British Journal of Nutrition (2020), 123, 780–791 doi:10.

1017/S0007114519003386
© The Authors 2020. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Micronutrient-fortified infant cereal improves Hb status and reduces

iron-deficiency anaemia in Indian infants: an effectiveness study

Shally Awasthi1, Narayan U. Reddy2, Monjori Mitra3, Shweta Singh4, Sanjeev Ganguly5, Ivana Jankovic6,
Dominik Grathwohl7, Colin I. Cercamondi6* and Apurba Ghosh3
1
Department of Pediatrics, King George’s Medical University, Lucknow, Uttar Pradesh 226003, India
2
Princess Esra Hospital, Deccan College of Medical Sciences & Allied Hospitals, Hyderabad, Telangana 500002, India
3
Department of Pediatrics, Institute of Child Health, Kolkata 700017, India
4
Department of Psychiatry, King George’s Medical University, Lucknow, Uttar Pradesh 226003, India
5
Global Medical Affairs, Société des Produits Nestlé S.A., 1800 Vevey, Switzerland
6
Nestlé Product Technology Center, Nutrition, Société des Produits Nestlé S.A., 1800 Vevey, Switzerland
7
Nestlé Research, Société des Produits Nestlé S.A., 1000 Lausanne, Switzerland
(Submitted 24 May 2019 – Final revision received 1 November 2019 – Accepted 3 December 2019 – First published online 3 January 2020)

Abstract
Anaemia affects approximately 69 % of Indian children aged 6–12 months, with Fe deficiency (ID) being a common cause. The effectiveness of
micronutrient-fortified infant cereal in improving Fe status and neurodevelopment was evaluated in non-anaemic and mildly anaemic Indian
infants. An intervention group (IC) enrolled at age 6 months consumed 50 g/d of rice-based cereal providing 3·75 mg Fe/d as ferrous fumarate for
6 months (n 80) and was compared with a matched static cross-sectional control group (CG) without intervention enrolled at age 12 months
(n 80). Mean Hb was higher in IC (118·1 (SD 10·2) g/l) v. CG (109·5 (SD 16·4) g/l) at age 12 months (adjusted mean difference: 9·7 g/l; 95 % CI 5·1,
14·3; P < 0·001), while geometric mean serum ferritin tended to be higher (27·0 (–1 SD 13·4, þ1 SD 54·4) v. 20·3 (–1 SD 7·5, þ1 SD 55·0) ng/ml);
P = 0·085) and soluble transferrin receptor was lower (1·70 (–1 SD 1·19, þ1 SD 2·43) v. 2·07 (–1 SD 1·29, þ1 SD 3·33) mg/l; P = 0·014). Anaemia
(23 v. 45 %; P = 0·007) and ID (17 v. 40 %; P = 0·003) were lower in IC v. CG. Bayley Scales of Infant and Toddler Development Third Edition
scores for language (P = 0·003), motor development (P = 0·018), social-emotional (P = 0·004) and adaptive behaviour (P < 0·001), but not cog-
nitive development (P = 0·980), were higher in IC v. CG. No significant difference in anthropometric Z-scores was observed between the groups.
Consuming a micronutrient-fortified infant cereal daily for 6 months during complementary feeding promoted better Fe status while reducing the
risk for anaemia and ID and was associated with superior neurodevelopmental scores.

Key words: Infants: Fortified infant cereal: Anaemia: Iron deficiency: Hb: Neurodevelopment: Bayley Scales of Infant and
Toddler Development Third Edition scores

Globally, the WHO estimates that 273 million young children are such as India, CF consist of home-made non-fortified cereals
anaemic(1), of which approximately 60 % is attributable to Fe- or starchy roots and tubers, many of which have a low concen-
deficiency anaemia (IDA)(2). Infants and toddlers between tration and/or bioavailability of Fe and, hence, will not provide
6 and 24 months of age have the highest rates of IDA(3). At sufficient Fe to the growing child(5). In India, the prevalence of
approximately 6 months of age, the Fe stores accumulated in anaemia in infants 6–12 months of age is estimated to be 69 %(6)
utero and the supply of highly bioavailable Fe from breast milk and is a major economic burden to the society(7).
are no longer adequate to cover Fe requirements to support the Infants with IDA are at risk for compromised cognitive,
rapid growth and development that continue in late infancy(4). motor, social-emotional and neurophysiological development
Consequently, if complementary foods (CF) do not provide in the short and long term(3). In several Fe intervention studies,
adequate amounts of bioavailable Fe, the young child is at early cognitive and/or motor development scores in Fe-deficient
high risk to develop a continuum, starting with Fe deficiency anaemic infants assessed at baseline were inferior compared
(ID) and then IDA. In many lower-middle-income countries, with infants with better Fe status(8–12). Fe supplementation for

Abbreviations: Bayley-III, Bayley Scales of Infant and Toddler Development Third Edition; CF, complementary foods; DRI, daily recommended intake;
FeF, ferrous fumarate; ID, Fe deficiency; IDA, Fe-deficiency anaemia; SF, serum ferritin; sTfR, serum soluble transferrin receptor.
* Corresponding author: Colin I. Cercamondi, fax þ41 21 924 28 12, email ColinIvano.Cercamondi@nestle.com
 Fortified infant cereal promotes iron status 781

