1

Efficacy of daily and weekly home fortification of weaning foods

with Sprinkles in improving iron deficiency anaemia among

young children in Bangladesh

Farhana Haseen

March 2004

BRAC Research and Evaluation Division

BRAC Centre, 75 Mohakhali Dhaka 1212, Bangladesh

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ACKNOWLEDGEMENT

RED-BRAC has conducted this study in collaboration with the Hospital for Sick Children

(HSC), Toronto, Canada. We are thankful to HSC for their financial and technical support.

Special thanks to Dr. SM Ziauddin Hyder of HSC for his tireless contribution and support in

the smooth operation and successful completion of the study. At BRAC, Dr. Imran Matin,

Mr. Ghulam Sattar, Dr. CSB Jalal, Mr. Fazlul Karim, Dr. Faruque Ahmed, Dr. Zeba Mahmud

gave us full support for this study. We render our grateful thanks to all of them. We specially

grateful to Professor Harun KM Yusuf, for giving us engorgement and editorial support. The

final editing of Hasan Sharif Ahmed is also highly acknowledged. We gratefully

acknowledge the help and cooperation of the BRAC-BDP mangers at Kaliganj in conducting

the study. Field supervisor Md. Miaznur Rahman and field data collectors gave their best

effort to do the work in time with quality. Last but not the least, we are grateful to the

children and their mothers, family members for their consent to participate in the study and

give blood samples which were a crucial part of this study. Without their support this study

would not have been possible.

Farhana Haseen

Junior Research Associate

Nutrition Research Unit

Research and Evaluation Division

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CONTENTS

EXECUTIVE SUMMARY 4 INTRODUCTION 7 METHODS 12 RESULTS 17 DISCUSSION 30 CONCLUSIONS 38 RECOMMENDATIONS 39 REFERENCES 40

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EXECUTIVE SUMMERY

Introduction - Iron deficiency anaemia is a major public health problem worldwide,

especially in developing countries. Infants and young children of up to 2 years of age and

pregnant women are the most vulnerable group. Although iron intervention programmes,

such as iron-folate tablets, have been instituted for pregnant women at the national level in

many countries, a suitable effective strategy for infants and young children is still lacking.

Recently, researchers at the Hospital for Sick Children and the University of Toronto in

Canada developed “Sprinkles”, an innovative iron ‘home-fortification’ strategy. Sprinkles

consist of lipid microencapsulated ferrous fumarate in powder form that is packed into single

serve sachets which are to be sprinkled onto any kind of weaning food and mixed just before

feeding. The efficacy and effectiveness of Sprinkles in improving anaemia status of young

children were tested in several countries including Canada, Ghana, China and Mongolia. The

results of these studies were encouraging. In view of the high prevalence of anaemia among

infants (>80%) and 12-24 months old children (>60%) in Bangladesh as revealed by recent

surveys, it was necessary to conduct a similar study in this country. The present study is a

community-based single blinded Randomized Controlled Trial (RCT) conducted in rural

Bangladesh to compare the efficacy of a daily vs. weekly intervention of Sprinkles in

improving the anaemia status of young children aged 12-24 months.

Subject and methods - The study was carried out in 13 villages of Kaliganj upzila in

Gazipur district, about 40 km north of Dhaka city. A total of 152 mild to moderate anaemic

children (haemoglobin between 70 and 110 g/L) were selected for the study. Of these, 79

children from 7 villages were randomly placed in the daily intervention group and 73 children

from 6 villages were randomly placed in the weekly intervention group. Each child in the

daily group received 7 Sprinkles sachets for one week, each containing 12.5 mg elemental

iron to be fed once daily. The weekly group was given one sachet of Sprinkles containing 30

mg elemental iron and 6 placebo sachets (containing Sprinkles-like powder, but no

micronutrients) for 8 weeks between September and December 2003.

Socioeconomic and demographic information of each child was recorded at baseline. Length

and weight were measured and blood haemoglobin, serum ferritin (sFt) and serum trasferrin

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receptor (sTfR) were analyzed at baseline and at the end of the intervention period. Data on

morbidity, compliance and child’s overall health condition were recorded every week.

Information on acceptability such as mothers’/caregivers’ liking or disliking of the Sprinkles

and their willingness to pay for it (if available in the market) was also obtained through

surveys and focus group discussions (FGD). Data were analyzed with SPSS/WIN software

and differences between groups and within groups were analyzed by chi-square, ANOVA,

and pried t-test. Ethical clearance for the study was obtained from appropriate authorities in

Canada and Bangladesh.

Results - Households in the two intervention groups did not differ with respect to most

indicators of socioeconomic status and childcare practices. Also, Gazipur has agro-ecological

characteristics similar to that of the plains in rural Bangladesh. At baseline, the two groups of

children had comparable prevalence rates of protein–energy malnutrition (stunting 30-37%;

wasting 24-26%, underweight 47-48%) and anaemia (55-58%). At the end of the 8-week

supplementation period, the mean haemoglobin concentration increased from 97 g/L to 112

g/L (increment of 16 g/L) in the daily group and from 97 g/L to 110 g/L (increment of 13

g/L) in the weekly group. In a subgroup of children who had initial haemoglobin

concentration <100 g/L, the increments were considerably higher- 23 g/L in the daily group

and 18 g/L in the weekly group. All these haemoglobin responses in the two groups were

statistically significant (p=0.000) within group, however, no significant differences between

groups (p=0.145 and 0.167) were observed. The recovery rates from anaemic to non-anaemic

states in the two groups were 54% (for all children) and 66-83% (for the subgroup). All these

data clearly show that Sprinkles has commendable efficacy in treating anaemia and also that

the weekly dosing was as efficacious as daily dosing.

The efficacy of Sprinkles in improving anaemia status was also evident in terms of increases

in sFt levels – from 8 µg/L to 19 µg/L in the daily group and from 11 µg/L to 20 µg/L in the

weekly group and in terms of decreases in sTfR levels - from 9 µg/L to 6 µg/L in the daily

group and from 8 µg/L to 6.5 µg/L in the weekly group.

As reported by mothers/caregivers, the treatment had no discernible side effects and the

compliance was high – more in the weekly than in the daily group. The intervention resulted

in an increase in the appetite, alertness and playfulness of children. Sprinkles, therefore, were

well accepted by mothers and caregivers. Most preferred the weekly regimen to the daily one

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mainly because of the psychological pressure experienced by the responsibility for daily

dosing.

Conclusion - Based on the above results, it may be concluded that Sprinkles either given

once daily or once weekly is equally efficacious in improving anaemia status in young

children aged 12-24 months. Since mothers had a preference for more flexible dosing

options, it is recommended that a weekly Sprinkles intervention programme be designed for

implementation to address the iron needs of infants and young children. Weekly

supplementation would also have the added advantage of less cost and other operational

flexibilities.

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INTRODUCTION

Iron deficiency anaemia is a major public health problem worldwide especially in developing

countries where two billion individuals are affected (1). Young children aged 6-24 months

are most vulnerable. These children cannot depend on breast milk alone to meet their iron

requirements. WHO and UNICEF has suggested that 6 months old infants should be given, in

addition to breast milk, frequent small complementary meals that are rich in energy, protein

and micronutrients. However, surveys show that while breastfeeding is generally continued

well into the second year of life, infants are given food that rarely contains items that supply

adequate nutrients (2). In addition, complementary food is heavily studded with cereal that

contains high amounts of phytate, which is a potent iron absorption-inhibitor. This makes

infants highly susceptible to suffer from iron deficiency anaemia, along with high rates of

morbidity and mortality (3). Indeed, recent surveys in Bangladesh show very high prevalence

figures of anaemia ranging from 70-90% among young children 6-24 months compared to

much lower prevalence rates among older children. Pregnant women were next to under-2

children in their vulnerability to develop anaemia (2,4,5).

For infants and young children, IDA has potentially irreversible adverse effects on cognitive,

motor and language development, future learning capacity, school performance, and

resistance to diseases (6,7,8). Thus, IDA in childhood eventually reduces wages and quality

of life in adulthood (9). IDA has been suggested to result in losses of up to 4% of a country’s

Gross Domestic Product (GDP) due to cognitive impairment and reduced labour productivity

(10). Considering these potentially negative impacts, the first, second, and fourth UN

Millennium Development Goals (MDG), namely “ Eradicate extreme poverty and hunger”,

“Achieve universal primary education” and “Reduce child mortality” will hardly be achieved

in any country if the problem of IDA among infants and young children is not sufficiently

addressed. Therefore strong arguments have been made in favour of targeting infants and

young children for supplementation (11).

Iron supplementation has proven to be a useful strategy to address the iron deficiency of

individuals when it has to be corrected rapidly (12,13). WHO has recommended blanket

supplementation, without screening, to all infants and young children 6 to 24 months of age

in regions where the prevalence of anaemia exceeds 20% to 30% (14). Although suitable

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forms of iron are available for treatment and prevention of IDA in adults and adolescents, it is

limited in the case of infants and young children (15). One of the reasons is the unavailability

of an iron formulation, which is efficacious, acceptable, easy to dispense, and which does not

conflict with country-specific breastfeeding and weaning practices. For the last 150 years,

oral ferrous sulfate drops have been the most common source of paediatric iron. But this

intervention has rarely been effective due to a number of reasons, mainly low compliance.

The taste of the commonly used iron drops is metallic and unpleasant, and the preparation

may stain babies’ teeth, and, if the dose is too high, it can result in gastric irritation and

abdominal discomfort (15).

Micronutrient Sprinkles

To overcome the above problems, a group of researchers led by Dr. Stanley Zlotkin at the

Hospital for Sick Children (HSC), in Toronto, Canada have developed a unique formulation

and strategy to deliver iron and other essential micronutrients to infants. ‘Sprinkles’ consist of

lipid microencapsulated ferrous fumarate in a powder form. Other micronutrients including

vitamin A and C, folic acid, and zinc can easily be added without changing the cost of

Sprinkles to any significant extent. Based on the assumption that several micronutrients can

improve the haemoglobin response to iron, it is believed that the presence of these additional

micronutrients would be more effective in reducing IDA than having only iron alone.

