NITI Aayog ICMR-NIN

EFFICACY AND SAFETY OF

IRON FORTIFIED RICE
IN INDIA

- A WHITE PAPER

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EFFICACY AND SAFETY OF IRON FORTIFIED RICE IN INDIA
- A WHITE PAPER

Publishing Agency: ICMR

Year of Publication: 2023

ISBN:

Suggested Citation: Hemalatha R, Samarasimha Reddy N, Sairam Challa,

Venkatesh K, Raghu Pullakhandam, Nandeep ER, Teena D, Mahesh
Kumar M, Raghavendra P. Efficacy and safety of iron fortified rice in India
- A white paper, ICMR-National Institute of Nutrition, Hyderabad. 2023.

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 NITI Aayog ICMR-NIN

EFFICACY AND SAFETY OF

IRON FORTIFIED RICE
IN INDIA

- A WHITE PAPER

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iv
TABLE OF CONTENTS
Foreword i
Message iii
Acknowledgements vi
List of Contributors vii
Abbreviations viii
Executive Summary ix
1. Scope of the Document 1
1.1 Background and Introduction 3
1.2 Fortification strategy of Government of India 5
2. Iron intakes after rice fortification and comparison with EAR and RDA 8
2.1 Iron intakes among Indian population through fortified rice 8
2.2 Total iron intake and risk of excess with iron fortified rice -
estimation by probability of inadequacy (PIA) approach 10
3. Limitations of the inadequacy analysis 13
4. Efficacy and safety of fortified rice 14
5. Dosage of oral iron supplements and its safety 21
5.1 Oral iron supplements and malaria 21
5.2 Oral iron supplements and diarrhoea, dysentery, and respiratory
infections 22
5.3 Oral iron supplements and gut inflammation and dysbiosis 23
5.4 Safety of iron used in rice fortification 24
6. Consumption of oral iron and the risk of non-communicable
diseases (NCDs): Diabetes Mellitus and hypertension 26

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 6.1 Diabetes Mellitus 26
6.2 Hypertension 28
7. Fortified rice intake and hemoglobinopathies 29
8. Fortified rice intake and behaviour change communication 32
8.1 Role of social and behaviour change communication on
fortified rice intake 32
9. Conclusions 35
References 39
Annexures 49

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 ACKNOWLEDGEMENTS
We thank the Secretary, Department of Health Research, Government of India
and the Director General, ICMR for the support and encouragement provided
for the preparation of the report.

Mr. PS. Ramarao, Technical Officer and Mr. S. Devendran, Senior

Technician-3 (Artist) are acknowledged and appreciated for designing and
layout.

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LIST OF CONTRIBUTORS
No. Name Designation Organization

Authors
1 Dr. Hemalatha R Director
2 Dr. Samarasimha Reddy N Scientist-E
3 Dr. Sairam Challa Scientist-E
4 Dr. Venkatesh K Scientist-E
ICMR - National Institute of
5 Dr. Raghu Pullakhandam Scientist-F
Nutrition, Hyderabad
6 Dr. Nandeep ER Scientist-B
7 Dr. Teena D Scientist-C
8 Dr. Mahesh Kumar M Scientist-C
9 Dr. Raghavendra P Scientist-C

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ABBREVIATIONS
AMB - Anemia Mukt Bharat
CNNS - Comprehensive National Nutrition Survey
EAR - Estimated Average Requirements
FPP - Ferric Pyrophosphate
FSSAI - Food Safety & Standards Authority of India
GOI - Government of India
ICDS - Integrated Child Development Services
MDM - Mid-Day Meal
MFPP - Micronized Ferric Pyrophosphate
NNMB - National Nutrition Monitoring Bureau
NPBI - Non-protein bound Iron
NFHS - National Family Health Survey
OWS - Other Welfare Schemes
Na Fe EDTA - Sodium iron ethylene diamine tetra acetate trihydrate
PM-POSHAN - Pradhan Mantri Poshan Shakti Nirman
PUFA - Poly Unsaturated Fatty Acids
RDA - Recommended Dietary Allowances
RNI - Recommended Nutrient Intakes
SBCC - Social and Behaviour Change Communication
SCFA - Short Chain Fatty Acids
SSNP - Social Safety Net Programs
TPDS - Total Public Distribution System
TUL - Tolerable Upper Limit
WHO - World Health Organization

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EXECUTIVE SUMMARY
Anaemia is a major public health concern among all age groups in India. The nationwide
data from the National Family Health Survey (NFHS-5) survey conducted in India, in
2019–21, showed prevalence of anaemia as 67%, 57% and 52% among children (aged 6–
59 months), women in the reproductive age group and pregnant women respectively.
Under the Anemia Mukt Bharat’s (AMB) six-pronged strategy, the government launched
fortified rice (with iron, folic acid and B12) through the social safety net programs such
as PM-POSHAN, Integrated Child Development Services (ICDS), Targeted Public
Distribution System (TPDS), and Other Welfare Schemes (OWS) as one of the strategies.

The Food Safety and Standards Authority of India (FSSAI) mandates the use of ferric
pyrophosphate (FPP: 28–42.5mg/kg) or sodium iron ethylenediaminetetraacetate
trihydrate (Na Fe EDTA 14–21.25 mg/kg) for fortification of rice with iron. Based on the
level of rice intake from the NNMB data, the total iron intake from FFP fortified rice was
estimated to be 0.9 mg/day among children aged 6–12 months, 5.9 mg/day among women
of reproductive age, 6.0mg/day among pregnant women, and 6.2mg/day among adult
men, with 35mg of ferric pyrophosphate (FPP) fortified in one kg rice. Alternatively, if
Na Fe EDTA is used at 17.6mg per kg rice, the total estimated daily iron intake from
fortified rice was estimated to be 0.5mg/day among children aged 6–12 months,
3.0mg/day among women of reproductive age, 3.0mg/day among pregnant women and
3.1mg/day among adult men. Fortification programs are designed to fill the gap between
the actual intake and the requirement (Estimated Average Requirement-EAR) of the
population. When comparing the estimated total iron intakes through FPP or Na Fe EDTA
fortified rice, the iron intakes are around the EAR for all the age groups, except for men
who may be taking 3mg iron higher than the RDA (ICMR-NIN, Nutrient
Recommendations, 2020). However, the iron intakes are well below the Tolerable Upper
Level (TUL) for all physiological age groups consuming fortified rice, and estimates
show no risk of excess iron consumption through fortified rice in India.

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By using the probability approach, the proportion of individuals with iron inadequacy
without any fortification ranged from 34% to 80%. The lowest (34%) inadequacy level
was found among sedentary adult males and highest (80%) was among 10–12 years and
16–17 years girls. Proportion of individuals with probability of inadequacy if rice alone
is fortified ranged from 5% to 59%, and the highest probability of inadequacy was seen
in 10–12 year-old girls (58%) followed by 16–17 year-old girls (59%). Proportion of
individuals with probability of inadequacy if both rice and salt are fortified ranged from
0.2% to 29%. The highest probability of inadequacy was seen in 10–12 year-old girls
with 29% followed by 23% in 16–17 year-old girls. However, with fortification of both
rice and salt, using the intake distribution it was observed that 0.99% of boys aged 16–
17; 2.4% of sedentary men and 3.8 % of moderate activity men are exposed to risk of
excess iron intake (above TUL). The average total iron intake with iron fortified rice does
not exceed 0.59 mg/kg/day. And, even with both fortified rice and fortified salt, the intake
does not exceed 0.78mg/kg/day.

Studies have consistently shown improvement in haemoglobin status with supervised

feeding, fortified foods or with iron supplements, but effectiveness studies are not
available. A Cochrane review, on impact and safety of rice fortification, analysed some
studies among children aged 5–18 year-old and non-pregnant, non-lactating women of
18–49 years, found a modest reduction in anaemia prevalence. As for safety issues, there
are no studies with fortified rice intake, but soluble oral iron supplements with 1–2 mg
iron/kg/day among children have shown increase in risk of diarrhoea, dysentery and
malaria (in endemic areas). In addition, the form of iron used in fortified rice is different,
from those that are commonly used in oral iron supplements, and therefore less likely to
pose any risk. Similarly, there are no primary or secondary studies conducted on the
association between fortified rice consumption and risk of diabetes mellitus or
hypertension or haemoglobinopathies. Also, studies on dietary non-haem iron intake have
not found any association of iron intake with type 2 diabetes, hypertension or
haemoglobinopathies or increase the risk of the same.

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Fortification of food is a cost-effective strategy to improve the nutrition status of
populations. However, as a public health measure fortification effort requires to be
dovetailed with regular monitoring of dietary intakes, impact evaluation, adverse effects
in different segments of populations, risk of over consumption, development of bio-
markers of excess intake and long-term health effects. Policy on Behavior Change
Communication (BCC) on consequences of anemia, role of fortification, importance of
dietary diversity and cooking procedures must be prioritized in the program. To inform
policy decisions, an impact evaluation and adverse effect study along with cost-
effectiveness analysis of fortified rice consumption is necessary.

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SCOPE OF THE DOCUMENT

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1. Scope of the document

This document provides a comprehensive analysis of the use of fortified rice in India with
a focus on its efficacy and safety. It covers the prevalence of anemia in India, from two
recent national surveys, and the various strategies adopted by the Government of India
(GOI) to address the issue. The document describes the plan of the GOI to implement the
usage of fortified rice through social safety net programs such as PM-POSHAN,
Integrated Child Development Services (ICDS) scheme, Targeted Public Distribution
System (TPDS), and Other Welfare Schemes (OWS).