3–6 months in Fe-deficient anaemic infants did improve devel- the age of 6 months and followed up until 12 months of age,
opmental test scores in some of the aforementioned studies(8,9) and a matched static cross-sectional control group (CG) of
but not in the others(10–12). Impaired cognitive and motor devel- infants who did not receive the intervention and who were
opment may be irreversible or only partially reversible by the only enrolled and assessed at the age of 12 months. We
provision of Fe depending on the duration, severity and timing hypothesised that infants in the IC would have better Fe status
of IDA(3,13). Longitudinal studies on long-term effects of IDA and more favourable neurodevelopmental outcomes than the
observed that children who had IDA in infancy did worse on infants in the CG group at 12 months of age.
tests of mental, motor and social-emotional functioning in
later childhood and adolescence, despite Fe therapy and Fe
status improvement(3). A limited number of studies suggest a Methods
beneficial effect of Fe-fortified foods on short-term infant Study design and population
neurodevelopment(14,15). Systematic reviews do not provide
This multi-center, open-label intervention trial with a matching
adequate evidence that Fe supplementation or fortification
static cross-sectional CG was conducted between April 2017
improves cognitive and motor development in the overall
and May 2018 in three sites in India: King George’s Medical
infant and young children population(16–19); however, sub-
University (Lucknow), Princess Esra Hospital (Hyderabad) and
group meta-analysis suggests a beneficial effect in Fe-deficient
Institute of Child Health (Kolkata). The study population
children(16) and provides limited evidence for benefits on
included a total of 160 healthy infants aged 6 and 12 months,
motor development in non-anaemic infants(19).
who were recruited simultaneously for IC (n 80) or CG (n 80)
A safe and cost-effective approach to alleviate nutritional ID
(Fig. 1) when they had their routine vaccination visits or well-
in infants is Fe fortification of CF which can be done either
being check-ups at the sites. Apparently healthy, single-birth
commercially at the time of food production or through the
infants who were 6 months of age with normal weight-for-
addition of nutrients in the home before consumption (referred
age within ±2 SD of WHO growth standards and who had CF
to as in-home fortification). Commercially fortified CF typically
introduced were eligible for the IC. Infants who had (1)
comprise milk or cereal products (e.g. porridge or gruel)(20).
chronic, acute ongoing or recent (last 2 weeks) illness necessi-
Two systematic reviews concluded that micronutrient-fortified
tating medical follow-up, (2) parasitic infections, (3) docu-
CF are an effective approach for providing additional dietary
mented intolerance to gluten or lactose, (4) documented
Fe and reducing anaemia rates(21,22). However, most of the
allergy to bovine milk proteins, (5) severe or moderate anaemia
evidence comes from Fe-fortified milk products, and only a
(Hb < 100 g/l), (6) inflammation as indicated by elevated
few studies are available investigating the efficacy of fortified
C-reactive protein (CRP) >10 mg/l and (7) participated in
infant cereals in improving Fe status. In a randomised con-
another clinical study ≤4 weeks prior to enrolment were
trolled trial (RCT), ID prevalence was reduced in Ghanaian
excluded from the IC. Apparently healthy, 12-month-old
infants receiving a micronutrient-fortified cereal-legume blend
single-birth infants, who did not have chronic, acute ongoing
fed ad libitum and providing 12–18 mg additional Fe as electro-
or recent (last 2 weeks) illness necessitating medical follow-
lytic Fe compared with a control group but did not improve
up and did not participate in another clinical study ≤4 weeks
Hb concentration or reduce anaemia(23). Similarly, micronu-
prior to enrolment, were enrolled in the CG. These infants
trient-fortified rusk providing 5 mg additional Fe as ferric
served as a static cross-sectional control group. With this
ammonium citrate had only a small significant benefit on Hb
design, we avoided any potential concerns of enrolling anae-
concentration in Chinese infants(24). RCT using ferrous fuma-
mic and/or Fe-deficient infants or infants that are in general
rate (FeF) as an Fe compound showed stronger effect on Fe
at high risk for ID into a control group. A simple matching
status with higher Hb and serum ferritin (SF) concentration
approach based on the close monitoring of five selected key
and reduced anaemia and ID in infants receiving additional
demographic characteristics (sex, birth weight, delivery mode,
5·5 or 12·5 mg Fe/d from a micronutrient-fortified maize
gestational age and milk feeding pattern) in the already
porridge compared with their control peers(14,25). However,
enrolled infants in IC was attempted to match infants in CG with
in the light of evidence that higher doses of Fe lead to a range
infants in IC.
of adverse events in low-income settings(26), there is a need to
The study was conducted according to the guidelines laid
test lower doses of FeF. Limited data are currently available on
down in the Declaration of Helsinki, and the protocol was
the impact of lower doses of FeF of less than 5 mg Fe/d. In
approved by the Institutional Ethics Committees of the King
Chinese infants, a low dose of approximately 1 mg additional
George Medical University in Lucknow, the Institute of Child
Fe/d as FeF from a multi-fortified infant cereal fed for
Health in Kolkata and the Deccan College of Medical Sciences
12 months showed marginally improved SF concentrations
& Allied Hospitals in Hyderabad. Written informed consent
and had no effect on Hb(27). Further evidence on low to mod-
was obtained from the parents or legally authorised representa-
erate doses of FeF is needed. Therefore, the aim of the present
tives. The study was registered prospectively with Clinical Trials
study was to generate data on the effectiveness of a micronu-
Registry-India (CTRI/2017/02/007767).
trient-fortified rice-based infant cereal providing a low to
moderate dose of additional 3·75 mg Fe/d as FeF in promoting
Intervention and study product
Fe status as well as investigating the effect on neurodevelop-
ment in Indian infants. The study was designed with a longi- Within 2 weeks of initial screening visit, infants in the IC had a
tudinal intervention group (IC) where infants were enrolled at baseline visit after which they received 50 g/d of a fortified cereal
782 S. Awasthi et al.

Fig. 1. Study design and participant flow chart. CRP, C-reactive protein.