Typically, Sprinkles are packaged into single-serve sachets and are to be sprinkled and mixed

with infant weaning food just before feeding. Encapsulation of iron prevents changes in the

flavour, colour, smell and taste of food, making it more acceptable. Sprinkles can, therefore,

be considered as a novel iron “home-fortification” strategy (16).

Composition of Sprinkles

Sprinkles were provided by HSC, Canada, and were produced by the Heinz Company, Italy.

This product has been tested and distributed among infants and young children in a number

of countries including Canada, China, Ghana, India, and Mongolia by researchers from HSC

and its respective partners. Each sachet of Sprinkles contains: 12.5 mg of elemental iron (as

ferrous fumarate), 300 µg of vitamin A (retinol acetate USP), 5 mg of zinc (zinc gluconate

USP), 50 mg of vitamin C (ascorbic acid USP-FCC) and 150 µg of folic acid (folic acid

USP). For efficacy test, this preparation is meant for daily supplementation. However, in the

weekly intervention group, the Sprinkles sachet would contain 30 mg of iron including all

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other nutrients in similar quantities to be fed on one particular day of the week. Six placebo

sachets containing no micronutrients are to be fed on the other 6 days.

Efficacy and safety of Sprinkles

A number of randomized controlled trials (RCT) have been conducted among under-2

children in Ghana, which show that weaning foods fortified with Sprinkles daily was as

efficacious as the conventional iron drops in treating anaemia (17). Moreover, the common

side-effects associated with drops – teeth staining, unpleasant metallic taste, gastrointestinal

irritation and measurement difficulties - were avoided (19). Sprinkles were more acceptable

to the mothers/caregivers and the reported compliance was also found to be higher as

compared to iron drops. Moreover, the benefits of the treatment (in anaemia reduction) that

was achieved after a two-month period could be sustained over a longer period of time- even

up to 18 months post-supplementation. Furthermore, the use of Sprinkles did not produce any

toxic effect even in non-anaemic children (17). A recent RCT in Ghana has indicated that an

iron dose of 12.5 mg (suggested dose for infants and young children by UNICEF/WHO)

supplied through daily Sprinkles home-fortification could increase mean haemoglobin by 10

g/L among anaemic under-2 children. This was comparable to the response produced by

higher iron doses, including 20 mg and 30 mg elemental iron per day (20).

Daily vs. Weekly Supplementation

Although, in attempts to curb anaemia, daily supplementation with iron has been found

effective in controlled settings, it was rarely found to be able to solve the problem of iron

deficiency anaemia when implemented as a public health intervention (21). In addition to a

number of programmatic and behavioural constraints including low compliance (22),

biological limitations, mainly reduced absorption of iron given daily has been blamed for this

low programme effectiveness. Based on an animal experiment, it was hypothesized that a

first dose of iron would load the mucosa so as to block subsequent doses from absorption

(23). According to this so called “mucosal block theory”, reducing the frequency of

supplementation matching the mucosal turn-over time, would result in better absorption and

higher effect. However, this theory could not be confirmed by studies using radio labeled

iron in man (24). Beaton and McCabe conducted an in-depth analysis of experience (meta-

analysis) using data from all available field trials comparing daily vs. weekly iron

supplementation (25). Although no firm conclusion could be drawn due to inadequate

information on compliance and other related methodological limitations, the analysis

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suggested that a daily dose of iron was more effective than the weekly in increasing the mean

haemoglobin concentration. However, it was concluded that if the compliance was good or

could be assured such as in supervised settings, the efficacy of weekly dosing might prove

more promising, which would also improve the cost-effectiveness of iron interventions.

In addition to the daily-weekly issue, little is known about the amount and duration of the

supplementation sufficient to produce a satisfactory haemoglobin response. In most studies

involving infants and young children, the design had limitations either by not having a

control group or by failing to blind the interventions properly. Studies conducted in

Indonesia (26, 27) and Viet Nam (28) made use of a daily iron dose ranging from 8-30 mg

and a weekly dose ranging from 20-30 mg, provided as syrups or drops. The supplementation

studies, which continued for 8-18 weeks, roughly concluded that although both

supplementation regimens were efficacious, the daily iron supplementation did not produce a

significantly higher haemoglobin response when compared to the weekly. However, in the

Bogor study (26), the daily supplementation schedule was found better in increasing serum

ferritin level, an indicator of storage iron.

Rationale

A mentioned earlier, iron deficiency anaemia is unacceptably high among under-2 children,

followed by pregnant women, in Bangladesh. To address the problem, government and non-

government health sectors have initiated intervention programs that are primarily targeted to

pregnant women in the form of iron-folate tablets for daily consumption. This intervention is

a part of the antenatal care program throughout the second and third trimesters of pregnancy.

Unfortunately, no such intervention program has been implemented in Bangladesh for under-

2 children. From a public health point of view, there are three possible interventions for the

prevention of anaemia - dietary diversification to include more iron rich foods, food

fortification with iron and provision of iron supplementation. Dietary diversification or food

fortification strategies are not logistically or economically feasible in poor countries like

Bangladesh. So, supplementation is the alternative option. The concept of ‘Sprinkles’ has

been evolved as a novel option to deliver iron and other micronutrients to children at risk,

using a home fortification approach (16).

Since large-scale programmes to combat iron deficiency among young children by daily or

weekly supplementation do not exist due to cost involvement, side effects and managerial

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burden, alternative approaches should be tried to find an appropriate strategy that reduces

such burdens as much as possible. Supplementation using intermittent dosing schedules may

offer such an alternative for large-scale programs targeted to young children. Weekly instead

of a daily supplementation would decrease the cost of supplementation programmes and

possibly increase compliance. It has been shown that weekly iron syrup supplementation is as

effective to improve iron status as the daily supplementation. Yet, no research has been

conducted to show that a dose of Sprinkles given once a week to children with mild and

moderate iron deficiency anaemia improves haemoglobin concentration to the same extent as

doses given daily.

Therefore, the present study was undertaken to compare the efficacy of home-fortification of

weaning foods with Sprinkles containing 12.5 mg elemental iron daily with that of Sprinkles

containing 30 mg elemental iron to be given weekly, in improving haemoglobin status among

infants and young children. If the weekly fortification was found as efficacious as daily, the

finding would have important policy implications in increasing the effectiveness of the

Sprinkles home fortification programme by broadening delivery options and lowering the

cost of interventions.

Goal

• To identify a suitable dose-frequency for the iron home fortification of weaning foods in

support of developing an appropriate community-based Sprinkles delivery strategy to

reduce IDA in infants and young children in Bangladesh.

Specific objectives

Primary

• To compare the dose-response of daily and weekly administration of multiple

micronutrient Sprinkles among infants and young children aged 12-24 months, containing

12.5 mg and 30 mg elemental iron, respectively.

Secondary

• To assess the impact of the Sprinkles on growth, and

• To assess compliance and acceptability of the intervention.

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Hypothesis

In light of the findings of Beaton and McCabe (25), it was hypothesized that the haemoglobin

response would be greater in infants and young children receiving weaning foods fortified

with Sprinkles containing 12.5 mg elemental iron daily for 8 weeks as compared to that in

children receiving Sprinkles containing 30 mg elemental iron weekly.

METHODS

Study area

The research was conducted in 13 villages of Kaliganj upazila (sub-district) under Gazipur

district, about 40 km north of Dhaka city, the capital of Bangladesh. Gazipur is one of the 64

districts in Bangladesh, with similar geo-ecological characteristics as the rest of the plains of

the country (fertile agricultural land, high prevalence of malnutrition, low rates of hookworm

and malaria infestations).

Study period

The study period was from September to December 2003.

Information conveyed to potential parents

Meetings were held with parents of potential infants and children of the selected villages

before the beginning of the baseline survey, to inform them about the study and to seek their

consent. Mothers were told that: i) Sprinkles provided iron and other nutrients necessary for

good growth of their children; ii) before giving to children as a public health programme, it

was necessary to test its efficacy under the prevailing socioeconomic situation; iii) there were

free medical check ups for their children at the beginning and at the end of the study; iv) all

children would receive one-month supply of Sprinkles at the end of the study free of cost; and

iv) they were free to withdraw their children from participation at any stage of the study. The

mothers who consented to their children’s participation were asked to sign or put a cross (X)

on a simple consent form.

Subjects, recruitment and randomization

All eligible children aged 12-24 months from the 13 villages were listed. Inclusion criteria

included: 12-24 months of age at the time of recruitment; consuming weaning food routinely

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in addition to breast milk; and blood haemoglobin concentration between 70 and 110 g/L as

measured during screening. It was difficult to take blood from young children. Therefore, for

screening purposes haemoglobin was determined by taking a drop of blood via finger prick.

Children with any chronic illness and severe anaemia (<70g/L) were excluded from the trial

and treated. All eligible subjects matching the inclusion criteria were randomly assigned by

their village to either the daily or weekly intervention group.

Study design

Since it would be unethical to provide a placebo to children with anaemia, we did not include

a placebo control group in our study. This was a community-based single blinded randomized

control trial with two intervention groups. There was the “daily-Sprinkles group” (each

receiving Sprinkles daily containing 12.5 mg elemental iron) and the “weekly-Sprinkles

group” (each receiving Sprinkles once a week containing 30 mg elemental iron and a

Sprinkles-like placebo powder without micronutrients for the remaining 6 days of the week).

The intervention in both groups was continued for 8 weeks.