The document also outlines the iron intake levels, the risk of inadequacy using the
probability approach and expected risk of excess intake among Indian population through
the consumption of fortified rice and salt using National Nutrition Monitoring Bureau
(NNMB) data. The efficacy and safety of rice fortification are evaluated based on the
latest update of the Cochrane review, other reviews that include randomized control trials
from around the world.

In addition, the document examines the potential risks of excessive iron intake from
fortified rice and its association with non-communicable diseases such as hypertension
and type-2 diabetes. The feasibility of side effects associated with iron from fortified rice
intake is analysed, and the impact of fortified rice on hemoglobinopathies is discussed.

Lastly, the document explores the role of social and behaviour change communication in
promoting the uptake of fortified rice among the general population. Overall, this
document provides a thorough assessment of the use of fortified rice in India, including
its benefits and potential risks, and the strategies for its implementation.

1.1 Background and Introduction

Anemia and iron deficiency are major public health concerns caused by a long-term
negative iron balance. Iron deficiency anemia, which is defined as low blood
haemoglobin concentration, is the most severe stage of iron deficiency. Although the

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terms ‘iron deficiency’ and ‘iron deficiency anemia’ are often used interchangeably, they
are not the same condition(1).

Recent nationwide data on iron deficiency anemia in different age groups is available
from the National Family Health Survey (NFHS-5) and the Comprehensive National
Nutrition Survey (CNNS)(2,3). According to the NFHS-5 survey conducted in 2019–21,
iron deficiency burden is highest among children aged 6–59 months (67.1%), women
aged 15–19 years (59.1%), and non-pregnant women in the reproductive age group
(57.2%). Men aged 15–19 years have a lower burden of 31.1%, while pregnant women
have a burden of 52.2%. However, the NHFS survey has been criticized for potentially
overestimating the anemia burden due to its use of capillary blood and estimation through
Hemocue photometer (hb 201+)(2).

The CNNS, lead by the Ministry of Health and Family Welfare, used venous blood and
estimated haemoglobin through the cyanmethaemoglobin method in children aged 1–19
years during 2016–2018. The prevalence of anemia in preschool children aged 1–4 years
is 40.5%, while it is 23.5% in school children aged 5–9 years and 28.4% in adolescents.
The prevalence of iron deficiency is 31.9% in preschool children (Serum Ferritin <12
mcg/lit), 17% in children aged 5–9 years (Serum Ferritin <15mcg/lit), and 21.5% in
adolescents(4).

Paradoxically, the CNNS showed higher prevalence of anemia in rural and poorer
children and adolescents and higher burden of iron deficiency in urban and richer
participants. Haemoglobin synthesis needs many other nutrients apart from iron including
good quality protein. The diets of poor children lack nutritious foods like fruits,
vegetables, milk, eggs etc. Moreover, they have more infections due to unhygienic
environment. Under these conditions, the utilization of iron for haemoglobin synthesis
becomes less efficient resulting in anemia. States such as Madhya Pradesh, Bihar,
Haryana, Jharkhand, U.P., West Bengal and Tripura have a high prevalence of anemia,
especially in children under 5 years of age.

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According to the World Health Organization (WHO), a prevalence of anemia ≥40% is a
serious public health problem, while a prevalence of 20–39.9% is a moderate public
health problem. A prevalence of 5–19.9% is considered a mild public health problem, and
less than 5% is not a public health problem(5).

1.2 Fortification strategy of Government of India

Anemia Mukt Bharat (AMB) was launched in March under the National Nutrition
Mission in India (Figure 1). The AMB has a comprehensive approach to prevent and
control anemia with six interventions, targeting six age groups, and six institutions(6).
The interventions include iron and folic acid (IFA) supplements, behaviour change
communication (BCC), test and treat anaemia, fortification with IFA, deworming and
addressing non nutritional causes of anaemia such as malaria, fluorosis,
hemoglobinopathies. One of the programs under intervention is the mandatory provision
of iron and folic acid fortified foods in government-funded health programs(6). The
implementation of fortified rice supply in India is planned in three phases with complete
coverage by March 2024(7). The government is supplying fortified rice through social
safety net programs like PM-POSHAN, ICDS, and Total PDS, targeting vulnerable and
high-risk groups(7).

Food fortification is one of the measures to reduce the burden of micronutrient

deficiencies and improve health of the population. CODEX defines fortification or
enrichment as ‘the addition of one or more essential nutrients to a food for the purpose of
preventing or correcting a demonstrated deficiency of nutrients in the population or
specific population groups(8).’ Fortification is a temporary measure to control
micronutrient deficiencies until more up-stream long term approaches such as
diversification of diets are made available. Micronutrient fortification is the most cost-
effective development intervention, as evidenced by reviews such as the Copenhagen
Consensus(9,10). Currently, the government of India's strategy for food fortification with
iron is targeted fortification, which aims to increase the intake of specific subgroups of
the population, rather than universal fortification(5). In contrast, mass fortification, which
adds one or more micronutrients to commonly consumed foods like cereals, milk, and

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condiments, is usually mandated, and regulated by the government sector(5). Fortification
programs are designed to fill the gap between the actual intake and the requirement
(Estimated Average Requirement-EAR) of the population.

Several countries worldwide are fortifying rice with iron, either as mandatory or voluntary
fortification, and details of fortification standards are described in Table 1.

Figure 1. Anemia Mukt Bharat Strategy

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 Table 1. List of countries with mandatory and voluntary fortification of
Rice with Iron(9)
Nutrient
S. Country Income Legislati level in
Region Standard comment
No & year status on status standard
(mg/kg)
Lower
Nicaragua
1 middle 24 24mg/kg
2014
income Americas
Panama High
2 24 24mg/kg
2009 income

Mandatory fortifycation
Papua New Lower
3 Guinea middle Oceania 30 3mg/100g
2007 income
Upper
Peru
4 middle Americas 42 4.2mg/100g raw fortified rice
2018
income
Philippines 60–90mg/kg acceptable
5 Lower Asia 75
2000 regulatory level raw rice
middle
Solomon Minimum level of 60mg/kg of
6 income Oceania 60
Islands 2018 iron
United States Each pound of the rice contains
7 of America Americas 42.9 not less than 13mg and not more
High
2017 than 26mg of Iron (Fe)
income
Bahrain Minimum allowance ppm 29,
8 43
2012 Maximum allowance ppm 57
Lower Asia
Bangladesh 5–7mg in 100 grams uncooked
9 middle 60
2015 rice, target range at factory
income
Upper Iron (Fe) Not less than 13mg
Belize
10 middle 19.5 and not more than 26mg;
2015
income we assumed the units were/ kg
Voluntary fortification

Americas This nutrient is required if

Canada High labeled ‘enriched’, at the
11 16
2021 income following amount per 100g of
pre-cooked rice: 1.6mg iron
28–42.5mg/kg level required for
India Ferric pyrophosphate. Different
12 35.25
2018 Lower levels required for Na Fe
middle Asia EDTA: 14–21.25mg/kg.
income 7mg per 100g uncooked rice;
Myanmar
13 70 the factory target range is 6.00–
2019
8.00 mg per 100g uncooked rice
Upper
Venezuela
14 middle Americas 150 15.0mg/100g
1993
income

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 2. Iron Intakes after rice fortification and comparison
with EAR and RDA
2.1 Iron intakes among Indian population through fortified rice
The Food Safety and Standards Authority of India (FSSAI) mandates the use of ferric
pyrophosphate (FPP: 28–42.5mg/kg) or sodium iron ethylenediaminetetraacetate
trihydrate (Na Fe EDTA 14–21.25mg/kg) for fortification of rice with iron in India. Ferric
pyrophosphate is added at a higher level to account for its lower bioavailability(17).
National Nutrition Monitoring Bureau (NNMB) data provides rice and iron intake
estimates for different age and physiological groups in the general population. These
estimates enable us to determine the iron intakes through ferric pyrophosphate (Table 2)
or Na Fe EDTA (Table 3) fortified rice consumption.

Table 2. Iron intakes with Rice fortification if Ferric Pyrophosphate is used for
rice fortification based on the NNMB data

Additional Total Iron EAR (RDA) of Iron deficit or

Total iron Iron intake intake Iron (mg/day) excess (mg/day)
Rice
intake from through with Requirement (requirement
Age group consumption
all foods in Fortified rice fortified as per (EAR) vs intake
(g/Day)
mg/day (mg/day) if rice 2020 with fortified
FPP is used* (mg/day) rice)
Women (WRA) 168.2 13 5.9 18.9 15 (29) 3.9
Pregnant women (0–6m) 172.7 13.23 6.0 19.3 21 (27) -1.7
Lactating women (0–6m) 185.6 14.35 6.5 20.8 16 (23) 4.8
Men 177.8 15.19 6.2 21.4 11 (19) 10.4
Infants 0–6m
6–12m 27.1 2.16 0.9 3.1 4 (6) 1.1
1–3 y 63.5 4.88 2.2 7.1 6 (8) 1.1
Children 4–6 y 90.3 7.59 3.2 10.8 8 (11) 2.8
7–9 y 115 9.02 4.0 13.0 10 (15) 3.0
10–12 y Boys 130.5 10.83 4.6 15.4 12 (16) 3.4
10–12 y Girls 136.7 9.93 4.8 14.7 16 (28) -1.3
13–15 y Boys 163.4 12.82 5.7 18.5 15 (22) 3.5
Adolescents
13–15 y Girls 147.4 11.2 5.2 16.4 17 (30) -0.6
16–18 y Boys 172.2 14.06 6.0 20.1 18 (26) 2.1
16–18 y Girls 150.2 11.27 5.3 16.5 18 (32) -1.5
*Ferric Pyrophosphate 35mg/kg is used for the above analysis

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 If 35 mg of ferric pyrophosphate is used for fortifying one kg rice, the estimated additional
daily iron intakes through rice consumption are 0.9mg/day among children aged 6–12
months, 5.9mg/day among women of reproductive age, 6.0mg/day among pregnant
women, and 6.2mg/day among adult men (Table 2), according to the NNMB data.