(Société des Produits Nestlé S.A.) throughout the 6 months of recorded using a calibrated digital baby scale (Seca 354 M)
intervention in addition to the habitual complementary feeding and length using a calibrated paediatric measuring board
regimen. The nutritional composition of the micronutrient- (Seca 417). Furthermore, head circumference was measured
fortified rice-based infant cereal is presented in Table 1. The using a flexible measuring tape (Seca disposable measuring
infant cereal provided 75 % (3·75 mg) of the Indian daily rec- tape 211). Weight-for-age, length-for-age, weight-for-length
ommended intake (DRI) for Fe in infants (5 mg)(28) so that other and head circumference-for-age Z-scores were calculated
CF or breast milk could still contribute to the DRI. Depending using WHO reference data(29). Concomitant medications,
on the infant’s age and feeding behaviour, caregivers were including the prospective use of Fe supplements based on a
instructed to feed 50 g of infant cereal either as one serving low Hb concentration (<100 g/l) during a study visit, were
or as two servings of 25 g. Caregivers were trained to reconsti- monitored throughout the entire study. Morbidity and safety
tute 25/50 g infant cereal powder with 75/150 ml of lukewarm were assessed from (1) a sickness questionnaire at baseline,
water in order to obtain a purée consistency allowing to feed midpoint and study end visit for IC and at study end visit
the infant cereal with a spoon. Post-baseline assessments in for CG and (2) recording of adverse events (AE) collected
the IC were conducted at midpoint (9 months of age) and at through infants’ diary cards during each visit for both groups.
study end (12 months of age). Infants in the CG were enrolled To make outcomes on AE and concomitant medications com-
at 12th month of life at the screening visit, and they had the parable between the two study groups (i.e. to control for the
study end visit within 2 weeks of the screening visit. The CG different amounts of time, each group was in the study), an
was considered a static cross-sectional non-interventional incidence rate for AE and for concomitant medications was
control. calculated as follows: Total number of AE or medications
reported among all enrolled subjects divided by the sum of
length of duration (in days) for all subjects that were on the
Socio-demographic, anthropometric, morbidity, safety
respective treatment arms multiplied by 100. Nutrient intake
and dietary outcomes
was evaluated using a 24-h dietary recall administered by a
To assess subject eligibility during screening, socio-demographic trained paediatric dietitian to the infant’s parent or caregiver
characteristics and child medical history data were collected via at study end visits for the IC and CG. Breast milk intake during
questionnaires and anthropometric measurements were taken the 24-h dietary recall was assessed as frequency of breast
in both groups. In the IC, anthropometric measurements were milk feeds. The daily intake of energy, macronutrients
also done at midpoint and study end. Infant weight was (fat, carbohydrates and protein) and selected micronutrients
 Fortified infant cereal promotes iron status 783

Table 1. Energy and nutrient composition of the rice-based micronutrient- visit in the IC and at study end visit only in the CG. SF was
fortified infant cereal consumed for 6 months by the infants in the measured by chemiluminescent immunoassay system
intervention group
(CMIA-ABBOTT ARCHITECT i2000). CRP and sTfR were
Nutritional component Amount/daily serving evaluated by nephelometry (Nephelometry-Siemens BN II).
Energy (kJ) 868 Anaemia was defined as Hb < 110 g/l. Moderate and severe
Protein (g) 7·5 anaemia were defined as Hb > 70 but <100 g/l and Hb
Total fat (g) 4·5 <70 g/l, respectively. In both groups, infants with Hb
Linoleic acid (g) 0·75
< 100 g/l at any of the study time points received Fe supple-
α-Linolenic acid (mg) 92·5
Carbohydrate (g) 34·25 ments as per local medical standards. In the IC, infants with Hb
Sugar (g) 4·5 < 100 g/l at screening or midpoint (major protocol deviation)
Fibre (g) 0·25 were excluded or withdrawn from the study, respectively. ID
Na (mg) 57·5
Ca (mg) 219
was defined as SF < 12 μg/l and CRP < 5 mg/l or SF < 30 μg/l and
K (mg) 175 CRP ≥ 5 mg/l; IDA was defined as Hb <110 g/l and SF < 12 μg/l
P (mg) 175 and CRP < 5 mg/l or Hb <110 g/l and SF < 30 μg/l and
Mg (mg) 22·5 CRP ≥ 5 mg/l(4).
Fe (mg) 3·75
Cu (mg) 0·15
Zn (mg) 1·25 Infant neurodevelopmental outcomes
Vitamin A (μg) 175
Vitamin D (μg) 2·5 Neurodevelopment was assessed using the Bayley Scales of
Vitamin E (mg) 1·25 Infant and Toddler Development Third Edition (Bayley-III)(31)
Vitamin C (mg) 18·75 at baseline and study end in the IC (6 and 12 months of age)
Thiamin (mg) 0·25
Riboflavin (mg) 0·185 and at study end (12 months of age) in the CG. The Bayley-III
Niacin (mg) 2·75 is a standardised test for 1- to 42-month-old children assessing
Pantothenic acid (mg) 0·75 age-appropriate skills in five developmental scales: cognitive,
Vitamin B6 (mg) 0·2
Folic acid (μg) 12·5
language, motor, social-emotional and adaptive behaviour.
Biotin (μg) 2·6 Cognitive, language and motor skills were tested by certified
Vitamin B12 (μg) 0·1 medical staff. To complete the questionnaires on the social-
emotional and adaptive behaviour development, caregivers
were assisted by the certified medical staff. An age-corrected
composite score was derived for each of the five scales and
(Fe, Zn, Cu, Mg, vitamins A, B12, C, D and folate) coming from scaled to a metric, with a mean of 100, a standard deviation of
CF at 12 months of age (not including nutrients from breast 15 and a range of 40–160(31).
milk) was calculated using Indian Food Composition
Tables(30). Quality of life losses due to impaired cognitive Statistical analysis
development as Disability Adjusted Life Years and the pro-
duction losses based on the Hb difference in our study were A sample size of approximately fifty infants (twenty-five per
calculated using data from the most recent National Family study group) was required to detect an expected difference of
Health Survey in India(6) and the methodology previously 8·0 g/l in Hb concentration between the two study groups at
described by Plessow et al.(7) not including severely anaemic 12 months of age, with a statistical power of 90 % and a two-sided
infants. significance level of 0·05. The assumed standard deviation for
Hb concentration was 8·5 g/l(4). Nonetheless, eighty infants per
arm were recruited to account for an anticipated drop-out rate
Haematological outcomes
of 30 % and to have adequate power for secondary end points.
Blood samples were taken at screening (6 months of age), mid- Data analysis was conducted in the analysis set (IC n 64; CG
point (9 months of age) and study end (12 months of age) in the n 80), which was defined as infants having a valid blood sample
IC and at the single time point during the screening in the CG at 12 months of age who did not require treatment with high-
(12 months of age). Non-fasting peripheral venepuncture blood dose Fe supplements at 9 months of age due to the develop-
samples were drawn into anticoagulant-coated tubes (Becton ment of moderate or severe anaemia, using the software
Dickinson) for Hb assessment and into plain tubes (Becton Statistical Analysis System (SAS, version 9.3 or higher).
Dickinson) for SF, serum soluble transferrin receptor (sTfR) Descriptive and demographic characteristics used for the
and CRP analysis. After collection, whole blood for SF, sTfR matching were compared between IC and CG using
and CRP analysis was allowed to clot at room temperature fol- Pearson’s χ2 or Fisher’s exact test for categorical data and
lowed by centrifugation to separate the serum. The respective independent t test for continuous data. Fe status assessed
serum containers were stored at refrigerated condition until by Hb, SF and sTfR concentrations, inflammation measured
assessment. Hb (primary end point) was measured at screening, as CRP and Bayley-III scores between IC and CG were com-
midpoint and study end in the IC and at screening only in the pared using ANCOVA models correcting for sex, exclusively
CG using automated haematology analysers (Beckman coulter breast-feeding until 6 months of age (yes/no), Kuppuswamy
DXH – 800/Sysmex XN 1000). SF, sTfR and CRP (secondary socio-economic status(32), birth weight, gestational age and
end points) were determined at screening and at study end study site. Anthropometric parameters were compared between
784 S. Awasthi et al.