As it was a single blinded control trial, only the key researchers were aware of the content of

the sachets. Proper distribution of sachets was necessary as well as the feeding of Sprinkles

on a regular basis. In the case of the weekly group, Sprinkles with micronutrients were fed as

a supervised dose at the feeding centre and consumption of the remaining 6 placebo sachets

at home was also counted and supervised to minimize bias. For blinding, sachets were

marked by a specific number, for example 1 for daily, 3 for weekly and 5 for placebo sachets.

The dosage of elemental iron in the daily group was 12.5 mg/day based on a recommendation

from a UNICEF consultation group (30). The dosage in the weekly group was 30 mg in one

sachet. This amount of weekly supplementation was based on rough estimates because no

previous data existed for multinutrient Sprinkles supplementation on weekly basis. So, this

dosage was chosen considering safety. In excessive dosages iron is toxic, particularly to

young children (Zlotkin, personal communication). Also several other studies were conducted

on children to compare the efficacy of daily and weekly dose with same amount of iron (30

mg) for weekly supplementation (31, 32).

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Data collection

During the baseline assessment, a questionnaire was developed and pre-tested to collect

socio-economic, demographic, nutritional and health data for each child.

Supervision of feeding at local feeding centre

In each village, all selected children and one of their parents/caregivers (usually the mother)

were invited at a center point (selected in consultation with parents and other community

leaders) to receive one meal of weaning food cooked with locally available ingredients. Each

bowl of food was mixed with one serving of Sprinkles (one sachet), which was then mixed

into the food and fed to each child under the supervision of local BRAC Sastho Shebikas

(SS) and other village volunteers. One female worker from each village was selected as a

volunteer to assist the SS in operating these weekly feeding centers including food

preparation, distribution and provision of safe water. Mothers and caregivers decided the

composition of weaning food each week, depending on the availability of raw ingredients in

local markets. During feeding time, intake of the content of one sachet by each child was

monitored and ensured. The remaining 6 sachets of Sprinkles were delivered to the mothers

of each child - 12.5 mg iron containing sachets to the daily group and placebo sachets to the

weekly group packed in airtight polythene bags to be used over the rest of the week.

At the end of the trial, all participating subjects received an additional one-month supply of

Sprinkles containing 12.5 mg iron per sachet, irrespective of their haemoglobin

concentration. All children were dewormed at the end of the study as an incentive.

The SS visited each child once a week to find out the level of consumption and address any

problems encountered if any. The purpose of these visits was also to motivate and encourage

parents to continue the regular use of Sprinkles with daily cooked weaning foods.

Morbidity and compliance

At the feeding center, data on weekly recall of morbidity and compliance was collected.

Registered books were maintained to note down symptoms of disease, any side effects of

Sprinkles (diarrhoea, vomiting, abdominal cramps, restlessness, colour of stool), ease of use

and adherence of Sprinkles over the last 6 days. To evaluate compliance, the number of used

and unused sachets was counted. At the feeding center field workers provided nutrition

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education materials and verbal educational support to parents to maximize compliance to

intervention.

Anthropometry

Anthropometric measurements included weight and length recorded at baseline and post

intervention using a standard technique. Height (length) was measured by using a wooden

scale to the nearest 1 cm and weight was taken using the UNISCALE to the nearest 100 g. Z-

scores of height for age, weight for age, and weight for height were calculated using the

NCHS (National Centre for Health Statistics, Atlanta, USA) reference standard and

ANTROPAC software. Two field workers completed the measurements in duplicate using

the standard WHO technique (33).

Blood haemoglobin

Capillary blood samples for haemoglobin concentration at the time of screening and end of

supplementation were obtained by finger prick using an aseptic technique. Haemoglobin

concentrations were measured in the field with a portable HEMOCUE B-haemoglobin

photometer (HemoCue, Angelholm, Sweden) by trained technicians using standard technique

(34). Haemoglobin values obtained at screening were considered as baseline Hb values.

Other biochemical analyses

All children who met the haemoglobin criterion and whose parents consented to participate

were invited to a private laboratory at Kaliganj (within 5 km proximity from all study

villages). One ml venous blood sample was collected from each child by a trained laboratory

technician at baseline and after intervention. Serum was separated at field office by

centrifugation in a portable bench centrifuge (10 min at 4000 rpm) before storage at -20°C.

All serum samples were transported under dry ice to the Sprinkles research laboratory at the

Hospital for Sick Children, Toronto for analysis. Serum ferritin (sFt) was analyzed using

enzyme-linked immunabsorbent assay (ELISA). sFt <12 µg/L is an indicator of depleted iron

stores (35). Serum transferrin receptor (sTfR) was also assessed by ELISA with values >8.5

mg/L indicating iron deficiency (36). Baseline and end-of treatment ferritin and transferrin

samples from an individual subject were assayed on the same day to minimize interassay

variations (from result files).

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Post intervention survey

After the 8-week intervention period, a special survey was conducted (using a semi-

structured questionnaire) to ascertain the opinion of the mothers about the intervention

including the advantages and disadvantages encountered. Questions related to acceptability

covered issues such as, mothers’ perceived benefit from Sprinkles, interest to buy Sprinkles,

change of colour, taste or texture of child’s food due to mixing Sprinkles, and nutritional

knowledge and attitude of the mothers, etc.

Two FGDs were conducted with mothers/caregivers and one with field workers to find out

the acceptability of Sprinkles. The objective of the FGDs was to obtain an overall picture of

the implementation process of this new Sprinkles intervention that may not be evident by the

information recorded in the questionnaire alone.

Sample size and power

The primary outcome was the successful treatment of anaemia (the proportion of children

with haemoglobin concentration ≥110 g/L). We estimated that there would be at least an 8

g/L difference in mean haemoglobin between the daily and weekly group in treating anaemia

and the standard deviation (SD) of Hb would be 15 g/L within these groups. Using type 1

error, α = 0.05 and power = 0.80, the estimated sample size for the independent t-test was 50

subjects per group. Assuming a 20% dropout rate, we planned to recruit 70 children per

group. It was our expectation that around 60% of the children in Kaliganj would have Hb

value within our target range (70-110 g/L), therefore a total 263 children were screened to

obtain the needed number of subjects for the study (5).

Data processing and analysis

Data forms were manually checked for completeness and consistency before submission for

processing. The forms were then coded and the data were entered in SPSSWIN (version 11.0)

statistical package. Data were entered at the Kaliganj field office and data queries were

resolved, whenever possible, by rechecking original data forms or repeat visits if required.

Data were analyzed with SPSSWIN software. Chi-square test was done to see the

confounding effects of socioeconomic status and dietary history in the two groups. Paired t-

test was used to analyze the change in haemoglobin, ferritin, transferrin and anthropometric

measurements over the intervention time in the two groups. Difference between the groups in

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terms of haemoglobin, ferritin and transferrin levels as well as anthropometric measurements

at the beginning and at the end of the intervention and also factors affecting haemoglobin

values were assessed by ANOVA. Differences in the prevalence of anaemia (Hb≤110 g/L)

and iron deficiency (ferritin <12 µg/L) were compared between the groups using chi square

analysis. Analysis of ferritin and transferrin values was conducted on log-transformed data

because of their skewed frequency distribution. Median values were presented and

comparisons were made by Mann-Whitney U-test. Differences were considered significant at

p<0.05.

Community and institutional approval

Ethical clearance was obtained by the Research Ethics Board of the Hospital for Sick

Children in Toronto, Canada. Ethical clearance was also taken from the Bangladesh Medical

Research Council (BMRC). Meetings were held in all villages before starting the trial to

explain both its aims and procedures Sprinkles use and to gain community consent. The entry

of children into the study was achieved after full explanation to the parents and after taking

verbal and written consents from them.

RESULTS

Study subjects

Initially at the screening stage, a total of 263 potentially eligible young children were

identified from the selected 13 villages for the study. Out of these, 152 were found to have

haemoglobin concentration between 70 to 110 g/L (58%) and were therefore recruited. All

these eligible children were randomly allocated into two groups, either the daily Sprinkles

group (7 villages) or the weekly Sprinkles groups (6 villages). Thus, 79 children were

recruited in the daily group and 73 in the weekly group (total 152). Only four children did not

complete the supplementation programme. Consequently, mothers of 148 children attended

the final acceptability survey. A total of 137 children completed the final assessments

including anthropometric measurements and blood serum sampling. The main reason for

dropout was the refusal to undergo blood sampling once again. Data for Hb were available

for 144 children who completed the study. Figure 1 shows the profile of the trial.

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Figure 1: Trial profile of the Sprinkles efficacy study

Socio-demographic information

Demography

Baseline demographic characteristics of the children are presented in Table 1. The mean age

of children was 18 months. There was no significant difference in age between daily and

weekly groups at baseline. The proportion of boys and girls was almost same in the two

groups. Despite random allocation for intervention, there was a balance in the distribution of

13 Villages screened initially (n=263)

7 villages randomly assigned to daily 6 villages randomly assigned to weekly

Children with Hb 70-110g/l included in weekly group (n=73)

Children with Hb 70-110g/l included in daily group (n=79)

Lost to follow-up • Hb (n=7)

Father’s death = 1; Mothers sickness = 1; Migrated = 2; Rejected blood sampling = 3

• Serum (n=8) Father’s death = 1; Mothers sickness = 1; Migrated = 2; Rejected blood sampling = 4

• Anthropometry (n=9) Father’s death = 1; Mothers sickness = 1; Migrated = 2; Rejected measurement = 5

• Acceptability (n=3) Father’s death = 1; Mothers sickness = 1; Migrated = 1

Lost to follow-up • Hb (n=1)

Mentally retarded = 1; • Serum (n=7)

Mentally retarded = 1; Rejected blood sampling = 5; Hemolyzed=1

• Anthropometry (n=6) Mentally retarded = 1; Rejected measurement = 5

• Acceptability (n=1) Mentally retarded = 1;

Children excluded (n= 111) • Hb<70 g/L (n= 4) • Hb >110 g/L (n= 88) • Non consent (n= 18) • Chronic illness (n= 1)

Children recruited from 13 villages (n=152)

Completed study (n=76) Analysed for Hb (n=72) Analysed for sFt and sTfR (n=71) Analysed for anthropometry (n=70) Analysed for acceptability (n=76)

Completed study (n=72)Analysed for Hb (n=72) Analysed for sFt and sTfR (n=71) Analysed for anthropometry (n=70) Analysed for acceptability (n=76)

19

sex in the two intervention groups. Households in the two intervention groups did not differ

in family structure in terms of the number of under-5 five children and number of total

children.