If 17.6 mg of Na Fe EDTA is used for fortifying one kg rice, the estimated daily iron
intakes through fortified rice consumption are 0.5mg/day among children aged 6–12
months, 3.1mg/day among adult men, 3.0mg/day among women of reproductive age, and
3.0mg/day among pregnant women (Table 3).

Table 3. Iron intakes with rice fortification if Na Fe EDTA is used for rice
fortification based on the NNMB data
Total Iron EAR (RDA)
Total iron Additional Iron of Iron Iron deficit or
intake
Rice intake intake through (mg/day) excess (mg/day)
with Requirement (requirement (EAR)
Age group consumpti from all Fortified rice
fortified as per
on (g/Day) foods in (mg/day) if Na Fe vs intake with
rice 2020
mg/day EDTA is used* fortified rice)
(mg/day)
Women (WRA) 168.2 13 3.0 16.0 15 (29) 1.0
Pregnant women (0–6m) 172.7 13.23 3.0 16.3 21 (27) -4.7
Lactating women (0–6m) 185.6 14.35 3.3 17.6 16 (23) 1.6
Men 177.8 15.19 3.1 18.3 11 (19) 7.3
Infants 0–6m
6–12m 27.1 2.16 0.5 2.6 4 (6) 0.6
1–3 y 63.5 4.88 1.1 6.0 6 (8) 0
Children 4–6 y 90.3 7.59 1.6 9.2 8 (11) 1.2
7–9 y 115 9.02 2.0 11.0 10 (15) 1.0
10–12 y Boys 130.5 10.83 2.3 13.1 12 (16) 1.1
10–12 y Girls 136.7 9.93 2.4 12.3 16 (28) -3.7
13–15 y Boys 163.4 12.82 2.9 15.7 15 (22) 0.7
Adoles-
cents 13–15 y Girls 147.4 11.2 2.6 13.8 17 (30) -3.2
16–18 y Boys 172.2 14.06 3.0 17.1 18 (26) -0.9
16–18 y Girls 150.2 11.27 2.6 13.9 18 (32) -4.1

*Na Fe EDTA 17.6 mg per Kg is used for the above analysis

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2.2 Total iron intake and risk of excess with iron fortified rice - Estimation
by probability of inadequacy (PIA) approach

This section summarizes the iron intakes for various physiological age groups in India
when rice is fortified with Ferric Pyrophosphate (FPP) or Na Fe EDTA and supplied
through different social safety net programs. These intakes are compared to the EAR,
RDA, and Tolerable Upper Limit (TUL) recommended by ICMR-National Institute of
Nutrition, 2020 (18).

The Estimated Average Requirement (EAR) is calculated based on balance studies or by

factorial approach using absorption and losses studies data or enzyme activity studies.
Thus, the EAR is adjusted for absorption. Adding two standard deviation to the EAR
gives the Recommended Dietary Allowance (RDA), which is the daily intake of 97.5%
of apparently healthy individuals in an age and sex-specific population group(18). The
RDA is conceptually similar to the Recommended Nutrient Intake (RNI) but may have
slightly different values for some micronutrients (Figure 2).

The probability of risk of inadequacy of nutrient intake was calculated as an average of

individual risk against the age and gender specific requirement distribution. Since the
NNMB data is a single day recall, it was not possible to derive the intra and inter-
individual variation, therefore, a 10% variation in dietary intakes of iron was considered
based on previous studies. The nutrient gap analysis was done by sequential and
incremental addition of the nutrient to the actual intakes (mean and SD) using R-program.
The iron inadequacy varied from 34 to 80% in the analyzed data; the lowest rate of iron
inadequacy was among ≥18 year old male subjects, and high level of iron inadequacy was
observed among adolescent girls and women (Table 4 & Fig 3). Also, inadequacy was
relatively higher among >10 year old female children and women, compared to male
subjects (Table 4).

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 Figure 2. Daily nutrient requirements in terms of EAR, RDA and TUL
(adopted from ICMR-NIN nutrient requirements for Indians, RDA & EAR, 2020)

The proportion of individuals with iron inadequacy even with fortification of rice was
significant; with probability of inadequacy ranging from 5% to 59%. The highest
probability of inadequacy was seen in 16–17 year-old girls with 59% followed by 58% in
10–12 year-old girls. Proportion of Individuals with probability of inadequacy if both rice
and salt are fortified ranged from 0.2% to 29%. The highest probability of inadequacy
was seen in 10–12 year-old girls with 29% followed by 23% in 16–17 year-old girls.
However, with consumption of both-fortified rice and salt, 1% of 16–17 year-old boys
and 2.4% to 3.8% of men are likely to get excess iron intake (above TUL) (Table 4 & Fig
3). And, all age groups cross the level of TUL, except 1–3 year-old children, through
regular intake of IFA through supplementation programs.

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 Table 4. Proportion of population with Probability of Inadequacy (PIA) and risk of
excessive iron intakes beyond TUL with fortified cereals and salt
Population
Population
Population with
Population with risk of
Population with PIA Expected
with PIA over Salt
Physiological with PIA with both risk with TUL in
without any consumption Intake
Group with fortified both mg
fortification of iron with in gm
fortified Rice and fortified
(%) fortified rice
Rice (%) Salt (%) Rice and
(%)
salt (%)
1–3 y 71 40 0 3 5 0 40
4–6 y 62 26 0 3 5 0 40
7–9 y 63 28 0.01 3 10 0.01 40
10–12 y
66 28 0.04 6 2 0.13 40
Boys
10–12 y
80 58 0.01 6 29 0.04 40
Girls
13–15 y
70 34 0.06 6 7 0.1 45
Boys
13–15 y
77 45 0.01 6 11 0.04 45
Girls
16–18 y
73 41 0 8 7 0.99 45
Boys
16–18 y
80 59 0 8 23 0.04 45
Girls
Male
34 8 0.63 8 0.4 2.41 45
(Sedentary)
Male
35 5 0.89 8 0.2 3.76 45
(Moderate)
Female
61 35 0.13 8 10 0.6 45
(Sedentary)
Female
64 30 0.17 8 8 1.01 45
(Moderate)

 The risk of probability of inadequacy (PIA) and excessive intakes beyond TUL were calculated based
on EAR, RDA and TUL values of ICMR-Nutrient Requirements 2020.
 The proportion of Individuals with Iron inadequacy with fortification of all cereals and with double
fortified salt was calculated by sequential and incremental addition of the nutrient to the actual intakes
(mean and SD) (Table 4).
 The fortification level of 35mg iron/kg rice (FPP) and 1mg iron/g of salt were considered, as per FSSAI
standards.
 The calculation is based on nutrient intake data of NNMB urban 2016.

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 Figure 3. Dietary iron intake and inadequacy by age groups
(Adopted from NNMB Urban data 2016)

3. Limitations of the inadequacy analysis

1. Double Fortified Salt (DFS): The DFS is not a mandatory fortification in India like
iodized salt. We have contacted 19 salt companies with whom NIN had MOU for
transfer of DFS technology. Most of the companies have not renewed the MOU with
NIN. Currently, only two states- Odisha and Himachal Pradesh are producing the NIN

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 DFS and are supplying through PDS. Using University of Toronto Technology, three
companies are producing the DFS with fumarate, however the supply details are not
shared. Nevertheless, assuming that DFS is consumed by every household we have
calculated the adequacy level by probability approach (Table 4).

2. As for Take Home Rations (THRs), we have analysed the data of THR from 30 states.
Only few states like Madhya Pradesh (Khichdi Premix), Kerala (Amrutham-
Nutrimix), Gujarat (Bal Sakhti) and Telangana (Balamrutham) are supplying iron
fortified THRs. However, this has not been included in the adequacy calculation as the
THR is not fortified in all states.

3. Prophylactic iron folic acid supplementation given through Anaemia Mukt Bharat
programme are given weekly or biweekly in some age groups which cannot be
considered for the daily iron intake estimations. Also, the compliance rates are
extremely poor, which was found to be <20% in spite of best efforts in the STAR Trial.
The NFHS-5 data also shows 29% compliance among pregnant women, which could
be much lower among other groups.

4. Efficacy and safety of fortified rice

The Cochrane Review on Rice Fortification analysed seven RCTs with a total of 1634
participants, ranging from 5–18 year-old school children and 18–49 year-old non-
pregnant, non-lactating women. The risk of anemia with unfortified rice was 388 per
1000, while fortified rice with iron alone or in combination with other micronutrients was
279 per 1000, resulting in an absolute reduction of 109 per 1000 and a relative risk of
0.72 (0.54–0.97). With TPDS coverage of 50% in urban regions and 75% in rural regions
and considering that 36% of the population lives in urban areas and 64% lives in rural
areas, fortified rice is estimated to have a minimum coverage of 66% in the country. We
have extrapolated the cases averted by considering only the age groups which were
included in the RCTs of the Cochrane review i.e Children in 5–19 years age group, WRA
(20–49 yrs). As per census 2011 (Ref: Census of India 2011) the above-mentioned age
groups will be 52.5% of the total population in India. Of this 52.5% population, 66% of
individuals are beneficiaries of Public Distribution System (PDS). After extrapolating to

14
the above mentioned age groups, the fortified rice programme will be catering to 34.6%
of the total population. Thus, we will be averting 5,26,22,545 ↓ (57,93,308–8,64,16,840)
cases of anemia and 3,76,56,500 ↓ (1,78,62,699–5,40,70,872) cases of iron deficiency
through iron fortified rice (Tables 5 & 6).