Table 2. Demographic infant and maternal characteristics in the intervention (IC) and static cross-sectional control group (CG) at enrolment
(Mean values and standard deviations; percentages)

IC (n 80) CG (n 80)
Characteristics Mean SD Mean SD P*

Infant characteristics
Age at enrolment (months)† 5·7 0·5 11·8 0·4
Gestational age at birth (weeks) 36·6 0·9 36·6 0·8 0·853‡
Sex (% boys) 46·3 52·5 0·429§
Birth weight (kg) 2·9 0·5 2·8 0·5 0·425‡
Delivery mode (% Caesarean section) 65·0 61·3 0·623§
Exclusively breast-fed up to 6 months of age (%) 77·5 93·8 0·003‖
Maternal characteristics
Main caregiver (% mother) 100 100
Maternal age (years) 27·3 4·3 26·4 3·8
Parity (number) 1·8 1·0 1·8 0·8
Level of education (%)
Unschooled/primary or middle school certificate 28·7 23·7
High school certificate/intermediate or post high school diploma 42·5 43·8
Graduate/postgraduate/doctorate/PhD 28·8 32·5
Employment status (% non-employment) 93·8 98·8
Living setting (%)
Urban 85·0 75·0
Sub-urban 13·8 18·8
Rural 1·2 6·2
Socio-economic status (%)¶
Upper/upper middle 16·2 15·0
Lower middle 22·5 27·5
Upper lower/lower 61·3 57·5

* P value between group comparison; only assessed for the characteristics that were used as matching criteria between infants in the IC and CG.
† Infants in the IC were enrolled at approximately 6 months of age; infants in the CG at approximately 12 months of age.
‡ Independent t test for between-group comparison.
§ Pearson’s χ2 test for between-group comparison.
‖ Fisher’s exact test for between-group comparison.
¶ Socio-economic status was based on Kuppuswamy’s scale(32).

the two study groups using ANCOVA models correcting for sex, Maternal and infant characteristics at screening are summar-
birth weight, gestational age and study site. Pearson’s χ2 test was ised in Table 2 and were comparable between the two groups.
used for the comparison of anaemia, ID and IDA prevalence There were no statistical differences between the groups in the
between IC and CG at 12 months of age. Changes in the Hb con- ratio of boys:girls, mean birth weight, gestational age and mode
centration (primary end point) within the IC over time from base- of delivery. The delivery mode in both groups was predomi-
line (6 months of age) to study end (12 months of age), baseline nately by caesarean section. The majority of the infants in IC
to midpoint (9 month of age) and midpoint to study end were (78 %) were exclusively breast-fed before enrolment at 6 months
analysed using paired t test. Frequency of breast-feeding, energy of age. These were slightly less infants than in CG (P = 0·003)
and nutrient intakes between the two study groups was com- where 94 % were exclusively breast-fed before other foods were
pared by independent t test. For not normally distributed data introduced at a mean age of 6·6 (SD 1·3) years. In the IC, foods
as checked by Q–Q plots (SF, sTfR, CRP, certain nutrient were introduced at a mean age of 5·6 (SD 1·3) years. The
intakes), tests were done on log-transformed data. All statistical socio-economic status based on Kuppuswamy’s scale(32)
tests were conducted using a two-sided test at an α = 0·05 level of showed that the majority of the infants in both groups were from
significance. Standardised effect size between the two groups in the upper-lower or lower socio-economic strata. The participat-
Bayley-III scores was estimated by Cohen’s d estimate, wherein ing mothers in both groups were predominantly high school
d values of 0·2, 0·5 and 0·8 represent small, medium and large graduates (31 % for IC v. 30 % for CG), non-employed (94 %
effect sizes, respectively(33). for IC v. 99 % for CG) and living in urban or suburban locations
(99 % for IC v. 94 % for CG).