Table 1. Baseline demographic characteristics of the study children

Sprinkles dose Characteristics Daily n=72

Weekly n=72

p-value

Sex of children, % Girls Boys

49.3 50.7

50 50

0.535

Age in month1 17.79±3.54 18.37±3.80 0.358 Number of under–5 children1 1.28±0.45 1.29±0.52 0.864 Number of children in household1 2.11±1.32 2.32±1.58 0.392

1=mean+SD

Educational level of parents

Educational level of the mothers and fathers of the children is shown in Table 2. Although the

children were randomly allocated to daily and weekly groups based on inclusion criteria,

there were significant differences in mother’s and father’s education and also in total length

of schooling between groups. The parents of children in the weekly group had a lower level

of education than those of children in the daily group. However, these indicators had no

significant association with the major study outcome, that is, Hb concentration at baseline.

Table 2. Educational level of parents of the study children

Sprinkles dose Characteristics Daily n=72

Weekly n=72

p-value

Mother’s education, % No schooling Non formal and primary education High school College or higher

15.3 27.8 50.0 6.9

36.1 18.1 41.7 4.2

0.035

Father’s education, % No. schooling Non formal and primary education High school College or higher

18.1 30.6 41.7 9.7

36.1 34.7 23.6 5.6

0.030

Total length of schooling in year1 Mother Father

6.06±3.42 5.97±3.77

4.57±3.94 4.29±3.91

0.017 0.010

1=mean+SD

20

Economic status

It was found that the children of the two groups did not differ in terms of economic status

(Table 3). Almost 40% households had cultivable land, with a size of 50 decimals in the daily

group and 39 decimals in the weekly group. The two groups also differed somewhat in terms

of the major source of household income. All households of children from both groups had

homestead land.

Table 3. Economical status of household of the study children

Sprinkles dose Characteristics Daily n=72

Weekly n=72

p-value

Household with cultivable land, % 40.3 37.5 0.432 Cultivable land size in dec1 49.83±109.02 38.78±74.21 0.479 Major source of household income, %

Manual labour Agriculture Business Service

31.9 20.8 25.0 22.2

30.6 27.8 27.8 13.9

0.527

1=mean+SD

Weaning practice

Tables 4 and 5 show detailed baseline information about weaning practice of the children.

Dietary characteristics did not differ significantly between the groups. The two groups were

similar in age when weaning food was introduced and in the frequency of weaning food

consumption (Table 4). However 26-30% mothers started giving weaning food as late as 7

months or more. No difference was also found in the food given to the children during the

proceeding 24 hours (Tables 5). Normally children of both groups took weaning food 3-4

times a day. Most of the children (90%) were still being breast-fed and breast milk was the

primary food for children. So, the highest frequency was found in this item. Rice was the

second as 99% children were given rice regularly. The intake of some food items like potato,

cow’s milk and fish during the proceeding 24 hours preceding the survey were significantly

different between the groups. However, haemoglobin values were not associated with these

foods at baseline.

21

Table 4. Baseline weaning practice related characteristics of children

Sprinkles Dose Characteristics Daily (n=72) Weekly (n=72)

p-value

Age of weaning in month % 4-5 months 6 months ≥ 7 months

23.6 45.8 30.6

20.8 52.8 26.4

0.706

Number of daily weaning meals usually taken1

2.97±0.89 3.38±0.70 0.003

1=mean+SD Table 5. Twenty four hour food intake of children at baseline

Sprinkles Dose Characteristics Daily (n=72) Weekly (n=72)

p-value

Frequency of food intake during last 24 hours1

3.94±1.40 3.83±0.98 0.492

Food item given in last 24 hours, % Breast Milk Rice Potato Wheat Green Vegetable Pulse Cow’s milk Fish Banana

93.1 97.2 61.1 47.2 44.4 43.1 31.9. 40.3 36.1

84.7 100 93.1 47.1 56.9 34.7 58.3 79.2 37.5

0.184 0.497 0.000 1.000 0.182 0.393 0.002 0.000 1.000

Frequency of food intake in last 24 hours1

Breast milk Rice Potato Wheat Green vegetable Pulse Cows milk Fish Banana

7.83±4.27 3.08±1.44 0.97±0.99 0.60±0.74 0.57±0.71 0.68±0.90 0.65±1.21 0.56±0.79 0.47±0.77

6.88±4.27 3.06±0.85 1.71±0.96 0.71±0.86 0.97±1.03 0.64±1.03 1.4±1.45 1.63±1.28 0.60±0.93

0.180 0.888 0.000 0.409 0.007 0.796 0.001 0.000 0.381

1=mean+SD

Efficacy of Sprinkles intervention

Anthropometric measurements

22

At the beginning of the study, length and weight of the children were the same in the two

groups (Table 6). Mean weight and height were 8 kg and 77 cm respectively. As expected of

these young growing children, the average weight and height in both groups increased

significantly during the study period. Anthropometric indicators of weight for age, height for

age and weight for height Z-scores also did not differ between groups at baseline and also at

the end of intervention, except for the weight for height Z-score which was lower in the

weekly than in the daily group (p=0.009). Significant decreases were observed in weight for

age, and height for age in the daily group and height for age and weight for height in the

weekly group. No treatment effect was found for weight for height in the daily group and

weight for age in the weekly group

Table 6. Anthropometric indicators at baseline and end of intervention

Sprinkles dose Characteristics Daily (n= 70 ) Weekly (n=67 )

p-Value across group

Weight in kg1 Baseline End of supplementation P value for difference

8.88±1.19 9.04±1.06

0.092

8.84±1.04 9.38±1.06

0.000

0.878 0.061

Length in cm1

Baseline End of supplementation P value for difference

76.43±3.91 77.70±3.83

0.000

76.74±3.90 77.95±3.99

0.000

0.644 0.710

Height-for- age Z score1

Baseline End of supplementation P value for difference Below -2SD (%) at baseline Below -2SD (%) after supplementation

-1.50±0.97 -1.74±0.90

0.000 30.0 34.3

-1.57±1.16 -1.79±1.12

0.000 37.3 43.3

0.684 0.782

0.234 0.183

Weight-for-height Z score1

Baseline End of supplementation P value for difference Below -2SD (%) at baseline Below -2SD (%) after supplementation

-1.31±1.12 -1.42±0.68

0.326 25.7 25.7

-1.41±0.94 -1.06±0.90

0.001 23.9 10.4

0.539 0.009

0.480 0.017

Weight-for-age Z score1 Baseline End of supplementation P value for difference Below -2SD (%) at baseline Below -2SD (%) after supplementation

-1.85±1.04 -2.06±1.80

0.012 48.6 54.3

-1.94±0.90 -1.85±0.90

0.217 47.8 41.8

0.575 0.147

0.530 0.098

1=mean+SD

23

Haemoglobin response

The distribution of haemoglobin concentration in the two Sprinkles supplemented groups

before and after intervention is shown in Table 7. At baseline, haemoglobin concentrations

were similar in the two intervention groups, with an overall mean value of 96.95±10.91 g/L.

In both supplemented groups, the haemoglobin concentration had increased significantly over

the baseline level (p=0.000), by 16 g/L in daily group and nearly 13 g/L in the weekly group.

The change in haemoglobin concentration was not significantly different between the groups.

At baseline all children were mildly to moderately anaemic. After 8 weeks of Sprinkles

intervention 54% (144 to 78) of the children advanced from the anaemic state to a non-

anaemic state (Hb > 110 g/L). The cure rate was the same in both the groups (Table 7).

Table 7. Efficacy of Sprinkles in improving haemoglobin status in two groups

Sprinkles dose Characteristics Daily (n=72) Weekly (n=72)

p-value across group

Mean + SD haemoglobin (g/l) Baseline End of supplementation Difference P value for difference

96.51±10.93 112.63±11.03

16.11 0.000

97.39±10.94

110.19±12.33 12.81 0.000

0.632 0.215 0.145

Percentage of anaemia (%) Baseline End of supplementation

100 45.8

100 45.8

1.000 1.000

Data were also analyzed to determine the percentage of children who responded positively to

the iron supplemention. A positive response is defined as an increase in haemoglobin of > 10

g/L during the intervention period. It was found that 46 (64%) children in the daily group and

42 (58%) children in the weekly group responded positively. The difference between the

intervention groups was statistically insignificant (p=0.608).

As numerous studies have shown that moderate anaemia (haemoglobin <100 g/L) is

associated with depressed mental (social and cognitive) and motor development in children,

which may not be reversible (6, 36, 37), it was of interest to compare the intervention effect

in this subgroup who had haemoglobin concentration <100 g/L at baseline. Results show that

a significant increase in blood haemoglobin level occurred in both the groups, but the

increase was somewhat higher in the daily group, compared to the weekly group. Moderate

anaemia cure rate was 83% in the daily group compared to 67% in the weekly group (Table

24

8). However, again the difference in intervention effect between the daily and the weekly

subgroups was not statistically significant (P=0.162).