The Cochrane review also analysed eight RCTs with 1733 participants, including 4–18
year old school children and 18–49 year-old non-pregnant, non-lactating women. The risk
of iron deficiency was reduced from 228 per 1000 with unfortified rice to 150 per 1000
with fortified rice, resulting in an absolute reduction of 78 per 1000 and a relative risk of
0.66 (0.51–0.84). This reduction in risk of iron deficiency in India could potentially
benefit at least 7,17,32,697 people (Table 5).

Studies on haemoglobin concentration changes estimated in 11 RCTs, with a total of 2163

participants, comparing rice fortified with iron or iron with other micronutrients with
unfortified rice showed some improvements. The mean haemoglobin concentration was
0.183g/dL higher in the intervention (fortified rice) group than the group with unfortified
rice. The participants included 4–18 year-old school children and 18–49 year-old non-
pregnant, non-lactating women (Tables 7 & 8). Furthermore, there was one RCT with 215
girls aged 14–18 years that found a 4.30 (nmol/L) higher mean serum or plasma folate
(nmol/L) in the intervention group (fortified rice)(19). As regards to episodes of
diarrhoea, one RCT with 258 participants showed no adverse effect(24); another RCT
with 785 children aged 6–16 years assessed the risk of hookworm infection with rice
fortified with multiple micronutrients. The risk with unfortified rice was 119 per 1000,
while the risk with fortified rice was 211 per 1000, resulting in an increased risk of 92 per
1000 (RR 1.78, 95% CI 1.18–2.70) (Table 5).

15
 Table 5. Summary of the Cochrane Review on rice fortification with iron or iron
with other micronutrients

other micronutrients

Expected Impact in
Absolute reduction

No. of participants
fortified with iron

combination with
unfortified rice

Population age
Relative effect
Risk with rice

Certainty of
alone or in
Risk with

(95% CI)
Outcome

evidence
(studies)

India*
group
5–18-year-old
388 109 per 5,26,22,545 ↓
RR 0.72 1634 school children,
Anaemia per 279 per 1000 1000 (57,93,308- Low1
(0.54-0.97) (7 RCTs) 18–49-year-old
1000 (12-179) 8,64,16,840)
NPNL WRA
4–18-year-old
228 78 per 3,76,56,500 ↓
Iron RR 0.66 1733 school children,
per 150 per 1000 1000 (1,78,62,699- Low2
deficiency (0.51-0.84) (8 RCTs) 18–49-year-old
1000 (37-112) 5,40,70,872)
NPNL WRA
4–18-year-old
Hemoglobin The mean hemoglobin concentration (g/dL) in 2163
school children,
concentration the intervention groups was 0.183 g/dL higher (11 Low3
18–49-year-old
(g/dL) (0.066 to 0.30 higher) RCTs)
NPNL WRA
Serum or The mean serum or plasma folate (nmol/L) in Girls aged 14-
215
plasma folate the intervention group was 4.30 (nmol/L) higher 18 years (Avg Low4
(1 RCT)
(nmol/L) (2.00 to 6.60 higher) age = 16.1y)
Increase
119
Hook worm risk of 92 RR 1.78 785 Children aged
per 211 per 1000 Low5
infection risk per 1000 (1.18- 2.70) (1 RCT) 6-16 years
1000
(21-201)
Children aged
6-12 years
RR 3.52 with
0 per 258 Very
Diarrhoea 0 per 1000 (0.18- Hb>9g/dL and
1000 (1 RCT) low6
67.39) <11.5g/dL (6-
11y) or
<12g/dL (12y)
1; serious limitation in study design or execution (risk of bias), indirectness, Baseline characteristics not
similar and method of randomization unclear in half of studies.
2; serious limitation in study design or execution (risk of bias), indirectness, as most of the studies except
one were conducted among children.
3; serious limitations in study design or execution (risk of bias) and one for indirectness.
4; risk of bias being serious in the included study (Hardinsyah 2016), having selection bias, reporting bias
and presence of other bias.
5; one for inconsistency and one for indirectness.
6; one for inconsistency, one for indirectness and one for imprecision.
*66% the population of India are covered with Fortified rice through TPDS, ICDS, PM POSHAN
(pib.gov.in/beneficiaries of PDS).

16
 Table 6. Individual studies of fortified rice usage and its impact on Anemia(10)

Duration Effect size

Study Intervention Control
Study name Type of fortification of inter- (Relative Risk,
Population (Anemia/N) (Anemia/N)
vention 95% CI)

Children aged
Ferrous Sulphate and
Angeles- 6-9 years with RR 0.57 [0.41-
Micronized Ferric 6 months 40/112 37/59
Agdeppa 2008 Hb>=7 and <12 0.78]
Pyrophosphate (FeP80)
g/dL

Micronized Ferric
NPNL women
Pyrophosphate (20mg RR 0.31 [0.09-
Hotz 2008 with Hb>10.5 6 months 3/75 9/70
iron daily through 1.1]
and <13.5
fortified rice)

RR 1.15 [0.5-
Micronized Ferric
2.63]
Pyrophosphate (MDM
Children aged At the end of 8
Radhika 2011 consisting of 125 g rice 8 months 10/63 9/65
5-11 years months: FR: 38.1
(dry weight) containing
to 15.9, UFR: 40
19 mg Fe)
to 13.8
RR 0.4 [0.26-
Iron (na), zinc, thiamine, 0.63]
Girls aged 14-18 folic acid, vitamin B12, At the end of 15
Hardinsyah
years (Avg age niacin, and vitamin A to 15 weeks 20/108 49/107 weeks:
2016
= 16.1y) fulfil 75% RDA) (150g Intervention: 50 to
fortified rice per day) 18.5, Control:
18.7 to 45.7
Children aged
Iron (17.8mg), Zinc,
7-11 years with
Parker 2015 Thiamine, FA (150g RR 1.05 [0.85-
Hb >=7.0 and 7 months 84/152 77/146
(C) fortified rice for 5 days a 1.29]
<12.0
week for 7 months)
Cluster RCT
Perignon 2016 Children aged Iron, Zinc, FA, Vit A, RR 0.85 [0.55-
6 months 60/339 22/106
(C) 6-16 years B1, B3, B12, B6 1.32]
40–50% recommended
nutrient intake (RNI) for
Children aged vitamin A, thiamine, RR 1.05 [0.85-
6-12 years with niacin, vitamin B-6, 1.29]
Thankachan Hb>9g/dL and vitamin B-12, folate, iron At the end of 6
6 months 71/156 41/76
2012 <11.5g/dL (6- (Micronized Ferric months: HI: 59 to
11y) or <12g/dL Pyrophosphate), and zinc 53, LI: 61 to 39,
(12y) (High iron (12.5mg/100g C: 62 to 54
of rice), Low iron
(6.25mg/ 100g))

17
 Table 7. Individual studies of fortified rice usage and its impact on hemoglobin

Duration of intervention and

Study Type of Control
Study name Intervention (n) the effect Size
population fortification (n)
(Hb in g/dL)

Ferrous Sulphate At the end of 6 months:

Children aged
Angeles- and Micronized FeSO4: 11.19±0.61 to
6–9 years with i. 55; FeSo4
Agdeppa Ferric 59; UFR 12.1±0.85, FeP80: 11.31±0.48
Hb>=7 and ii. 57; FeP80
2008 Pyrophosphate to 12.23±0.73, Control:
<12 g/dL
(FeP80) 11.35±0.44 to 11.65±0.82

Iron (na), zinc,

Girls aged thiamin, folic At the end of 15 weeks:
Hardinsyah 14–18 years acid, vitamin 108; 150g fortified 107; Intervention: 12.03±1.19 to
2016 (Avg age = B12, niacin, and rice per day UFR 12.46±0.99, Control:
16.1y) vitamin A to 12.45±1.04 to 12.08±1.20
fulfil 75% RDA)

At the end of 6 months:

NPNL women Micronized 75; 20mg iron daily Intervention: 13.1 (12.9–13.4)
Hotz 2008 with Hb>10.5 Ferric through fortified 70; UFR to 14.2 (13.9–14.4), Control:
and <13.5 Pyrophosphate rice 13.0 (12.8–13.3) to 13.8 (13.5
- 14.1) p=0.069

6–13y old iron Micronized At the end of 7 months: FR:

Moretti 80; Fortified rice
deplete ferric 90; UFR 12.1±1.2 to 11.9±0.9, UFR:
2006b meals (10mg/g)
children pyrophosphate 12.1±1.3 to 11.6±1.1

At the end of 6 months:

Iron, Zinc, FA, Pl:12.36 to 12.26, URO:12.43
Perignon Children aged URO: 445, URN: 425;
2016 Vit A, B1, B3, to 12.41, URN: 12.36 to 12.30,
6–16 years 464, Nutririce: 454 Placebo
(C) B12, B6 Nutririce: 12.41 to 12.35;
Non-Significant differences