Results
Iron status
Participant characteristics
Table 3 shows the Fe status parameters and CRP concentration
A total of ninety-nine and eighty-five infants were screened for at 6 and 12 months of age for the IC and at 12 months of age only
enrolment in the IC and CG, respectively, and eighty infants were for the CG. At 12 months of age, four infants in each group
recruited in each group (Fig. 1). During the intervention, sixteen had elevated CRP concentration (>10 mg/l). At 12 months of
infants dropped out in the IC and sixty-four infants completed age, compared with the CG, Hb concentration was higher in
the study. All eighty infants included in the CG completed the IC (adjusted mean difference: 9·7 g/l; 95 % CI 5·1, 14·3;
the study. P < 0·001), whereas sTfR concentration was lower in the
 Fortified infant cereal promotes iron status 785

Table 3. Iron status indices and C-reactive protein concentration of infants in the intervention group at 6 and 12 months of age (IC) and in the static cross-
sectional control group (CG) at 12 months of age
(Mean values and standard deviations; geometric mean and –1 standard deviation and þ1 standard deviation)

IC (n 64) CG (n 80)
6 months 12 months 12 months
Geometric Geometric Geometric
Parameter mean –1 SD, +1 SD mean –1 SD, +1 SD mean –1 SD, +1 SD P*

Hb (g/l)
Mean 113·4 118·1 109·5 <0·001
SD 8·7 10·2 16·4
Serum ferritin (ng/ml) 40·0 16·4, 78·7 27·0 13·4, 54·4 20·3 7·5, 55·0 0·085
Serum soluble transferrin 1·68 1·22, 2·31 1·70 1·19, 2·43 2·07 1·29, 3·33 0·014
receptor (mg/l)
Serum C-reactive 0·46 0·16, 1·34 0·84 0·20, 3·60 0·77 0·17, 3·39 0·741
protein (mg/l)

* P value for between-group comparison (ANCOVA model correcting for sex, exclusively breast-feeding until 6 months of age (yes/no), Kuppuswamy socio-economic status(32), birth
weight, gestational age and study site).

IC (–18·1 %; 95 % CI –32·4, –3·7; P = 0·014). Compared with for adaptive behaviour (d = 0·91) and language development
the CG, the SF concentration in the IC at 12 months of age (d = 0·65) and medium for motor development (d = 0·53) and
tended to be higher (26·6 %; 95 % CI –3·7, 56·8; P = 0·085). social-emotional behaviour (d = 0·39).
Hb concentration significantly increased from 6 to 12 months
of life in the IC (P < 0·001), with a Hb concentration at mid- Anthropometry
point of 115·9 (SD 9·9) g/l. In the IC, a trend for a significant
increase in Hb concentration between 6 and 9 months of age At 12 months of age, growth outcomes in the two groups were
(P = 0·081) and a non-significant increase from 9 to 12 months comparable as indicated by similar anthropometric Z-scores.
of life was observed (P = 0·116). In the sixteen infants, who Z-scores at 12 months of age for IC and CG, respectively, were
dropped out in IC, mean Hb was 111·0 (SD 7·4) g/l, geometric (1) weight-for-age: –0·5 (SD 1·0) v. –0·3 (SD 0·8), P = 0·360;
mean SF was 29·2 (–1 SD 9·6, þ1 SD 89·1) and geometric mean (2) length-for-age: –1·6 (SD 1·0) v. –1·3 (SD 1·4), P = 0·117;
sTfR was 1·95 (–1 SD 1·54, þ1 SD 2·46) at baseline. Fig. 2 shows (3) weight-for-length: 0·4 (SD 1·1) v. 0·4 (SD 1·1), P = 0·931
that at 12 months of age, the prevalence of anaemia in IC was and (4) head circumference-for-age: –0·9 (SD 1·2) v. –0·9
49 % lower than that in CG (23 % for IC v. 45 % for CG; (SD 1·2), P = 0·424. In the IC at 6 months of age, Z-scores were
P = 0·007) (Fig. 2(a)), ID was 58 % lower (17 % for IC v. (1) weight-for-age: –0·6 (SD 0·8); (2) length-for-age: –1·2 (SD
40 % for CG; P = 0·003) (Fig. 2(b)) and IDA was 77 % lower 0·8); (3) weight-for-length: 0·2 (SD 0·9) and (4) head circumfer-
(6 % for IC v. 26 % for CG; P = 0·002) (Fig. 2(c)). At 12 months ence-for-age: –0·3 (SD 1·5). In the IC at 9 months of age, Z-scores
of age, 22 % of the infants in the IC had mild anaemia (Hb >100 were (1) weight-for-age: –0·6 (SD 0·8); (2) length-for-age: –1·6
but <110 g/l) and 1 % had moderate anaemia (Hb >70 but (SD 1·0); (3) weight-for-length: 0·4 (SD 0·9) and (4) head circum-
<100 g/l). In the CG, the prevalence of mild and moderate ference-for-age: –0·8 (SD 1·4).
anaemia at 12 months of age was 19 and 26 %, respectively.
Dietary outcomes
Neurodevelopment
CF other than breast milk were provided to all sixty-four
At 12 months of age, the Bayley-III score for language devel- infants of the IC at 12 months of age and for all eighty infants
opment was higher (adjusted mean difference: 5·3; 95 % CI of the CG. Mean daily energy intakes from CF were not differ-
2·0, 8·5; P = 0·001) in the IC (107·2 (SD 11·6)) than in the CG ent between the IC and the CG (2030 (SD 675) v. 1986 (SD 768)
(100·5 (SD 9·2)), and the motor development score was better kJ/d, respectively; P = 0·714) at 12 months of age. The mean
(3·4; 95 % CI 0·5, 6·3; P = 0·022) in the IC (103·9 (SD 8·7)) com- frequency of breast milk feeds was lower in the IC v. the
pared with the CG (99·1 (SD 9·5)). Compared with the CG CG group at 12 months of age (6·6 (SD 3·3) times/d v. 9·1 (SD
(90·6 (SD 10·5)), the social-emotional behaviour score in the 5·7) times/d; P = 0·002). As reported in Table 4, the intakes
IC (94·3 (SD 8·0)) was higher (4·2; 95 % CI 1·3, 7·1; of total fat, linoleic acid and α-linoleic acid from CF were
P = 0·005), and the adaptive behaviour score was better higher in the IC compared with the CG at 12 months of age
(6·0; 95 % CI 3·7, 8·3; P < 0·001) in the IC (90·2 (SD 9·6)) than (P < 0·001), while there was no difference for carbohydrate
in the CG (81·3 (SD 9·9)) at 12 months of age (Fig. 3). The mean and protein intake between the groups (P > 0·05). Geometric
Bayley-III scores for cognition did not differ between the IC mean intake of Fe from CF was approximately three times
(94·4 (SD 8·2)) and the CG (94·1 (SD 7·5)) at 12 months of higher in the IC compared with the CG (P < 0·001).
age (P = 0·982). Based on Cohen’s d estimate, the magnitude Similarly, intakes of Zn, Cu, Mg, vitamins A and C from CF
of difference (effect size) between the IC and CG was strong were also higher in the IC than in the CG at 12 months of
786 S. Awasthi et al.