Table 8. Efficacy of Sprinkles in improving haemoglobin status of children with haemoglobin concentration <100 g/L at baseline in the two groups

Sprinkles dose Characteristics Daily (n=36) Weekly (n=33)

p-value across group

Mean + SD haemoglobin (g/l) Baseline End of supplementation Difference P value for difference

87.86±8.71

110.72±11.21 22.86 0.000

87.52±8.25

105.82±12.55 18.30 0.000

0.866 0.091 0.167

Percentage of moderate anaemia (%) (Hb <100 g/L) Baseline End of supplementation

100 16.7

100 33.3

1.000 0.162

Ferritin response

Table 9 shows that sFt concentration (median) did not differ between the two groups at

baseline nor at the end of the intervention. There were significant increases in sFt in both the

groups after 8 weeks of intervention. The increase was significantly higher in the daily group

than in the weekly group.

Table 9. Response of serum ferritin to Sprinkles supplementation in the two groups

Sprinkles dose Characteristics Daily (n=71) Weekly (n=66)

p-value across group

Median ferritin (µg/L) Baseline End of supplementation Difference P value for difference

8.07±11.42 19.34±24.96

10.38 0.000

10.33±14.40 19.92±46.61

5.73 0.028

0.126 0.654 0.015

Iron deficient (%) (sFt <12 µg/L) Baseline End of supplementation

66.7 16.9

56.9 25.8

0.303 0.217

The proportion of children with biochemical iron depletion (ferritin <12 µg/L) also registered

marked decrease due to the intervention, more in the daily than in the weekly group (Table

9), but the difference was not significant.

25

Transferrin response

At baseline sTfR concentrations were similar in both intervention groups. From baseline to

the end of the study, sTfR decreased significantly in both groups but no difference was found

between the groups. The sharp decrease is also an indication of iron repletion in the body.

Table 10 shows the changes of sTfR level in the daily and weekly groups before and after

Sprinkles intervention.

Table 10. Response of sTfR to Sprinkles intervention in the two groups

Sprinkles dose Characteristics Daily (n=71) Weekly (n=66)

P-value across group

Median sTfR (mg/L) Baseline End of supplementation Difference P value for difference

9.09±4.03 6.31±1.67

-2.51 0.000

8.46±4.05 6.55±2.86

-1.80 0.000

0.607 0.432 0.160

Compliance

One week after starting the intervention and then every week through to the end of the study,

mothers were asked about the consumption of Sprinkles. Field workers also checked the

number of sachets of Sprinkles used. On the basis of these combined data collected over a

period of 8 weeks at the feeding center, it was found that 85% mothers never failed to come

to the feeding center every week to feed their children weaning food mixed with Sprinkles.

Seventy five percent of the children consumed the entire amount of Sprinkles mixed food at

the feeding center. Mothers or caregivers of 64% children reported using the full content of

the sachets at all meal times at home and 97% children ate all the food in the bowl. No

caregiver or mother gave the Sprinkles to a ‘non-study’ child or shared their food with other

children in the household (data not shown).

Acceptability and perceived benefits

Table 11. Likings of mothers of study children who accepted Sprinkles as an intervention

%

26

(n=148) Dislike 0 Like 40.5 Like very much 59.5

The mothers were asked how they liked the Sprinkles. No mother disliked the Sprinkles as an

intervention. (Table 11). In fact, 60% of the mothers liked it very much. Mothers were also

asked what benefits, if any, they perceived to have got out of this Sprinkle feeding. Most

mothers were happy telling that Sprinkles feeding increased the appetite, activeness and

playfulness of their babies. The overall health condition of the children also improved. There

was also an extra pleasure in seeing the children happily eating together in the feeding center.

Moreover, mothers thought that Sprinkles gave them the drive to give their babies

complementary food everyday (Table 12).

Table 12. Reasons of liking the intervention (multiple answers considered)

%

(n=148) Sprinkles were given free of cost 22 All eating together 29.7 Household visited by health worker 21.6 Increased children’s appetite 27.0 Increased activity and playfulness 27.0 Free treatment to the children at home 4.1 Received health education during group meeting 4.8

Mothers were asked if they had any problem using Sprinkles. Sixty-eight percent of the

mothers reported to have no problems in using Sprinkles. Those who reported of same

problem mentioned about the extra time and attention needed to feed Sprinkles regularly.

They sometimes felt tired of daily compulsory feeding. Other problems mentioned included

loose motion, vomiting and constipation in the children (Table 13).

Table 13. Problems associated with feeding weaning food mixed with Sprinkles (multiple answers considered)

%

(n=148) No problem 68.0 Required extra time and attention for feeding 14.3 Loose motion 7.5 Forgot /Felt tired to mix Sprinkles everyday 6.1 Vomiting 2.7 Constipation 0.7

27

Increased stool frequency and volume 1.4

Almost all mothers found Sprinkles useful for the improvement of their child’s health (Table

14). Some mothers even mentioned improvement of their child’s brain development and

learning capacity due to Sprinkles feeding.

Table 14. Perceived usefulness and benefit of Sprinkles intervention Usefulness %

(n=148) Was not useful 0.7 Somewhat useful 36.5 Highly useful 62.8 Other benefit General improvement of child’s health 100 Prevention of disease 23.0 Development of brain 28.3 Increase of appetite 21.0 Increase of child’s playfulness 7.8 Improvement of child’s learning capacity 6.8

Type of weaning food

Rice was the most common weaning food given to the study children; majority of the

mothers (43%) preferred rice as a good vehicle to mix Sprinkles. The next choices were

Khichuri (rice and lentil based weaning food) and Suzi (broken wheat granules) to add

Sprinkles for their children (Table 15).

Table 15. Appropriate food for mixing Sprinkles as weaning food %

(n=148) Rice 42.6 Khichuri 33.8 Suzi 16.9 Vegetables 3.4 Potato mash 0.7 Others 2.7

Mothers nutritional knowledge

Mothers were asked about their knowledge regarding iron and anaemia. Most mothers (86%)

had an idea about anaemia as they were informed about it in parents meeting and in feeding

centers. However, many of them could not recall the cause or prevention of anaemia. About

28

half of them could not tell about the source of iron. Only 6% of the mothers recognized

Sprinkles as source of iron to reduce anaemia (Table 16).

Table 16. Mother’s knowledge on anaemia

% (n=148)

Familiar with anaemia (%) 85.8 Don’t know the cause of anaemia (%) 18.2 Don’t know the prevention anaemia (%) 20.3 Don’t know the source of iron 45.3 Reported Sprinkles as a source of iron 6.1

Time of Sprinkles feeding

Morning time was preferred by majority mothers (61%) for feeding the Sprinkles-added

weaning food. About one-fifth of the mothers fed the children at noon time (Table 17).

Table 17. Timing of feeding Sprinkles-added weaning food

% (n=148)

Morning 61.2 Mid of morning and noon 8.2 Noon 19.7 Afternoon 2.7 Night 8.2

Changes of colour, odour or taste

No mother reported unpleasant odorus in Sprinkles mixed food, but 71% mothers said that

Sprinkles brought about a mild change in the colour of food from white to brown. The iron of

Sprinkles could be responsible for the change in color of white rice as most of the mothers

added Sprinkles in rice. Indeed, no change was found when Sprinkles was added to yellow

Khichuri or any other colored food (Table 18). Most mothers (over 80%) reported no change

in the taste of the food.

Table 18. Effect of Sprinkles on color, odor and taste of weaning food

% (n=148)

Change of smell No change Mild change

90.5 9.5

Change of color No change Mild change Strong change

27.7 70.9 1.4

Change of taste

29

No change Mild change Strong change

81.8 16.9 1.4

Willingness to pay for the Sprinkles

When asked whether they would continue feeding the Sprinkles by buying from the market,

more than half of the mothers replied in the affirmative and another 42% said they would

probably buy Sprinkles if they were available in the market (Table 19). The major reasons

indicated for buying were: they found Sprinkles beneficial for their child’s health and it was a

good source of nutrition. They said they were ready to pay 2-3 taka for each sachet.

Table 19. Willingness of mothers to pay for Sprinkles

Willingness %

(n=148) Definitely would buy 54.7 Probably would buy 42.1 Would not buy 4.1 Reasons for continued use (multiple answers considered)

To improve babies health 55.4 Sprinkles are high in nutrition 40.6 Sprinkles increase appetite 14.2 Sprinkles increase brain/intelligence 11.5 Sprinkles make children playful 7.5 Sprinkles reduce morbidity 4.7 Sprinkles increase growth 1.4 Ready to pay how much (Taka) per sachet (multiple answers considered)

Mean 2.8 Standard deviation ±1.82 Mode 2.00 Minimum 0.25 Maximum 10.00

When mothers were asked during FGDs to give a name of Sprinkles, the commonly cited

name that came out from them was “Pusti” and “Pusti gura” (“nutrition” and “nutrition

powder”). They considered Sprinkles as a “vitamin” which when added with weaning food

would increase the strength of their children (from FGDs).

Side effects of Sprinkles

30

Mothers were asked every week in the feeding center about any side effects that were seen in

the children during the last seven days due to feeding of Sprinkles. Change in stool colour

was the major complaint (80-90%). The next was diarrhea which was more common in the

weekly (32%) versus the daily (16%) group. Other complications like vomiting or stomach

cramps were rare (Table 20). The reason for the significantly higher incidence of diarrhea in

the weekly group needs to be investigated, but it is possible that too much iron at a time (30

mg) could cause stomach irritation leading to watery stool. Increased appetite was also

mentioned by most mothers (85-90%) as a side effect, but it was considered a ‘good’ side

effect.

