90.8)
22
62/68 (91.2)
61/61 (100)
Number of subjects who missed
2/46 home visits during the
entire 6-mo trial
1
58/60 (96.7)
52/58 (89.7)
2
32/67 (92.5)
59/60 (98.3)
1
2

Iron MNP, iron-containing micronutrient powder; PP, placebo powder.

P = 0.018 (Fishers exact test, 2-tailed).

Downloaded from ajcn.nutrition.org by guest on December 15, 2014

Families for whom data

were collected [n (%)]
1
2
Maternal age (y)
1
2
Maternal weight (kg)
1
23
Maternal duration of education (y)5
1
2
Maternal literacy (%)
1
2
Familial monthly income (US$)5,6
1
2
Size of dwellings main room (m2)5,7
1
2
Tube well near dwelling [n (%)]
1
2
Sanitary toilet near dwelling [n (%)]
1
2

Iron MNP

a protective effect of iron MNP was observed in the 4-mo period

that followed the intervention. Furthermore, it did not increase
the likelihood of hospitalization or mortality.
We propose 3 explanations for these results. First, recent
pharmacokinetic studies in pregnant women showed that supplementation or treatment with microencapsulated iron resulted
in lower peak plasma iron concentrations when compared with
tablets (30). Because the iron source used in this study (ferrous
fumarate) is similarly microencapsulated, we posit that the lack
of increased infectious morbidity may have been explained by
a reduction in iron bioavailability to pathogens. Second, it is
possible that zinc, which is included in standard MNP, may have
mitigated the negative potential of iron. Indeed, zinc supplementation hastens recovery from acute diarrheal or respiratory
episodes (31). Because the recurrent event analysis used in this
study takes into account both frequency and duration of episodes,
these properties of zinc could have positively influenced our
outcome. Of note, neither folic acid nor vitamin A appear to
affect the incidence or severity of these infectious morbidities
(31); there are no data for vitamin C. Finally, the previously
observed negative effects of the provision of iron to malnourished
infants may have been overestimated because the data originated
from uncontrolled studies (8, 9).
The trend toward a protective effect of iron MNP, noted during
the intervention period of phase 1, may reflect important betweenphase differences at 3 levels: intervention, subjects, and exposures.

591

SAFETY OF IRON MNP IN MALNOURISHED CHILDREN

TABLE 4
Hemoglobin concentrations at 2 and 6 mo1
Time points
Characteristic and group

First, only systematic, phase-specific deviations from the intervention plan could account for such effects. We believe that this
hypothesis is not supported by the data because the effect of iron
MNP on hemoglobin was similar in both phases. Second, the
distinctive phase-specific effects noted may be explained, at least
in part, by some striking and unexpected between-phases differences identified in the subjects characteristics: stunting was more
common in subjects from phase 1, the group that also appears to be
more impoverished based on many between-phase differences in
key socioeconomic indicators. This raises the possibility that
poorer more stunted children from phase 1 may have reaped
greater benefit from the intervention than did their counterparts
from phase 2. Finally, as per the study design, subjects were likely
exposed to distinct seasonal-specific infectious agents. That the
subjects in phase 1 fared better was thus surprising because the
yearly peak of diarrheal diseases occurs between February and May
in this area (32). If this scenario is valid, it may be safe for intervention programs to operate even during seasons of highest
expected burden of diarrheal disease.

FIGURE 3. Overall relative risk of diarrhea, dysentery, and lower respiratory

tract infections with iron-containing micronutrient powder (MNP) compared
with placebo powder (PP). The vertical dashed line represents the margin of
noninferiority D, which was determined a priori. The solid line represents the
null effect. The light gray rectangle illustrates the area within which the
relative risk and its corresponding 95% CI need to fit to conclude that iron
MNP is at least as safe as PP.

6 mo

125
122

125
118

115.3 6 8.22
(113.8, 116.7)

110.0 6 11.33
(108.0, 112.0)

105.1 6 10.9
(103.1, 107.0)

106.5 6 13.2
(104.1, 109.9)

Iron MNP, iron-containing micronutrient powder; PP, placebo powder.

Significantly different from the PP group (t test): 2P ,0.0001, 3P = 0.02.