Extruded rice
with 10 mg Fe, 9
At the end of 5 months: TFR:
mg Zn, and 1050
12.7 (8-14.1) to 12.5 (10.2-
Pinkaew 4–12 y-old mg VA/g 101; Triple 102;
14.7), UFR: 12.6 (9.9-15.2) to
2013 children extruded rice Fortification UFR
12.4 (10.3-14.9); non-
(140 g cooked
significant difference
rice per school
meal per child)

18
 63; MDM At the end of 8 months: FR:
Micronized
Radhika Children aged consisting of 125 g 11.5±1.09 to 12.5± 1.05, UFR:
Ferric 65; UFR
2011 5–11 years rice (dry weight) 11.4±1.00 to 12.5±1.01 [Not
Pyrophosphate
containing 19 mg Fe significant]

40–50%
recommended
nutrient intake
Children aged
(RNI) for i.76; High iron
6–12 years At the end of 6 months: HI:
vitamin A, (12.5mg/100g of
with 11.2±0.61 to 11.4±0.87, LI:
Thankachan thiamine, niacin, rice)
Hb>9g/dL and 76; UFR 11.1±0.72 to 11.5±0.99, C:
2012 vit B6, vit B12,
<11.5g/dL (6- ii.80; Low iron 11.2±0.63 to 11.3±0.77;
folate, iron
11y) or (6.25mg/100g) (p<0.05)
(Micronized
<12g/dL (12y)
Ferric
Pyrophosphate),
and zinc

35 in each group;
Gp1: Iron fortified
Micronized meals, Gp2 : Beta-
At the end of 6 months: Gp1:
Ferric carotene fortified
Iron and 10.5±0.17 to 12.3±0.15, Gp2:
Pyrophosphate meals, Gp3: Retinyl
vitamin A 10.4±0.26 to 12.1±0.17, Gp3:
Hussain (4 mgFe/100g), palmitate fortified
depleted 5-8y 37; UFR 9.9±0.21 to 11.6±0.31, Gp4:
2014 retinyl palmitate meals, Gp4: Iron +
old school 10.0±0.21 to 11.9±0.30, Gp5:
600IU/g, and retinyl palmitate
children 10.2±0.15 to 12.0±0.21, C:
beta-carotene fortified meals,
10.4±0.10 to 10.6±0.21
2000IU/g Gp5: Iron + beta-
carotene fortified
meals

Children aged At the end of 7 months:

Iron (17.8mg), 547; 150g fortified
Parker 7–11 years 524; Intervention: 10.6 (1.1) to 11.7
Zinc, Thiamine, rice for 5 days a
2015 (C) with Hb >=7.0 UFR (1.5), Control: 10.9 (0.9) to
FA week for 7 months
and <12.0 11.8 (1.6): Not Significant

6; 100 Baseline Hb 10.6 ± 1.6 g

Seventeen
g/d of At the end of 2 weeks:
women with
9; 100 g/d of UFR Subjects in the iron fortified
iron deficiency Iron-fortified
Losso fortified rice rice (two group (+0.52) had a
(low iron rice (18 mg/100g
2017 (two cooked 0.75 cooked statistically significant
and/or low as FeSO4)
cup servings) 0.75 cup increase compared to placebo
ferritin)
servings) (-0.30) in Hb
anemia
(0.82 g, p=0.0035)

19
Table 8. Individual studies of fortified rice usage and its impact on iron deficiency

Study Study Duration of Intervention Control Effect size

Type of fortification
name population intervention (n/N) (n/N) RR, 95% CI

Children Ferrous Sulphate and

Angeles- aged 6–9 Micronized Ferric
years with Pyrophosphate (FeP80) 1.59 [0.07-
Agdeppa 6 months 1/112 0/59
Hb>=7 and 38.51]
2008
<12 g/dL

Girls aged Iron (na), zinc, thiamin,

Hardinsyah 14–18 years folic acid, vitamin B12, 0.79
15 weeks 27/108 34/107
2016 (Avg age = niacin, and vitamin A [0.51,1.21]
16.1y) to fulfil 75% RDA)
NPNL Micronized Ferric
women with Pyrophosphate
Hotz 2008 6 months 17/75 19/70 0.84[0.47,1.47]
Hb>10.5
and <13.5
6–13 y-old Micronized ferric
Moretti iron deplete pyrophosphate 0.51 [0.34,
7 months 23/92 45/92
2006b children 0.77]

Children Iron, Zinc, FA, Vit A,

Perignon aged 6–16 B1, B3, B12, B6 0.86 [0.48,
years 6 months 37/366 14/119
2016 (C) 1.53]

4–12 y-old Extruded rice with 10

children mg Fe, 9 mg Zn, and
Pinkaew 1050 mg VA/g 0.23 [0.05,
5 months 2/91 8/84
2013 extruded rice (140 g 1.06]
cooked rice per school
lunch meal per child)
Children Micronized Ferric
Radhika
aged 5–11 Pyrophosphate 8 months 9/63 24/65 0.39 [0.2, 0.77]
2011
years
Children 40–50% recommended
aged 6–12 nutrient intake (RNI)
years with for vitamin A,
Hb>9g/dL thiamine, niacin,
Thankachan 0.88 [0.41,
and vitamin B-6, vitamin B- 6 months 16/154 9/76
2012 1.89]
<11.5g/dL 12, folate, iron
(6-11y) or (Micronized Ferric
<12g/dL Pyrophosphate), and
(12y) zinc

20
5. Dosage of oral iron supplements and its safety
This section examines various clinical trials to analyse the relationship between the dose
of supplemental iron used and its adverse effects on outcomes such as mortality,
hospitalization, diarrhoea, respiratory tract infections, inflammation, and dysbiosis. There
are no studies that have looked at safety of fortified rice consumption across different age
groups, hence we have summarised some studies that dealt with oral iron supplements
and safety. Fortification programs aim to prevent nutrient deficiencies, while
supplementation is used to treat nutrient deficiencies. Iron is unique among nutrients in
that it has a narrow range of adequacy, making it challenging to fortify foods with it
without risk of adverse effects. Two possible mechanisms are explained behind the
adverse effects of excess iron: firstly, excessive non-protein bound iron (NPBI) can lead
to the production of reactive oxygen species and inflammation. Secondly, gut microbial
dysbiosis can occur due to unabsorbed iron. Since, the absorption rate of oral iron rarely
exceeds 30%, the unabsorbed iron can impact the microbial balance in the distal gut.
However, these findings from supplemental studies may not be directly applicable to
fortified rice consumption. Nevertheless, we have attempted to compare the safety level.
To determine the safe dose of iron when fortifying rice, the dose associated with adverse
effects is compared with the total daily intake of iron.

5.1 Oral iron supplements and malaria

The Pemba Clinical Trial conducted in Tanzania in 2006 was a key study that raised
concerns about iron supplementation (Annexure Table 1)(26). The trial used a dose of
approximately 1mg/kg/day of iron for 18 months, and supplementation was stopped due
to an increase in mortality and morbidity in the intervention group. Further analysis
showed that adverse effects were more common in iron-replete children than in those who
were iron deficient(26). Another study conducted in Ghana in 2013 by Zlotkin et al., also
reported an increased risk of hospitalization in the iron intervention group. This study
used a microencapsulated form of ferrous fumarate at a dose of 1–2 mg/kg/day for five
months. However, a concurrent study in Nepal, which is non-endemic for malaria and

21
was conducted by the same researchers who conducted the Pemba Trial, did not observe
any adverse effects of iron supplementation(27). Therefore, it is recommended that in
malaria endemic areas, iron deficiency must be corrected after prevention and treatment
of malaria(28). Three Cochrane reviews conducted after the Pemba Trial found no
evidence of increased adverse effects of iron in malaria-endemic regions if malaria
control and treatment programs were implemented(29–31).

5.2 Oral iron supplements and diarrhoea, dysentery, and respiratory

infections
Well-designed randomized controlled trials by Jaeggi et al., (2014) in Kenya and Soofi et
al., (2013) in Pakistan reported an increase in diarrhoea and dysentery upon iron
supplementation(34,35) (Annexure Table 2). These studies used ferrous fumarate at a
dose of 2mg/kg/day and found that children under the age of two were more predisposed
to gastrointestinal adverse effects. Mitra et al., (1997) from Bangladesh observed an
increased risk of diarrhoea, especially in infants, when supplemented with ferrous
gluconate at 2–3mg/kg/day(33). However, older children did not have an increased risk
for diarrhoea or respiratory illness. Soofi et al., (2013) also reported a negative effect of
zinc when supplemented along with iron (35) (Annexure Table 2). The co-administration
of zinc with iron increased the incidence rate of bloody diarrhoea and proportion of days
with watery diarrhoea, which may be due to competition between zinc and iron for the
surface transporter on the luminal epithelium of the gut. A systematic review by
Neuberger et al., (2016) also reported an increased risk of diarrhoea in studies that
supplemented with zinc and iron(29) (Annexure Table 3). However, iron supplementation
without zinc did not increase the risk of diarrhoea in children, as evidenced by a
systematic analysis of several studies (Annexure Table 4). Analysis by Neuberger et al.,
(2016) did not show an increased risk for respiratory infections on iron supplementation
(29) (Annexure Table 5). Similarly, Gera et al., (2012) did not find any conclusive
evidence for the risk of RTIs and diarrhoea in their systematic review(36). A dose of 1mg/
kg/day of soluble iron, when not administered with zinc, is likely to be optimal for

22
supplementation programs. However, depending on host and environmental factors, this
dose may be associated with diarrhoea/dysentery in children less than two years of age.