Adverse events, morbidity, concomitant medication, and

quality of life and production losses
After controlling for the shorter observational period in the CG
(2 weeks only), the incidence rate of AE was 0·19 and 0·26 %
in the IC and CG, respectively. Overall, twenty-eight AE were
reported in twenty-two infants in the IC and four AE occurred
in three infants in the CG. The AE reported in the CG included
pyrexia (n 3) and nasopharyngitis (n 1). In the IC, nasopharyng-
itis (n 10), lower respiratory tract infection (n 1), pyrexia (n 8),
diarrhoea (n 5), cough (n 3) and severe anaemia (n 1) were
observed. There were no incidences of AE related to the studied
infant cereal. The incidence rate of concomitant medication,
controlling for the shorter observational period in the CG
(2 weeks only), was 0·16 and 1·49 % in the IC and CG, respec-
tively. Overall, twenty-four administrations of concomitant med-
ications were reported in the IC and twenty-three
administrations in the CG. Fe-containing supplements were
more commonly required in the CG than in the IC. Twenty-
one infants in CG had low Hb concentration <100 g/l at
12 months of age and needed Fe supplements, while only seven
infants in IC needed Fe supplements due to low Hb at 9 months
(n 6) and 12 months of age (n 1). In the IC, seven infants took
analgesics, whereas only two infants took the same in the CG.
In our model on quality of life losses and production losses
not including the severely anaemic infants, we found that a
fortified infant cereal could save future production losses of
1353 million USD in India and approximately 313,000
Disability Adjusted Life Years, which correspond to thirteen
complete lifespans saved in India every single day.

Discussion
In our study using a static cross-sectional group comparison
design, infants aged 6 months who received a multi-fortified
rice-based cereal for 6 months had better Fe status at 12 months
of age and lower rates of ID and IDA than infants who did not
receive the study cereal. This indicates that the additional Fe
from the study cereal helped the infants in the IC to significantly
reduce the risk of developing ID and IDA by 58 and 77 %, respec-
tively. In the IC, the mean intake of Fe from CF (4·6 mg/d) was
close to the Indian DRI for Fe (5 mg/d) and approximately three
times higher than that in the CG infants (1·5 mg/d). Our study
design did not allow randomisation and the measurement of
Fig. 2. Prevalence of anaemia (a), iron deficiency (b) and iron-deficiency anae-
Fe status in the CG at 6 months of age. We, however, assume that
mia (c) at 6 and 12 months of age for infants in the intervention group (IC; n 64)
and at 12 months of age for infants in the static cross-sectional control group the CG infants had comparable Fe status at 6 months of age with
(CG; n 80). , CG; , IC. Significantly different from CG using Pearson’s the IC infants at age 6 months and were mainly Fe-replete
χ2 test: * P = 0·007; † P = 0·003; ‡ P = 0·002. Anaemia defined as Hb <110 g/l; because the vast majority was exclusively breast-fed (94 %)
iron deficiency defined as serum ferritin <12 μg/l and C-reactive protein
(CRP) < 5 mg/l or serum ferritin <30 μg/l and CRP ≥ 5 mg/l; iron-deficiency
and had food introduced after 6 months of life (mean age of
anaemia defined as Hb <110 g/l and serum ferritin <12 μg/l and CRP < 5 mg/ food introduction: 6·6 months). Exclusive breast-feeding up to
l or Hb <110 g/l and serum ferritin <30 μg/l and CRP ≥ 5 mg/l. 6 months of life is associated with better Fe status in infants as
it provides highly bioavailable Fe(34) and reduces diarrhoeal dis-
eases (and other infections) that accompany early introduction
age (P < 0·001; except for Cu with P < 0·005). The vitamin B12 of CF, particularly in resource-limited areas where water and san-
intake from CF in the IC tended to be higher than that in itation facilities are inadequate(35). We therefore assume that the
the CG (P = 0·053). Folate and vitamin D intake from CF better Fe indices (Hb and sTfR) as well as the lower prevalence of
was not different between the groups at 12 months of anaemia, ID and IDA in the IC at 12 months of life compared with
age (P > 0·05). the CG are mainly due to the additional Fe from the study cereal
 Fortified infant cereal promotes iron status 787

Table 4. Nutrient intake from complementary foods in the infants of the intervention group (IC) and in the static cross-sectional control group (CG)
at 12 months of age using 24-h food recall
(Mean values and standard deviations; geometric mean and –1 standard deviation and þ1 standard deviation)

IC (n 64) CG (n 80)
Nutrient Geometric mean –1 SD, +1 SD Geometric mean –1 SD, +1 SD P*