Table 20. Percentage of mothers who reported side effects related to Sprinkles supplementation during 8 weeks of the study period

Side effect Sprinkles dose Daily (n=72) Weekly (n=72)

p-value across group

Diarrhea 15.5 31.9 0.030 Vomiting 8.5 9.7 1.000 Stomach cramp 7.0 5.6 0.745 Increase appetite 84.5 90.3 0.325 Change of stool color 90.1 80.6 0.155

DISCUSSION

The present study was carried out in 13 villages of Gazipur district, the socio, agro-

demographic and economic characteristics of which are comparable to the rest of the plains

of the country. Also, the study sample of 12-24 months old children showed an anaemia

prevalence profile (152 anaemic out of total 263, i.e. 58%), which was very close to the 55%

figure obtained by HKI in rural Bangladesh in 2001 in this age group (4), the national

average figure being 58% (5). The present experimental setting may therefore be considered

as representative of the under-2 child population in the vast plains of rural Bangladesh. It has

been already established from community-based studies in several countries that iron

Sprinkles is efficacious in curing anaemia in infants and young children (17, 19). The present

research was aimed at investigating whether a daily dose or a weekly dose of the Sprinkles

would be more suitable from operational and programmatic point of view. A dose of 12.5 mg

elemental iron was used in the daily regimen while the weekly dose was 30 mg. This is the

first kind of research ever conducted to compare the efficacy of microencapsulated iron in

curing anaemia in a rural community set up in Bangladesh.

31

The daily-weekly dose issue

Eligible study subjects were randomly allocated, by village, into two groups: daily and

weekly supplementation. Examination of socioeconomic and demographic characteristics of

the two groups showed little or no difference, indicating that whatever differences were

observed in the response in the two groups were due to the two different supplementation

regimens.

Use of daily or weekly Sprinkles resulted in similar increases in haemoglobin concentration

and identical cure rates of anaemia (54%). This rate of treatment for anaemia in the current

study was somewhat lower than that found in another study with Sprinkles (69%) (19). After

8 weeks of intervention, 46% of children still remained anaemic. Several factors may have

influenced the observed cure rate of anaemia. For example, the study began at the end of the

rainy season (October) and was completed by the end of winter (December). Common cold

and ARI was likely to have been more severe during this cold season, possibly resulting in

increased infection. Such infection might interfere with the utilization of absorbed iron.

Existence of non-iron deficiency anaemia could be another reason.

Intestinal parasite infestation with roundworm and whipworm is common among children in

Bangladesh (38). Numerous studies dating back to 1920 have found a significant correlation

between haemoglobin levels and worm load and/or faecal egg count (39,40). This may be

another explanation for the non-response of children. In our study, the children were not

dewormed prior to the Sprinkles intervention. Our results, therefore, reflect the true efficacy

of Sprinkles in curing anaemia, as opposed to some studies in which children were dewormed

first, e.g. the 2-5 years old Indonesian children (27).

Although we did not include a placebo control group due to ethical reasons, it is unlikely that

the observed improvement in anaemia would have occurred had no treatment been provided.

In Bangladesh, weaning practice is very poor, with typical cereal based food like plain rice,

suzi, which has poor iron bioavailibility. So, it can be predicted that children with anaemia

would likely have remained anaemic if the intervention was not provided.

32

We hypothesized that haemoglobin response would be greater in children receiving daily

supplementation of 12.5 mg elemental iron as compared to those receiving weekly

supplementation of 30 mg elemental iron. Results from the current study do not support this

hypothesis. However, response of ferittin was significantly higher in the daily than in the

weekly group.

There has been a debate during the past 10 years regarding the desirability of intermittent iron

supplementation compared with daily iron supplements (41). The main argument against

daily supplementation is its low compliance and the need to improve the coverage of at-risk

populations with limited financial resources. The theory behind intermittent oral iron

supplementation was based on the “mucosal block” of iron absorption (42). This theory

argues that mucosal enterocytes down-regulate iron absorption in response to daily exposure

to a high intake of iron. There is an increase in mucosal ferritin synthesis, an increase in the

proportion of enterocyte iron that is stored in the cell, and a decrease in the transfer of iron to

transferrin in the vascular pool (41). In the human, the gut mucosal turnover is between five

and six days, so that iron administration given weekly should be more efficient than iron

given daily or every three days (43). Intermittent iron dosing to conform to the cycle of

intestinal mucosa turnover has been suggested as a method to improve the efficiency of

uptake of therapeutic doses of iron (44). However, this theory remains to be tested for infants

and young children.

For large-scale supplementation programs, the advantages of weekly, or intermittent,

supplementation would be reduced costs and possibly better compliance. Several community-

based studies in different population groups have shown that weekly dosing successfully

reduces anaemia and is as effective as daily administration in pre-school children (27),

adolescent girls (45), and non pregnant (46, 47) and pregnant women (48). Studies in China,

Bolivia, Indonesia and Vietnam also did not show marked differences in haemoglobin

response to weekly or daily iron supplementation, similar to the present results. Also, a

weekly supplementation of 30 mg iron resulted in significant increases in haemoglobin

among 2-5 years old (27) and 6-24 months old children (28). A study from China also

investigated young children and the potential effect of intermittent compared with daily iron

supplements (43). The results of these brief therapeutic trials were that daily and twice

weekly or once weekly iron supplements worked equally well regardless of the severity of

anaemia.

33

Although a close comparison is not feasible between the present study and those described

above due to differences in the method of iron distribution, duration of supplementation

period, initial haemoglobin level and environmental setting, the findings from these studies

agree on the similar efficacy of an intermittent iron supplementation to that of a daily iron

supplementation. Though the present study was conducted with Sprinkles, results support the

findings of these studies.

All children of the present study were anaemic at the beginning of the study. After 8 weeks of

iron supplementation, 54% became non-anaemic, regardless of the dose of intervention. This

figure is less compared to 86.2% children of daily and 82.7% of weekly supplementation

improving to the non-anaemic condition in a study conducted in Bolivia with weekly

supplementation and 5 days per week supplementation over a period of 16 weeks (49).

Sprinkles were added to fiber-based weaning food, so iron absorption was not the same as

from iron syrup. An iron absorption study conducted in Ghana showed mean iron absorption

from Sprinkles to be about 5% in non-anaemic infants and about 9% in anaemic infants (50).

At the end of the 8 weeks of treatment with iron, serum ferritin concentration (an indirect

measure of iron stores) had increased significantly in both groups. Generally the increases we

observed in serum ferritin were similar to the increases in anaemic Indonesian children who

received twice weekly supplementation of 30 mg Fe for 2 months (27). These results suggest

that more iron was absorbed than was needed for immediate erythropoiesis (17). However,

the changes in ferritin concentrations from baseline to the end of the study were greater in the

daily group (11 µg/L) than in the weekly group (5.7 µg/L). However, the average ferritin

concentration reached by subjects supplemented weekly after 2 weeks can be considered

quite satisfactory.

Viteri et al (51) and Liu et al. (43) also reported higher serum ferritin increases for the daily

dose than for the weekly dose. Some other previous studies also showed that serum ferritin

levels of children given daily iron increased significantly more than those given weekly

supplementation (52, 53).

34

Daily supplementation would seem to be more efficient than weekly supplementation

because the increases in haemoglobin and ferritin were larger in the group supplemented

daily than in the group supplemented weekly. However, iron absorption may depend on

physiological needs (54), and the changes in haemoglobin and ferrtin caused by the

supplementation were related to the initial haemoglobin concentration. After correction for

the confounding influence of initial haemoglobin concentration, no statistically significant

differences in treatment effects existed between groups (27).

The extent of haemoglobin increase was higher among more anaemic children (Hb <100 g/L)

when they took the daily dose than the weekly, similar to the study of Berger et al (49) and

Liu et al (55). Results from an iron absorption study demonstrated that infants regulate iron

absorption according to their iron needs; thus, anaemic children absorb more iron than non-

anaemic children because of their higher need for iron (50). The findings of Cook & Reddy

suggest that absorption efficiency of the daily dose becomes better than the weekly dose as

iron status declines (24).

Anthropometry The anthropometric assessment of children at baseline indicated high prevalence of stunting

(33.6%), wasting (24.8%) and underweight (48.2%), as is typical of a population

experiencing chronic undernutrition in Bangladesh (56). In our study, supplementation led to

a significant increase in weight gain between groups. Previous studies have shown that iron

supplementation is associated with increaseed growth (57, 58).

Our results show a significant negative association between initial age and final weight for

age (underweight) and weight for height (stunting) Z-score in daily group and stunting Z-

score in weekly group. In one study, a decrease in height for age Z score was found from

baseline to the final measurement (17). Similarly decreases in mean weight-for-age and

weight-for-height Z-score in children between 6 and 24 months of age has been reported

elsewhere (59-61). It is likely that with increasing age, children are not meeting dietary

energy and nutrient requirements (62). These observations are consistent with the conclusions

of Brown et al. (63) that typical cereal-based complementary foods in the developing world

are inadequate sources of nutrition for breast-fed infants in the first 2 years of life.

35

Compliance

Our findings suggest important policy and programme implications for the treatment of

anaemia. Although we did not measure compliance with the different dosing regimens

directly, our data suggest that compliance was sufficient to treat anaemia and increase iron

stores. Compliance with Sprinkles was higher in the present study (75% never missed

Sprinkles mixed food) compared to another Sprinkles study in Ghana (67%) (17).

From the results of compliance, it is expected that Sprinkles would be widely accepted and

preferred as a means of iron supplementation if they are promoted in the population.

Sprinkles added to food do not change the colour or texture of the food. The taste of food is

also not affected by the addition of Sprinkles. A single-dose sachet is simple to use as

reported by mothers. Similar findings were described in the study of Zlotkin et al. conducted

in Ghana to treat anaemia through Sprinkles (17).

One of the reasons for the high compliance observed is due to mothers’ perceived increase in

the appetite of their children, in agreement with the observation of previous studies (64).

Other reasons could be the perceived improvement of general health conditions, activeness

and playfulness of the children.

Side effects

One side effect reported by the mothers was diarrhoea, especially in the weekly group. The

other side effect was black stool, but vomiting and stomach cramps were rare. Both Cook

(65) and Viteri (66) suggest that failure of most supplementation programmes lied mostly in

non-compliance. Gastrointestinal side-effects are often touted as a reason that many stop

taking iron supplementation (21). A study by Ridwan et al. (48) found no significant

difference in compliance between daily and weekly doses. Still yet, Liu et al (55) found that

children taking weekly doses of iron had fewer side effects than those taking daily doses.