Gastrointestinal side effects (diarrhoea, constipation and abdominal pain) are observed in
adult women on iron supplementation (Annexure Table 6). A dose of more than 60 mg/
day of elemental iron is associated with an increase in GI side effects.

5.3 Oral iron supplements and gut inflammation and dysbiosis

Excess unabsorbed iron in the colon can potentially impact the microbiome. A study
conducted in Kenya by Jaeggi et al., (2014) found that a daily dose of 1 mg/ kg of iron as
ferrous fumarate increased faecal calprotectin and Enterobacteriaceae, indicating
potential dysbiosis(34) (Annexure Table 7). However, an Ivory Coast study that used
~1mg/kg/day of electrolytic iron for six months in school children did not report any
increase in gastrointestinal side effects but did find an increase in faecal calprotectin and
enterobacteria, as well as a decrease in lactobacilli. Additionally, the baseline levels of
enterobacteria were already high in the population studied and supplementation did not
improve iron stores(37). In South African children with a low enteropathogen burden,
iron supplementation (2mg/kg/day as FeSO4) did not significantly affect the dominant
bacterial groups in the gut, faecal SCFA concentration, or gut inflammation(38). Thus,
the efficacy and side effects of iron supplementation are related to baseline levels of
enteropathogens in the host.

Both iron deficiency and excess can lead to dysbiosis and inflammation. Iron
supplementation (30–60mg) during pregnancy has been shown to decrease diarrhea and
puerperal infection (Annexure Table 8). Furthermore, iron supplementation (60mg as
FeSO4) during pregnancy has been shown to decrease serum levels of hs-CRP in an Indian
study by Rajendran et al(39). In an Australian study by Nitert et al., low-dose iron
supplementation was found to increase the faecal levels of butyrate-producing
bacteria(40). Additionally, supplementation with vitamin E along with iron has been
shown to minimize the adverse effects of freely available colonic iron on the
microbiome(41). Concurrent administration of prebiotic galacto-oligosaccharide (GOS)

23
has also been found to decrease adverse effects and reduce the required supplementation
dose(42). In a study conducted in Kenyan children, the supplementation of 5 mg of iron
along with GOS was as effective as 12.5mg in reducing anemia(43). Finally, n-3 PUFA
supplementation along with iron has also been shown to reduce adverse effects and
increase iron stores effectively(44, 45).

5.4 Safety of iron used in rice fortification

Ferric Pyrophosphate is a type of iron used in rice fortification. Unlike other soluble forms
of iron like Ferrous Sulphate, Ferric Pyrophosphate is insoluble. However, its
bioavailability is enhanced through micronization, which increases the surface area of the
fortificant. Another recommended fortificant is Sodium iron ethylenediaminetetraacetate
trihydrate (Na Fe EDTA), which is a soluble form of iron that increases bioavailability in
the presence of phytates and polyphenols.

The use of EDTA in food is limited and approved by the FAO/WHO. Although the
approved limit of iron from Na Fe EDTA is 0.2mg Fe/kg/day, the recommended dose for
fortified rice (14–21.25mg/kg) is well within the approved limits for the dietary intake of
various age groups (Table 10).

The adverse effects of iron supplementation based on studies using soluble iron
compounds like FeSO4 and Fe Na EDTA cannot be extrapolated to micronized ferric
pyrophosphate, an insoluble form. Studies have shown that micronized FPP fortified with
rice or salt (20mg/day) has not caused an increase in serum CRP levels in India and
Africa.

Although Na Fe EDTA is more expensive and used at a lower concentration, the daily
intake of soluble Na Fe EDTA at the recommended low level is unlikely to cause any side
effects. With rice fortification using MFPP or Na Fe EDTA, the total intake of iron is less
than 1mg/kg/day in all age groups and, therefore, unlikely to cause adverse effects (Table
10).

24
 Table 10. Total iron intake in mg/kg body weight per day on consumption of rice
fortified with Ferric Pyrophosphate or Na Fe EDTA and fortified salt
(FPP 35mg/kg rice and Na FeEDTA 17.6 mg/kg rice)

Total iron
Total iron Total iron intake if
Body Rice intake if Na
intake fortified salt is used
Age group weight consumption Fe EDTA is
if FPP is used* with FPP rice
(kg) (g/Day) used#
(mg/kg/day) (mg/kg/day)
(mg/kg/day)
Women (WRA) 55 168.2 0.34 0.29 0.49
Pregnant women
65 172.7 0.30 0.25 0.42
(0–6m)
Lactating women (0–6) 55 185.6 0.38 0.32 0.52
Men 65 177.8 0.33 0.28 0.45
Infants 0–6m 5.8
6–12m 8.5 27.1 0.36 0.31 -
1–3 y 12.9 63.5 0.55 0.47 0.78
Children 4–6 y 18.3 90.3 0.59 0.50 0.75
7–9 y 25.3 115 0.51 0.43 0.63
10–12 y
34.9 130.5 0.44 0.38 0.61
Boys
10–12 y
36.4 136.7 0.40 0.34 0.57
Girls
13–15 y
50.5 163.4 0.37 0.31 0.49
Boys
Adolescents
13–15 y
49.6 147.4 0.33 0.28 0.49
Girls
16–18 y
64.4 172.2 0.31 0.27 0.44
Boys
16–18 y
55.7 150.2 0.30 0.25 0.44
Girls

Summary of Evidence
• The form of Iron used in rice fortification in India is insoluble micronized Ferric
pyrophosphate. Adverse effects are seen with soluble forms of iron like FeSO4 or
Ferric Fumarate at high dose (more than 1mg/kg body weight per day). Therefore,
studies on the adverse effects of soluble iron compounds cannot be applied to iron-
fortified rice with FPP.

25
 • The total iron intake through fortified rice is less than 0.59mg/kg/day for any age
group. Even if fortified salt is consumed, the highest daily iron intake for any age
group is 0.78mg/kg/day which is less than 1mg/kg/day.

• The dose (28-42.5mg/kg rice) and form of iron (FPP) used for rice fortification in
India is less likely to cause any adverse effects.

6. Consumption of oral iron and the risk of Non-

Communicable Diseases (NCDs): Diabetes Mellitus
(DM) and Hypertension

6.1 Diabetes Mellitus

There is currently no Cochrane review available on the relationship between iron intake
(whether through diet, fortification, or supplementation) and non-communicable diseases
(NCDs) such as diabetes or hypertension. However, for the purpose of this white paper,
we have examined the evidence from four systematic reviews that explore the association
between dietary iron intake and type 2 diabetes mellitus (T2DM)(51–54). We excluded
systematic reviews on type 1 DM and gestational diabetes mellitus since they do not
address diabetes mellitus as an NCD outcome.

The most recent systematic review by Shahinfar et al., (2022) is an improvement on

previous reviews since it addresses many limitations, including a predominantly western
population, short follow-up durations, and a lack of dose-response relations(63). It
includes 11 prospective cohort studies with over 320,000 participants and 28,837 incident
cases of T2DM from different geographic areas, with a mean follow-up period of 9.7
years. Most studies have adjusted for various factors, including age, gender, BMI,
hypertension, and lifestyle habits. However, the main limitation of this review is that since
the studies are observational, and with a long follow-up period, the causality of the risk
factors being investigated can be affected by unmeasured or residual confounding factors.

26
The review assessed the risk of T2DM associated with four dietary iron intake forms:
total dietary iron intake, dietary haem iron intake, dietary non-haem iron intake, and
dietary supplemental iron. The findings show that dietary total iron, non-haem iron, or
supplemental iron intakes are not significantly associated with T2DM. A 5mg/day
increment in non-haem iron intake was not associated with the risk of T2DM, and a 5
mg/day increment in total iron intake was not related to the risk of T2DM. However, there
was a non-significant inverse association, with the risk decreasing from total iron intake
of 5–20mg/ day, with flattening of the curve at higher intake (Annexure Table 9 &10).

On the other hand, a higher haem iron intake was significantly associated with a greater
risk of T2DM, with individuals with the highest level of haem iron intake having a 20%
higher risk than those with the lowest level. The association was significant independent
of family history of T2D and intake of saturated fats and dietary fibre. A 1mg/day
increment in haem iron intake was related to a 16% higher risk of T2DM (Annexure Table
9 & Table 10). The main dietary source of haem iron is red and processed meat. Previous
meta-analyses of cohort studies have also shown a positive association between haem
iron intake and the risk of T2DM(64-66).

The underlying mechanisms of the positive association of dietary haem iron consumption
and T2DM appear to be complex and varied, with various hypotheses being proposed.
These include high bioavailability of iron from the haem form, excessive load of iron
stores due to the absence of iron excretion, oxidative stress, DNA damage, and disrupting
the integrity of the cell membrane, thus interfering with glucose uptake of muscle cells
and adipocytes and decreasing the action of insulin, long-term hyperinsulinemia, elevated
iron deposition, and the hazardous effects of reactive oxygen species on β-cells, all
contributing to β-cells destruction and T2DM.

27
Summary of Evidence
A systematic review based on long term cohort studies on dietary iron intake (as a proxy
for fortified iron) shows a positive association between haem iron intake and diabetes
mellitus but no association between non-haem iron intake and type 2 diabetes mellitus.
As rice fortification in India uses non-haem form of iron (FPP), type 2 diabetes mellitus
is not a cause of concern (67,68).