Total fat (g/d) 8·0 4·5, 14·0 3·1 0·9, 10·3 <0·001
Linoleic acid (g/d) 3·9 1·4, 11·0 1·2 0·1, 12·7 <0·001
α-Linolenic acid (mg/d) 86·8 16·5, 455·6 7·5 1·1, 53·0 <0·001
Carbohydrate (g/d)
Mean 66·0 69·5 0·420
SD 23·9 27·7
Protein (g/d)
Mean 18·1 17·4 0·590
SD 7·1 10·0
Fe (mg/d) 4·6 3·4, 6·3 1·5 0·3, 6·8 <0·001
Zn (mg/d) 2·0 1·2, 3·4 1·2 0·4, 3·1 <0·001
Cu (mg/d) 0·3 0·2, 0·5 0·2 0·1, 0·6 0·002
Mg (mg/d) 42·7 23·6, 77·2 8·5 2·1, 35·4 <0·001
Vitamin A (μg/d) 209·6 153·3, 286·6 30·2 2·3, 389·9 <0·001
Vitamin B12 (μg/d) 0·18 0·01, 2·21 0·08 0·01, 0·72 0·053
Folate (μg/d) 18·7 1·5, 236·9 34·4 3·5, 334·8 0·137
Vitamin C (mg/d) 24·0 14·3, 40·2 2·4 0·6, 9·1 <0·001
Vitamin D (μg/d) 10·5 3·4, 32·1 6·4 0·9, 44·3 0·060

* P value from independent t test.

Fig. 3. Neurodevelopment (Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) scores) of the infants in the intervention group at 6 and 12 months
of age (IC; n 64) and in the static cross-sectional control group at 12 months of age (CG; n 80). , IC 6 months; , IC 12 months; , CG 12 months. *†‡§ P value (ANCOVA
model correcting for sex, exclusively breast-feeding until 6 months of age (yes/no), Kuppuswamy socio-economic status(32), birth weight, gestational age and study site).
* Significantly different from IC 12 months (P = 0·001). † Significantly different from IC 12 months (P = 0·022). ‡ Significantly different from IC 12 months (P = 0·005).
§ Significantly different from IC 12 months (P < 0·001).

reducing the risk of a decline in Fe status from 6 to 12 months of Fe bioavailability is an important aspect of Fe-fortified
age in the IC. In our study, this is further supported by the higher infant cereals as cereals contain phytate, which is the most
needs of Fe supplements in the CG compared with the IC important Fe absorption inhibitor, binding non-heme Fe in
(twenty-one v. seven infants). Fe stores present at birth are an insoluble complex in the intestine, making it unavailable
mainly accumulated during the last 10 weeks of gestation and for absorption(39). For our rice-based infant cereal, we, how-
cover Fe requirements during the first 4–6 months of age in ever, assume little influence of phytate as polished rice has a
healthy term infants(36). After this period, CF needs to provide low phytate concentration comparable with refined wheat
sufficient Fe. However, home-made non-fortified CF in lower- flour, which is frequently used for infant cereals(40). We esti-
middle income countries often have low Fe concentration and mate intermediate bioavailability of 10–15 % from the studied
bioavailability(5,37) and do not cover the high Fe needs during infant cereal as proposed by WHO for cereal foods with some
rapid growth in infancy(38); hence, infants develop ID and IDA vitamin C(41). We assume that this bioavailability is substantially
in late infancy when CF are introduced. This is confirmed by higher than that from home-made non-fortified CF consumed
the low Fe intake from CF in the CG infants in the present study in the CG not containing vitamin C, a strong enhancer of Fe
(1·5 mg/d) and their increased rates of ID (40 %) and IDA (26 %) absorption(39). Assuming 10–15 % Fe bioavailability, the infants
at 12 months of age. in the IC absorbed between 0·38 and 0·56 mg Fe/d from the
788 S. Awasthi et al.