Viteri et al. (51) found that the rate of attrition was twice as high for the daily than the weekly

dose, mainly due to side-effects. In our study, the overall side-effects of Sprinkles were

negligible between the groups.

36

Other benefits

One additional benefit of the Sprinkles concept is its involvement in infant complementary

food practices. In many developing countries, infant weaning practices are poor, such as

prolonged exclusive breastfeeding and delayed introduction of semi-solid foods. During the

present study, in an effort to encourage mothers to feed their children weaning food and to

demonstrate correct Sprinkles use, mothers and their children were allowed to meet once

weekly at a local feeding centre. A group of women health workers prepared a communal

meal of ‘khichuri’, a mixture of rice, lentil, vegetables and spices. Mothers were given

khichuri in small bowls and were instructed to mix Sprinkles with the khichuri and then feed

it to their children. This group sharing of food not only showed mothers how to make

nutritious complementary food, but also helped develop healthy infant weaning practices.

Therefore, Sprinkles was not only a promising and sustainable way of delivering iron and

micronutrients, it also contributed to the promotion of more positive infant weaning

practices.

About 10 years ago, the World Health Organization (WHO) (21) published recommendations

on the design of large-scale iron supplementation programms with the aim of reducing the

prevalence of iron deficiency anaemia in populations of developing countries. A decade later,

however, little has changed in the situation of iron deficiency anaemia.

WHO/UNICEF recommends that universal iron supplementation should be implemented for

children six months through five years of age, in populations where the prevalence of

anaemia is over 30% (67). In this recommendation, no specific information was provided

about when and for how long supplements should be administered.

New approaches need to be developed that address the needs of at-risk groups that improve

compliance, that have fewer side effects, and that simplify the logistics of either curing or

preventing iron deficiency (68). From a practical perspective, the option of using Sprinkles,

therefore, may improve compliance with treatment and thus the success rate for the treatment

of anaemia. The results of the present study indicate that, in a controlled setting, a weekly

micronutrient Sprinkles supplement is as efficacious as daily dosing in curing anaemia.

37

Weekly supplementation is not only more efficient but also far less demanding of

organizational and administrative efforts. Also, the reduced number of sachets allow for an

increase in the coverage of the programme.

Moreover, less-frequent supplementation schedules may have other positive effects on the

programmes (27). It is evident that weekly iron supplementation is better than daily

supplementation in two aspects: iron absorption is more efficient and has less side-effects

compared to the daily dose. Based on serum ferritin distribution patterns, intermittent iron

supplementation avoids temporary iron overload that is seen with daily iron supplemented

children (43). Furthermore, it is likely that if supplements were to be taken once a week,

compliance would be better. Also, the cost involved in supplementation programmes would

be reduced if supplementation could be taken less frequently. This would reduce costs to one-

seventh of the daily administration. Another positive effect of less-frequent supplementation

would be the less adverse interactive effect of large amounts of iron on the absorption of

other micronutrients, such as zinc (69). Therefore even if the absolute increase in

hematological indices in individuals was slightly higher with daily supplementation, the

positive effects in public health terms at the population level may be larger with less frequent

supplementation.

Supplementing such young infants with iron would be beneficial not only because it would

prevent anaemia, but also it would prevent mental retardation and augment motor

development. The primary objective of long-term weekly supplementation in young children

should be to prevent iron deficiency. One additional benefit of this strategy would be to build

up adequate iron reserves which will ensure protection from iron deficiency later in life,

particularly during adolescence (49). The study of Liu et al (55) shows that the weekly dose

is safe and tolerated by children.

LIMITATIONS

Results described in this report were obtained from a small, carefully supervised efficacy

trial. Testing for the efficacy in a real life setting in the community would be more

informative. Another limitation of this study was that the true effect of Sprinkles on

haemoglobin concentration could not be assessed directly; due to ethical concerns, the study

design did not permit inclusion of a placebo group of anaemic infants who did not receive

iron.

38

CONCLUSION

1. The results of the present study suggest that Sprinkles with iron and other essential

micronutrients such as zinc and vitamin A could play an important role in reducing

anaemia in under-2 children – the most difficult population group to reach with

nutritional supplements.

2. Although the study was conducted in a controlled supervised setting, it is expected

that Sprinkles would be equally efficacious as a public health intervention, if the

community in general and the mothers/caregivers are aware of its importance in

maintaining good health and well-being of children.

3. Weekly dosing was found to be as efficacious as the daily dosing in most of the

responses, including, most importantly, blood haemoglobin. From an operational

standpoint the weekly programme would therefore be most preferred.

4. Mothers did not prefer to have any strict instructions on how to use Sprinkles.

Instead, they preferred flexibility in using Sprinkles rather than a medical model. This

is because mothers felt psychologically stress when a dose was missed in the daily

dose regimen. So weekly supplementation of Sprinkles may be easier to administer

for them, as they could select any day of the week to feed the Sprinkles. Weekly

Sprinkles supplementation is also cheaper and offers opportunities for wider

coverage.

5. The treatment had no side-effects and there was little chance of overload.

6. Once the iron status of the children is restored, chances are favourable that it will

remain adequate for a prolonged period of time.

7. Compliance was also high. The Sprinkles intervention was well accepted by the

mothers and/or caregivers as well as by the community.

8. Sprinkles could promote a healthy weaning practice, which otherwise is a neglected

agenda in rural Bangladesh.

9. Findings of the present study could lead to revisions of iron supplementation

strategies through Sprinkles for prevention and control of iron deficiency and anaemia

among the young children globally.

39

RECOMMENDATIONS

On the basis of the results from this study the following recommendations are made for

further research:

1. Study should be carried out to see why about 40% under-2 children do not improve

from anaemic to non-anaemic state after 8 weeks of Sprinkles intervention and to find

a suitable cost-effective strategy to make Sprinkles intervention more far reaching.

2. The efficacy of intermittent or weekly Sprinkles supplementation compared with iron

tablet in older anaemic subjects, such as pregnant women should be studied.

3. The optimal model of dosing, use and distribution of Sprinkles supplement for

different age groups should be investigated.

4. The current intervention was aimed at children aged 12-23 months; however, the

population group most at risk of iron deficiency is the infants aged 6-12 months. An

optimal supplementation regimen for infants, therefore, needs to be worked out.

5. Further studies are needed to test the effectiveness of Sprinkles supplementation for

the treatment and prevention of anaemia.

6. The effectiveness of Sprinkles supplementation on a weekly basis at the community

level needs to be investigated.

7. Appropriate measure should be taken to scale up the Sprinkles intervention in

Bangladesh to reduce existing high rates of IDA among infant and young children.

8. While Sprinkles should be available to a general population, efforts need to be made

to cover the poorest through BRAC’s special programmes, e.g. TUP Program.

40

REFERENCES

1. Conference International sur la Nutrition (CIN) OMS-FAO; Rapport final de la

Conferences, 1992

2. HKI/IPHN. The Nutritional Surveillance Project in Bangladesh in 1999. Towards the

goals of the 1990 worlds summit for children, 1999

3. World Health Organization, Malnutrition. The global picture, Geneva: World Health

Organization, 2000

4. HKI/IPHN. Iron deficiency anaemia throughout the life cycle in rural Bangladesh.

Dhaka: Helen Keller International, 1999.

5. BBS/BRAC/UNICEF. National Anaemia Survey in urban area and Chittagong hill

tracts. 2003; Data is not published yet.

6. Lozoff B, Jimenez MD, Hagen J, Mollen E, Wolf AW. Poorer behavioral and

developmental outcome more than 10 years after treatment for iron deficiency in

infancy. Pediatrics 2000 Apr; 105 (4):51e-51

7. Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on

cognitive development in children. J Nutr 2001 Feb; 131 (2S-2): 649S-668S

8. Pollitt E. The developmental and probabilistic nature of the functional consequences

of iron-deficiency anaemia in children. J Nutr 2001 Feb; 131 (2S-2): 669S-675S.

9. Thomas D, Frankenberg E. Health, nutrition and prosperity: a microeconomic

perspective. Bulletin of the World Health Organization 2002; 80: 106-113.

10. Ross J and Horton S. Economic Consequences of Iron Deficiency. Ottawa: The

Micronutrient Initiative, 1998.

11. Stoltzfus RJ, Dreyfuss ML. Guidelines for the use of iron supplements to prevent and

treat iron deficiency anaemia. Washington DC: INACG/WHO/UNICEF, 1997.

12. Hercberg S. La carance en fer en nutrition humaine. Editions Medicales

Internationales et Documentation, Lavoiser, France, 1988. 2003 p

13. Horne E. iron folate supplements during pregnancy, supplementing everyone treats

those at risk and is cost effective, Br. Med. J. 1988; 297 (Clin. Res. Ed.):1325-1327

14. World Health Organization. Iron deficiency anaemia assessment, prevention and

control: A guide to programme managers 2001; Geneva:8

15. Nestel P, Alnwick D. Iron/multi-micronutrient supplements for young children:

summary and conclusions of a consultation held at UNICEF, Copenhagen, Denmark,

August 1996. Washington D.C.: OMNI/USAID 1996.

41

16. Schauer C, Zlotkin S. Home fortification with micronutrient Sprinkles – a new

approach for the prevention and treatment of nutritional anaemias. Paediatr Child

Health 2003; 8:87-90.

17. Zlotkin S, Arthur P, antwi KY, Yeung G. Treatment of anaemia with

microencapsulated ferrous fumarate plus ascorbic acid supplied as Sprinkles to

complementary (weaning) foods. Am J Clin Nutr 2001; 74:791-795.

18. Zlotkin S, Antwi KY, Schauer C, Yeung G. Use of microencapsulated iron (II)

fumarate Sprinkles to prevent recurrence of anaemia in infants and young children at

high risk. Bulletin of the World Health Organization 2003; 81 (2):108-115.