6.2 Hypertension

One prospective cohort study from China (69) provides evidence on the association
between iron intake and new onset hypertension, while no Cochrane or systematic
reviews are available. However, other studies have found inconsistent results on the
association between dietary iron intake and BP levels, and they were predominantly cross-
sectional studies(70–72).

The study on Chinese adults found a U-shaped association between dietary total iron
intake (including non-heme iron) and new-onset hypertension, with the lowest risk
observed at quintile 2–3(69). However, the association between dietary heme iron intake
and new-onset hypertension followed an L-shape. Participants with quintiles 2–5 of
dietary heme iron intake had a significantly lower risk of new-onset hypertension
compared to those in quintile 1 (Annexure Table 11). These findings suggest that the
association between dietary iron and the risk of hypertension is nonlinear, following a U-
shape for total or nonheme iron intake, and an L-shape for heme iron intake. If confirmed,
these findings highlight the importance of maintaining appropriate levels of dietary iron
for primary prevention of hypertension.

Adjustments for important covariates, including physical activity levels and the intakes
of vitamins A, B2, niacin, C, sodium, potassium, calcium, copper, zinc, magnesium, and
selenium, the intake of red meats, grains, fruits, and vegetables, or self-reported diabetes,
stroke, and myocardial infarction did not substantially alter the association between
dietary iron and new-onset hypertension.

28
The mechanism underlying this association is not certain, but low iron intake is thought
to deplete iron storage and contribute to iron deficiency, which may have adverse effects
on enzymatic reactions(73,74). Iron deficiency is also thought to activate chronic
inflammation and produce reactive oxygen species(75,76), leading to endothelial
dysfunction, which is the initial phase in the development of hypertension(77). Therefore,
moderate iron intake may be significantly associated with a reduced risk of hypertension.
However, when total or nonheme iron intake exceeds a certain level, the risk of
hypertension may increase. Higher iron intake may catalyse the generation of reactive
oxygen species, lipid peroxidation, and LDL-oxidation, which damage cellular
macromolecules, promote endothelial injury, and atherosclerotic plaque
formation(78,79). Further studies are needed to confirm these mechanisms.

Summary of Evidence

Primary or secondary studies have not examined the association between iron intake
through fortified rice and hypertension. A single prospective study on dietary iron intake
and new onset hypertension among Chinese adults shows an association between haem
iron intake and new onset hypertension. From the available evidence, it cannot be
concluded that the consumption of iron fortified rice increases the risk of hypertension.

7. Fortified rice intake and Hemoglobinopathies

Hemoglobinopathies

Hemoglobinopathies are genetic disorders that result from structural changes in

haemoglobin, which cause red blood cells to be improperly formed and prevent them
from effectively carrying oxygen to the body's tissues. In India, hemoglobinopathies like
sickle cell haemoglobin, beta-thalassemia, and haemoglobin E-related disorders are major
contributors to genetic morbidity and mortality (80).

The most affected states and communities are (80)

1. Sickle Cell Anemia (SCD)-Tribal populations (ST communities) in all Indian states.

29
 2. Thalassemia (beta type is most common) - Sindhis, Punjabis, Gujaratis, Bengalis,
Mahars, Kolis, Saraswats, Lohanas, and Gaurs are the most affected populations.
3. Hb-E-North eastern India.

Prevalence/ Burden of Hemoglobinopathies in India (80)

1. Sickle Cell Anemia (SCD)-The national prevalence ranges from 1 to 35%.
However, there are almost 7.5 crores carriers of the sickle cell trait in India.
2. Thalassemia (beta type is most common) - The national prevalence ranges from 1
to 10%. There are 65,000 beta-thalassemia patients with an annual increase of
10,000 patients. However, there are almost 3 crores carriers of beta-thalassemia in
India.
3. Hb-E - The prevalence ranges from 5% in the Bengali population to 3–50% in a
few pockets of Assam. However, other parts of India have not reported this trait.

30
Figure 4. Reported prevalence of hemoglobinopathies in India(80)

31
Iron Metabolism in Hemoglobinopathies
There are three types of presentations in any type of hemoglobinopathy. The first is the
carrier state, where individuals are apparently normal. The second type is where
individuals have mild symptoms with impairment of iron metabolism (absorption,
utilization, and storage). The third and most severe type of presentation is where
symptoms of iron impairment are worse, and regular blood transfusion is required(81,82).

Effect of Iron fortified rice on Haemoglobinopathies

According to available literature, iron-fortified rice may be beneficial for individuals with
mild forms of hemoglobinopathies with iron deficiency and those in carrier states(81,82).
However, caution must be exercised for those with severe forms of hemoglobinopathies,
where lifelong blood transfusion is required(81,82). According to the Thalassemia
International Federation guidelines, transfusion dependent patients should focus on
chelation and less on iron content from food.

Summary of Evidence

Iron overload and adverse effects in sickle cell anemia and thalassemia patients is due to
repeated blood transfusion and not due to rice fortification. Evidence shows that there is
no harm in carriers and in mild forms of hemoglobinopathies; and dietary iron is in fact
beneficial. However, people with severe hemoglobinopathies are under close supervision;
and the primary focus of people on transfusion dependant hemoglobinopathies should be
on chelation rather than iron content from food.

8. Fortified rice intake and behaviour change

communication
8.1 Role of social and behaviour change communication on fortified rice
intake
Any concerns from the public could be addressed through effective Social and Behaviour
Change Communication (SBCC) programs tailored to specific populations and cultural
practices. A study conducted in 2006 in Bengaluru(83) found that rice grains fortified
with Micronized Ferric Pyrophosphate (MFPP) were indistinguishable from unfortified

32
rice in both cooked and uncooked forms. Similarly, a feeding trial(66) conducted in
Hyderabad in 2011 found that the sensory qualities of cooked fortified rice and unfortified
rice were similar, with an overall acceptability of 86% and 97%, respectively. However,
SBCC can help to encourage choosing, identifying, and consuming fortified rice and
address any concerns regarding taste or acceptability.

In China(85), the National Nutrition Improvement Program of China used social

marketing strategies based on the six Ps (Product, Price, Place, Promotion, Policy, and
Partnership) to improve women's knowledge and attitudes about Iron-Fortified Soy Sauce
(FeSS). Similarly, an intervention program in Tanzania(86) encouraged vitamin A
fortified oil through community events and mobilization activities, resulting in
significantly higher knowledge and consumption of fortified oil in the intervention
districts compared to the control districts after nine months.

While rice fortification can be a midterm strategy for controlling iron deficiency, a long-
term approach is to improve dietary diversity, which can also prevent other micronutrient
deficiencies. SBCC can be used to improve dietary diversity, as demonstrated by the
Alive and Thrive initiative in Bangladesh(87) and a pilot-scale randomized trial among
women in Ghana(88), both of which showed improved diet diversity and consumption of
animal-sourced foods through counselling, community mobilization, and mass media
campaigns.

An amalgamation of fortification strategies and effective BCC strategies are thus a

prudent requirement for the success of any fortification intervention. SBCC should be
designed to include the importance of iron deficiency anemia and role of fortification,
importance of dietary diversity and cooking procedures.

33
34
9. CONCLUSIONS

35
36
9. Conclusions
The goal of food fortification is to ensure that 95% of the population in each life-stage
group consumes the Estimated Average Requirement (EAR) of the nutrient of concern.
Accurate intake data, including nutrient and vehicle, are critical for determining the
appropriate level of nutrients to be added, the vehicle to be used, and the population to be
targeted. Public health efforts to fortify food require regular monitoring of dietary intakes,
impact evaluation, adverse effects in different population segments, risk of
overconsumption, development of biomarkers for excess intakes, and long-term health
effects.

 There is a high level of iron inadequacy in Indian diet.

 Iron inadequacy may persist among adolescent girls despite rice fortification.
 Fortified rice consumption will result in a modest decrease in anaemia.
 The total iron intake through fortified rice is less than 0.59mg/kg body weight/day
for any age group, hence it is unlikely to cause any adverse effect.
 The form of iron used for rice fortification is insoluble micronized ferric
pyrophosphate. Adverse effects are observed when employing soluble iron forms
such as FeSO4 or ferric fumarate at high doses (exceeding 1mg/kg body weight per
day). Consequently, studies investigating the adverse effects of high doses of soluble
iron compounds cannot be extrapolated to fortified rice containing the insoluble form
of iron.
 There is no evidence that dietary non-haem form of iron increases the risk of type 2
diabetes mellitus or hypertension.
 There is no evidence for adverse outcomes related to iron fortified foods among
people with haemoglobinopathies. Iron overload and adverse effects in sickle cell
anemia and thalassemia patients is due to repeated blood transfusion and not due to
rice fortification. The primary focus of people on transfusion dependent
haemoglobinopathies should be on chelation rather than iron content from food.
 The dose (28–42.5mg/kg rice) and form of iron (FPP) used for rice fortification in
India should not be a cause of concern for any adverse effects.