2,3

We used iron MNP instead of iron syrup or drops for several

reasons. First, iron MNP are now routinely used in home fortification programs, including many UNICEF-supported micronutrient
projects around the world. Second, iron MNPs are taste-neutral
and, unlike iron drops or syrup, do not stain childrens teeth. The
acceptability of iron MNP has been shown in diverse settings (19,
33). Third, excellent bioavailability of the microencapsulated
iron in the iron MNP has been shown in infants (34).
Few data have documented the effect of iron supplementation
on iron stores in malnourished children. In this study, hemoglobin was used as the sole surrogate for iron status because of
community concerns about excessive bloodletting. As expected,
hemoglobinsignificantly increased with iron MNP compared
with PP. The largest effects were noted immediately after
the interventions, and hemoglobin was still significantly above
baseline at the end of the trial. A similar trend was observed
with PP, albeit of lesser magnitude. We concluded that a 60-d
regimen of iron MNP likely helped replenish iron stores in
malnourished children.
No clear effect of iron MNP on growth variables was noted. In
fact, analysis of anthropometric data showed that, in both phases
and for all intervention groups, growth rates were near normal
during the intervention periods but were significantly reduced
during the postintervention periods. This may have been because
the mothers from both groups were equally likely to change their
behavior after receiving education on appropriate complementary
feeding before the trial. In addition, a substantial proportion of
the positive effects of iron MNP on hematologic and anthropometric outcomes were likely attributable to the intensity of the
follow-up itself (35). In retrospect, the primary outcome was
probably not immune to this trial effect either and may explain in
part why the overall incidence rates of infections were lower than
anticipated in both groups. It is critical to realize, however, that
had historical controls been used in lieu of a PP arm for the
statistical analyses, we may have overestimated the effects of iron
MNP on these outcomes.
One of the major strengths of this study was the quality of data
gathered during the intervention. Most previous studies relied
solely on maternal recall over periods ranging from weeks to
months. This study addressed this weakness by using more
frequent home visits combined with direct observation of each

Downloaded from ajcn.nutrition.org by guest on December 15, 2014

FIGURE 2. Estimates of the effect of iron-containing micronutrient

powder (MNP) treatment on the expected number of incident episodes of
diarrhea, dysentery, and lower respiratory tract infections (DDL) when
compared with placebo powder (PP). In each case, the data from both phases
are presented independently (left and middle panels) and with the entire data
set aggregated. Data from the entire period of observation (6 mo) are presented.
For more detailed graphs of the data from the 2-mo-long intervention (data
collection on alternate days) and from the 4-mo period after the intervention
period (weekly home visits), see supplemental Figure 3 under Supplemental
data in the online issue. The calculated relative risk (RR) and 95% CIs are
presented above each graph. The black rectangles represent the period of
supplementation.

Subjects tested at each time point (n)

Iron MNP
PP
Hemoglobin concentration (g/L)
Iron MNP
Mean 6 SD
95% CI
PP
Mean 6 SD
95% CI

2 mo

592

LEMAIRE ET AL

We acknowledge Cristina Goia and Derek Stephens (Hospital for Sick

Childrens Biostatistics, Design, and Analysis consultation service) for help
with the sample size calculation and the conceptual design of the trial, Lindsay Borthwick for a critical review of the manuscript, Alexandre Lagache for
cartographic expertise, Imran Matin (Deputy Executive Director, BRAC International) and Syed Masud Ahmed (Senior Research Coordinator at BRAC)
for support, Farid Ahmed (field manager for BRAC) and the other members of
BRACs field team for assistance; and the members of Data Safety Monitoring
Committee.
The authors responsibilities were as followsML, SHZ, ZH, FH, QSI,
MP, FA, and MAK: designed the research; QSI, MP, FA, and MAK: conducted
the research; ML, SHZ, QSI, MP, FA, and MAK: designed and optimized the
database; ML, SHZ, RJC, and HS: analyzed the data; ML and SHZ: wrote the
manuscript; and SHZ: had primary responsibility for the final content. All
authors read and approved the final manuscript. The two funding bodies
(Thrasher Research Fund and HJ Heinz Company Foundation) were not involved in the design, implementation, analysis, and/or interpretation of the
data. SHZ had beneficial interests in certain intellectual property rights to
his invention known as Sprinkles. These interests include 1) patent rights
for the United States and Canada, which are held by Ped-Med Limited (a
Canadian corporation of which SHZ is the sole shareholder) and 2) trademark rights in various jurisdictions to the name Sprinkles, which are held
by either Ped-Med Limited or the Sprinkles Global Health Initiative Inc (a
Canadian not-for-profit corporation of which SHZ is a member). ML received two travel grants (in 2005 and 2006) from the Rockefeller/Evans
International Health Fund/International Health Elective Scholarship from
the University of Toronto during the early parts of this project; while working on the manuscript, ML was supported by a Howard Hughes Medical
Institute research fellowship from July 2009 until June 2010 and then by

a postdoctoral fellowship from KRESCENT/CKF/CIHR; ML is part of the

Investigative Medicine PhD training program and the Yale Center for Clinical Investigation at Yale University School of Medicine (New Haven, CT).
None of the remaining authors had competing interests.

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child by trained assessors. As a result, the duration and timing of

each infection episode was more precisely delineated. Another
strength was the use of statistical analyses of repeated measures
for the primary outcome. Most previous studies compared the
sum of all episodes occurring in each group, an approach that is
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improving hemoglobin status.

SAFETY OF IRON MNP IN MALNOURISHED CHILDREN

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