19. Zlotkin S, Arthur P, Schauer C, Antwi KY, Yeung G, Piekarz. Home-fortification

with iron and zinc Sprinkles alone successfully treats anaemia in infants and young

children. Journal of Nutrition 2003; 133: 1075-1080.

20. The Sprinkles research group at the Hospital for Sick Children (personal

communication)

21. DeMaeyer E. Preventing and controlling iron deficiency anaemia through primary

health care. A guide to health administrators and programme managers. Geneva: the

World Health Organization 1989.

22. ACC/SCN. Controlling iron deficiency: Geneva: ACC/SCN 1991.

23. Viteri F, Liu X, Tolomei K, Martin A. True absorption and retention of supplemental

iron is more efficient when iron is administered every three hours rater than daily to

iron normal and iron deficient rats. J Nutr 1995; 125: 82-91.

24. Cook J, Reddy M. Efficacy of weekly compared with daily iron supplementation. Am

J Clin Nutr 1995; 62: 117-120.

25. Beaton GH, McCabe GP. Efficacy of intermittent iron supplementation in the control

of iron deficiency anaemia in developing countries: an analysis of experience. Ottawa:

The Micronutrient Initiative 1999.

26. Hussaini T, Unpublished, Citation in the writings of Beaton and McCabe 1999.

27. Schultink W, Gross R, Gliwitzki M, Karyadi D, Matulessi P. Effect of daily vs twice

weekly iron supplementation in Indonesian preschool children with low iron status.

Am J Clin Nutr 1995; 61: 111-115.

28. Thu B, Schultink W, Dillon D, Gross R, Leswara ND, Khoi HH. Effect of daily and

weekly micronutrient supplementation on micronutrient deficiencies and growth in

young Vietnamese children. Am J Clin Nutr 1999; 69: 80-86.

42

29. INACG/WHO/UNICEF. Guidelines for the use of iron supplements to prevent and

treat iron deficiency anaemia. Washington DC: USAID and ILSI 1998.

30. Nestel P, Anwick D, editors. Iron/multi-micronutrient supplements for young

children. Summery and conclusion of a consultation held at UNICEF Copenhagen,

Denmark, 1996 August 19-20. Washington DC: International Life Science Institute

1997.

31. Pulpi L. Schultink W, Achadi E, Gross R. Effective community intervention to

improve haemoglobin status in preschoolers using once-weekly iron supplementation.

Am J Clin Nutr 1997; 65:1057-61

32. World Health Organization. Measuring changes in nutritional status. Geneva: WHO

1993.

33. Chen, A.R. & Seidi-Friedman, J. HemoCue system for haemoglobin measurement.

Evaluation in anaemic and nonanaemic children. Am. J. Clin. Path 1988; 90: 302-305.

34. Institute of Medicine. Nutrition during pregnancy. Washington DC: National

Academy Press 1990:272-298.

35. Flowers C, J, Skikne B, Covell A, Cook J. The clinical measurement of serum

transferring receptor. J Lab Clin Med 1989; 114:368-377.

36. Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on

cognitive development in children. Journal of Nutrition 2001; 131:649S-68S.

37. Lazoff B, Brittenham GM, Wolf AW, McClish DK, Kuhnert PM, Jimenez E et al.

Iron deficiency anaemia and iron therapy effects on infant developmental test

performance. Padiatrics 1987; 79:981-95

38. Mascie-Taylor CG, Alam M, Montanari RM, Karim R, Ahmed T, Karim E, Akhter S.

A study of the cost effectiveness of selective health intervention for the control of

intestinal parasites in rural Bangladesh. J Parasitol 1999; 85(1):6-11.

39. Roche. M. Layrisse M. The nature and cause of ‘hook worm anaemia”. Am J Trop

Med Hyg 1966; 15:1031-100

40. Layrisse M, Roche M. The relationship between anaemia and hookworm infection:

results of surveys of rural Venezuelan population. Am J Hyg 1964; 79:279-301

41. John L Bread. Weekly iron intervention: the cause for intermittent for iron

supplementation. Am J Clin Nutr 1998; 68:209-12

42. Brwon EG Jr, Dubach R, Moore CV. Studies on iron transportation and metabolism.

IX. Critical analysis of mucosal block by large doses of iron in human subjects. J Lab

Clin Med 1958; 52:335-55

43

43. Liu XN, Liu PY. The effectiveness of weekly iron supplementation regimen in

improving the iron status of Chinese children and pregnant women. Biomedical and

Environmental Sciences 1996; 9:341-347

44. Solomons, N. W. Weekly versus daily oral iron administration: are we asking the

right questions? Nutr. Rev 1995; 53:326-327.

45. Ketalhut A, Schultink W, Angels I, Gross R, Pietrzik K. The effects of weekly iron

supplementation with folic acid, vitamin A, vitamin C on iron status of Indonesian

adolescents. Asia Pacific J Clin Nutr 1996; 5(3):181-5

46. Tee ES, Cavalli-Sforza LT, Kandiah M, Narimah A, Chong SM, Satgunasingan N,

Kamarudin L. A study of the effectiveness of iron supplementation in adolescent

secondary school girls in Malaysia: preliminary findings. In: Towards achieving

nutritional goals of the Asian region. Abstract of the 7th Asian Congress of Nutrition.

Beijing: Chinese Nutrition Society 1995: 127.

47. Gross R, Schultink W, Juliawati. Treatment of anaemia with weekly iron

supplementation (letter). Lancet 1994; 344:821

48. Ridwan E, Schultink WJ, Dillon D, Gross R. Effects of weekly supplementation of

Indonesian pregnant women similar are similar to those of daily supplementation. Am

J Clin Nutr 1996; 63:884-90

49. J Berger, VM Aguayo, W Tellez, C Lujan, P Traissac, JL San Miguel. Weekly iron

supplementation is as effective as 5 day per week iron supplementation in Bolivian

school children living at high altitude. European Journal of Clinical Nutrition 1997;

51:381-386.

50. Zlotkin S. Sprinkles combating iron deficiency anaemia in infants and young children.

A status report, The Hospital for Sick Children: Iron absorption study in Ghana,

results presented at the Experimental Biology meeting in April 2003; Data is not

published yet.

51. Viteri F, Ali F, Tujague J. Weekly iron supplementation of fertile-age women

achieves a progressive increment in serum ferritin. FASEB J 1996; 10:1680

52. R. Sungthong, L. Mo-suwan, V. Chongsuvivatwong, et al. Once weekly is superior to

daily iron supplementation on height gain but not on hematological improvement

among school children in Thailand. J. Nutr 2002 Mar; 132:418-422 (Nutrition

Research Newsletter, 2002 May; website: http://www.findarticles.com/

cf_dls/m0887/5_21/86826649/p2/article.jhtml)

44

53. Angeles-Agdeppa I, Schultink W, Sastroamidjojo S, Gross R, Karyadi D. Weekly

micronutrient supplementation to build iron stores in female Indonesian adolescents.

Am J Clin Nutr 1997; 66:177-83

54. Whittaker PG, Lind T. Iron absorption during normal human pregnancy: a study using

stable isotopes. Br J Nutr 1991 65:457-63

55. Liu XN, Kang J, Zhao L, Viteri F. Intermittent iron supplementation in Chinese

preschool children is efficient and safe. Food Nutr Bull 1995 16:139-46

56. BBS. Child Nutrition Survey of Bangladesh, 2000. Bangladesh Bureau of Statistics,

Planning Division, Ministry of Planning, Dhaka 2002.

57. Chwang L, Soemnatri AG & Pollitte E. Iron supplementation and physical growth of

rural Indonesian children. Am J Clin Nutr 1988; 47:496-501

58. Lantham Mc, Stephenson LS, Kinoti SN, Zaman SM, Kurt KM. Improvements in

growth following iron supplementation in young Kenyan school children. Nutrition

1990 6:159-165.

59. Lartry A, Manu A, Brown K H, Peerson J M, Dewey K G. Predictors of growth from

1 to 18 months among breast-fed Ghanaian infants. Eur J Clin Nutr 2000; 54:41-49

60. Allen L H. Nutritional influences on linear growth: a general review Eur J Clin Nutr

1994; 48:S75-S89

61. Idjradinate P, Watkins W, Pollitte E. Adverse effect of iron supplementation on

weight gain of iron-replete young children. Lancet 1994; 343:1252-1254

62. Neumann C G, Harrison G G. Onset and evolution of stunting in infants and children.

Examples from the Human Nutrition Collaborative Research Support Program. Kenya

and Egypt studies. Eur J Clin Nutr 1994; 48:S90-S120

63. Brown K, Bewey K, Allen L. Complementary feeding of young children in

developing countries: a review of current scientific knowledge. WHO/NUT/98.1.

WHO Geneva, Switzerland 1998.

64. Lawless J W, Latham MC, Stephenson LS, Kinoti SN, Perter. Iron supplementation

improves appetite and growth in anaemic Kenyan primary school children. J Nutr

1994; 124:645-654

65. Cook J. Reply to FE Viteri. Letters to the Editor. Am J Clin Nutr 1996; 63: 610-4

66. Viteri F. Weekly compared with daily iron supplementation. Letter to the Editor. Am J

Clin Nutr 1996; 63:610-4

45

67. UNICEF/WHO. World Summit for children. Strategic approach to operationalizing

selected end-decade goals: reduction of iron deficiency anaemia. Geneva: World

Health Organization 1994.

68. ACC/SCN. Controlling iron deficiency. A report based on an ACC/SCN workshop.

In: Gillespie S, Kenvany J, Mason J, eds. Geneva: United Nations Administrative

Committee on Coordination Subcommittee on Nutrition (State of the art paper no.9)

1991.

69. Solomons NW. Competitive interaction of iron and zinc in the diet: consequences for

human nutrition. J Nutr 1968; 116:927-35