study cereal which is more than half (52–78 %) of their basic traditional complementary feeding in India is rich in green
daily physiological Fe requirements needed for growth and leafy vegetables, which are exceptional sources of folate.
coverage of basal Fe losses (0·72 mg/d)(42). As for every forti- Folate deficiency in breast-fed Indian infants from low- to
fied food vehicle, achieving good organoleptic properties middle-income communities was reported to be low
and high Fe bioavailability can be challenging(43). The Fe (6 %)(57), and folate concentrations in breast milk are main-
compound selected should be the one with the highest relative tained even when the mother is deficient in folate and are unaf-
bioavailability that causes no sensory changes when added to fected by maternal folate supplementation(58).
the food vehicle. FeF used in our study cereal is one of the In our study, infants in the IC had a statistically significantly
compounds recommended for the fortification of CF(41). This higher Bayley-III scores for language and motor development
recommendation is based on the compound’s good sensory than infants in the CG, who had significantly higher prevalence
properties and on results from isotope studies that reported of ID and IDA than the IC infants. This suggests that by prevent-
similar Fe absorption values for FeF and ferrous sulphate ing the decline in Fe status in the IC, the fortified cereal helped
(FeSO4) (relative bioavailability of FeF with regard to FeSO4 the infants in the IC to make use of their full neurodevelopmental
as standard: 100)(44,45). Unlike FeSO4, FeF caused few or no potential. Several previous studies reported detrimental motor
sensory changes in stored cereal products or colour changes and cognitive development in infants with ID or IDA(8–12,59),
in porridges made by adding hot milk or water to the infant which can impair development in infants via altered myelination
cereals(46). Together with ferric pyrophosphate and electro- of white matter, changes in monoamine metabolism in the stria-
lytic Fe, FeF is the most commonly used Fe compound to tum and functioning of the hippocampus(60). In children 4–
fortify CF. FeF should, however, be preferred due to its better 23 months of age, studies on Fe supplements (≥10 mg Fe/d)
bioavailability(43). and fortification do however not provide conclusive evidence
The aetiology of anaemia is multifactorial(2), and our data for a beneficial effect of Fe on the cognitive and motor develop-
using SF < 12 μg/l to define ID indicate that other factors than ment(16–19). We found only one other study assessing the effect of
Fe alone contributed to anaemia in our population group. a fortified infant cereal on motor development outcomes, in
Inflammation and infections can cause anaemia and reduce which mainly Fe-depleted infants receiving a multi-fortified
the sensitivity of SF to detect ID but can be ruled out as substan- maize-based cereal had better Fe status and parent-assessed
tial contributors in our study population because we did not gross motor milestones than their counterparts in the control
include sick infants and the CRP concentrations were low in both group(14). To our knowledge, our study is the first study assessing
groups. Nutritional deficiencies in folate, vitamin A and vitamin the social-emotional and adaptive behavior of infants in a study
B12 also contribute to anaemia via ineffective erythropoiesis(47,48) with fortified cereals using the Bayley-III scores and also the first
and might have played a role in the anaemia of the infants in CG data for Indian infants, in general, using this tool. Previous stud-
as they did not receive additional amounts of these micronu- ies using different tools for the assessment of infant behaviour
trients and were at risk for deficiencies. Vitamin B12, which is and other vehicles than cereals to provide Fe reported a benefi-
not found in any plant foods, seems to be of particular interest cial effect of Fe on social interaction, irritability and orienta-
as a substantial proportion of Indian women are vegetarians tion engagement(13,61). It is likely that the favourable
(30 %)(6), and the concentration of vitamin B12 in breast milk Bayley-III scores in our study are not only a result of the addi-
was associated with maternal diet(49–51) as well as with maternal tional Fe but also of the other essential micronutrients as well
and infant status of vitamin B12(52). Hence, low maternal vitamin as essential fatty acids provided by the infant cereal. In our
B12 status may have put the infants in our study at risk for vitamin study, complementary feeding with the fortified cereal resulted
B12 deficiency at 6 months of age due to an inadequate supply of in significantly higher intakes of several key nutrients for brain
vitamin B12 during exclusive breast-feeding. Two recent studies development in the IC v. CG (except folate and vitamin D). In
reported high prevalence of vitamin B12 deficiency in Indian our intake calculations, we did not consider nutrient intake from
infants (44 and 57 %)(53,54), and vitamin B12 status was an impor- breast milk consumption which was perhaps higher in the CG as
tant predictor for Hb concentration(55). By receiving additional indicated by the breast-feeding frequency data. However, with
vitamin B12 from the study cereal, infants in the IC were likely the limited volumes of breast milk consumed in older infants
to improve their vitamin B12 status which may have had a pos- and the fact that higher breast-feeding frequency does not auto-
itive impact on their Hb concentration. Indeed, the vitamin B12 matically imply consumption of higher volumes of breast milk,
intake from CF in the IC (0·18 μg/d) was much closer to the that is, higher nutrient intake, we assume little influence of the
Indian B12 DRI (0·20 μg/d) than in the CG (0·08 μg/d). The con- different breast-feeding frequencies on the differences in
centration of vitamin A in breast milk has also been associated nutrient intake between the two groups observed at 12 months
with maternal diet(49), and high prevalence of vitamin A defi- of age. Furthermore, the energy intake from CF was the same in
ciency has been reported in Indian women and young chil- both groups (2030 kJ/d in IC v. 1986 kJ/d in CG) indicating that it
dren(56). Our study infants were likely to be at risk for vitamin is unlikely that the CG infants consumed much more breast milk
A deficiency as even the significantly higher intake of vitamin than the IC infants in addition to the CF. Our data suggest that
A in the IC (210 μg/d) compared with the CG (30 μg/d) was still although all Bayley scores for both groups are in the normal
below the Indian DRI for vitamin A (350 μg/d). For folate, we range, providing essential macro- and micronutrients helps the
do not assume a substantial impact on Hb concentration in our infants to better explore their full development potential.
study. We found no difference in intakes between the two Studies with Fe-fortified cereals in infants using a classical
groups at 12 months of age. This is likely because the RCT design are of potential ethical concern because (1) in the
 Fortified infant cereal promotes iron status 789

control group, Fe is withheld from anaemic and/or Fe- Acknowledgements

deficient infants or infants highly susceptible to ID during a
The authors thank the caregivers who consented to their infants’
critical period of rapid growth when insufficient intake of
participation in the present study, as well as the investigators and
Fe might have an irreversible negative impact on the infant’s
their study teams for their major contributions to the present
development and cognition and (2) severe and moderate
study. The authors also thank Santosh Kumar, Vinay Gupta
anaemic infants in the intervention group likely need higher
and Rakhee Vinod Arora (JSS Medical Research India Pvt. Ltd)
dosages of Fe to recover their Fe status than conventional cer-
for the statistical analysis, data management and study supervi-
eal fortification can provide. We therefore chose a design with
sion. We also thank Patrick Detzel (Nestlé Research) for calcu-
a static observational group which did not withhold provision
lating the estimated savings of production losses and
of Fe from anaemic and/or Fe-deficient infants or infants at
Disability Adjusted Life Years.
risk for ID in a CG, and we did not include severe or moderate
The present study has been supported by Société des
anaemic infants in the IC. This allowed us to assess specific
Produits Nestlé S.A.
real-world effectiveness data with high public health signifi-
The authors’ contributions are as follows: S. G. and I. J.
cance as non-anaemic or mildly anaemic infants account for
designed the research; S. A., U. N. R., M. M., S. S. and A. G. con-
approximately 60 % of the Indian infant population (31 and
ducted the research; C. I. C., D. G. and S. G. analysed the data;
29 %, respectively)(6) and would benefit most from a food-
S. A., C. I. C. and A. G. wrote the paper; S. A., S. G., C. I. C. and
based intervention that is more cost effective and sustainable
A. G. had primary responsibility for the final content. All authors
than Fe supplementation. On the other side, our design did
read and approved the final version of the paper.
not allow us to randomise the infants; hence, unknown con-
S. G., I. J., D. G. and C. I. C. are current employees of Société
founders might have influenced our results. This limitation
des Produits Nestlé S.A. The remaining authors report no con-
was partially overcome by having infants in the static obser-
flicts of interest.
vational group that were matched on certain key characteris-
tics with the IC. We analysed only one 24-h recall and were
therefore not able to capture day-to-day or seasonal varia-
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