37
38
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39
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ANNEXURES

49
50
 ANNEXURES
Table 1. Adverse effects of oral iron: Children mortality and hospitalization in
malaria endemic regions

Study Participants /groups Intervention Duration Results

Iron suppl. groups

(Gp1+Gp2) vs Placebo
a) Adverse events
RR 1·12 (1·02–1·23; p= 0·02)
b) Mortality
1-11 months RR 1·15 (0·93–1·41; p=0.19)
Sasawal Children 1–35 months;
Iron 6.25mg/d; c) Hospital admission
2006, Tanzania,
12-35 months RR 1·11 (1·01–1·23; p=0.03)
Pemba Gp1: Fe+FA (4037), 18 months
12.5mg/d as Gp1 (Fe without Zn) vs
trial, RCT Gp2: Fe+FA+Zn (4085)
ferrous sulfate Placebo
with 3 arms Gp3: Placebo (4073)
(~1mg/kg/d) Hospital admission
RR 1·08 (0·97–1·21; p =
0.16)
Gp2 (Fe with Zn) vs Placebo
Hospital admission
RR 1·14 (1·03–1·28; p = 0.02)

Adverse effect in
Gp1: Fe+FA (412), a)_Iron deficient vs placebo –
Pemba sub-
Gp2: Fe+FA+Zn (429) RR 0.62 (0·41–0·93; p = 0.02)
study
Gp3: Placebo (380) b) Iron sufficient vs placebo
RR 1.63 (0·72–3·66; p = 0.24)

Children 6 to 35 12.5 mg/d iron

months, (Hb>7g/dl), as micro Iron group vs No iron group
Zlotkin
Ghana Gp1: encapsulated Hospital admission RR, 1.23
2013, RCT 5 months
Iron+Zn+VitA+VitC ferrous (1.02-1.49). (Malaria,
with 2 arms
(942) fumarate. Diarrhoea, RTI and others)
Gp2: No iron (962) (1-2mg/kg/d)

Children 6–59 months

Uganda
Jaramillo immediate vs delayed iron
with malaria and 2mg/kg/d as 28 days
2017, RCT IRR all-cause sick-child visits
anaemia liquid ferrous concurrent/
with 2 arms to the clinic = 1.76 (1.05–3.03,
Gp1: Immediate Iron sulfate delayed
(33) p = 0.033)
(45)
Gp2: Delayed Iron (43)

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 Table 2. Adverse effects of oral iron: Diarrhoea/Dysentery

Study Participants/groups Intervention Duration Results

Children 6 months, Kenya, Home-fortified
Jaeggi RCT1 maize porridge with
27.3% of infants in +12.5
2014, 2 Gp1: MNP NaFeEDTA (25) MNP (2mg/kg/d)
mgFeMNP required treatment for
RCTs with Gp2: No iron (25) a) 2.5mg/d Fe as 4 months
diarrhoea versus 8.3% in -12.5
2 arms RCT2 NaFeEDTA
mgFeMNP (p=0.092);
each Gp1: MNP ferfumarate (25) b) 12.5 mg/d Fe as
Gp2: No iron (25) ferrous fumarate
Between 6-18 months
Proportion of days with diarrhoea
For 18
Soofi Children 6 months. Pakistan. Iron 12.5 mg/d as Fe MNP – OR 1.15 (1.00-1.33)
months;
2013, RCT Gp1: control (671), Gp2: microencapsulated Fe+Zn MNP – OR 1.31 (1.13-1.51)
outcome
with 3 MNP without Zn (646) ferrous fumarate Bloody diarrhoea IRR
at 24
arms Gp3: MNP with Zn (659) (2mg/kg/d) Fe MNP- IRR 1·63 (1·12–2·39)
months
Fe+Zn MNP- IRR 1·88 (1·29–
2·74)
49% greater episodes of dysentery
Mitra Children 2-48 months, in a subset of the study children <
Iron as Ferrous
1997, RCT Bangladesh, Gp1: 15 12 months old on supplementation
gluconate 15mg/d
with 2 Iron + MVit(172) Gp2: months (p = 0.03). No difference in older
(1-3mg/kg/d)
arms (34) Mvit (177) children with respect to diarrhoea,
dysentery, and ARI.

Table 3. Systematic review: Iron and evidence for increased risk of Diarrhoea
(studies with and without zinc)

Studies without ZINC Iron (n) Control (n) Iron form/dose Risk Ratio, 95% CI
Richard 6mth-15 yrs 1060 1073 0.75mg/kg/d 7mth FeSO4 0.99 [0.81,1.2]
Zlotkin 20 ± 8 mth 4835 4955 1mg/kg/d 5mth Fe-Fum 1.13 [0.85,1.5]
Adam 6-84 mth 1215 1146 3mg/kg/d 12wks FeSO4 1.03 [0.73,1.45]
Berger 2006 6 ± 1 mth 1200 1182 1.5mg/kg/d 6mth FeSO4 0.89 [0.6,1.32]
Berger 2000 6-36 mth 252 237 2-3mg/kg/d 3mth Febetain 0.56 [0.28,1.15]
Lawless 6-11 yrs 154 147 1.5mg/kg/d 14wks FeSO4 0.84 [0.3,2.3]
Dossa 3-30 mth 52 58 7.5mg/kg/d 6wks Fe-Fum 1.34 [0.41,4.39]
Subtotal 42.67% 8768 8798 0.99 [0.87,1.13]
Studies with ZINC Iron (n) Control (n) Iron form/dose Risk Ratio, 95% CI
Richard 0.5-15 yrs. 1071 1087 0.75mg, Zn 20mg/d 7mth 1.36 [1.19,1.57]
2mg/kg/d FeSO4
Fahmida 5 ± 1 mth 930 954 1.18 [0.93,1.51]
Zn 10mg 6mth
Berger 2006 6 ± 1 mth 1134 1170 1.5mg/kg/d 6mth FeSO4 0.99 [0.67,1.46]
Subtotal 57.33% 3135 3211 1.29 [1.15,1.44]
Total 100% 11903 12009 1.15 [1.06,1.26]

52
 Table 4. Systematic review: Iron and no evidence for increased risk of diarrhoea

Iron Control Risk Ratio,

Study Age Iron form/dose
Epi/ch-yr Epi/ch-yr 95% CI
Irigoyen 6 mth 20/114 13/53 3-6 mg/kg/d 3mth FeSO4 0.72 [0.34,1.56]
12–18
Idjradinata 19/8 21/7.6 3 mg/kg/d 4mth FeSO4 0.87 [0.44,1.69]
mth
Rosando 1.5–3 yrs 122/109
102/110 2 mg/kg/d 12mth FeSO4 1.2 [0.92,1.59]
1-3 mg/kg/d 15mth Fe
Mitra 2–48 mth 670/127 695/139 1.05 [0.95,1.17]
Gluconate
0.5-2 mg/kg/d
Rice 3–56 mth 388/268 376/267 1.03 [0.89,1.19]
12mthFeSO4
Lawless 6–11 yrs 7/11 8/10.5 1.4 mg/kg/d 3mth FeSO4 0.84 [0.26,2.63]
Atukorala 5–10 yrs 31/43 7/17 1 mg/kg/d 2mth FeSO4 1.72 [0.74,4.63]
Tielsch, 1 mg/kg/d until 36mth
1–36 mth 1327/341 1355/352 1.01 [0.94,1.09]
2006 FeSO4
Soofi, 2 mg/kg/d 18 mth Fe
6 mth 5813/3709 5607/3460 1.05 [0.94,1.17]
2013 Fumarate
Total 2584/1022 2577/957 0.97 [0.93,1.0]

Table 5. Systematic review: Iron and risk of RTIs

Iron Control Risk Ratio,

Study Age Iron form/dose
(n) (n) 95% CI

Berger 2006 6 ± 1 mth 1200 1182 1.5mg/kg/d 6mth FeSO4 1.05 [0.81,1.37]

Berger 2006 6 ± 1 mth 1134 1170 1.5mg/kg/d 6mth FeSO4 1.05 [0.8,1.38]

Richard2006 6mth–15 yrs 1060 1073 0.75mg/kg/d 7mth FeSO4 0.8 [0.52,1.23]

Richard2006 6mth–15 yrs 1071 1087 0.75mg/kg/d 7mth FeSO4 0.83 [0.52,1.33]

Esan 2013 6 –59 mth 315 312 3mg/kg/d 3mth 1.07 [0.5,2.27]

Zlotkin 2013 20 ± 8 mth 4835 4955 1mg/kg/d 5mth Fe-Fumarate 1.21 [0.54,2.7]

Berger 2000 6–36 mth 252 237 2-3mg/kg/d 3mth Febetaine 0.75 [0.3,1.91]

Fahmida 2mg/kg/d FeSO4

5 ± 1 mth 930 954 1.54 [0.26,9.21]
2007 Zn 10mg 6mth
Total 10797 10970 0.99 [0.85,1.15]

53
 Table 6. Systematic review: Adverse effects of iron in Non-Pregnant Women

Adverse effect No. of No. of Measure of difference

trials participants
Non-Pregnant Women 19–49 years
Gastrointestinal side effect 5 521 RR 1.99 [1.26 to 3.12]
Gastrointestinal side effect dose
31–60 mg 2 293 RR 1.23 [0.84,1.81]
61–100 mg 1 145 RR 3.00 [1.45,6.20]
>100 mg 2 83 RR 2.42 [1.45,4.05]
Loose stools/diarrhoea 6 604 RR 2.13 [1.10,4.11]
Hard stools/constipation 8 1036 RR 2.07 [1.35,3.17]
Abdominal pain 7 1190 RR 1.55 [0.99,2.41]
Nausea 8 1214 RR 1.19 [0.78,1.82]

Table 7. Adverse effects of Iron: Gut inflammation and dysbiosis

Study Participants /groups Intervention Duration Results
+FeMNPs increased faecal
calprotectin (p=0.002)
Children 6 months, Kenya, Home-fortified +FeMNPs increased enterobacteria,
RCT1 maize porridge particularly Escherichia/Shigella
Gp1: MNP NaFeEDTA with MNP (p=0.048), the
Jaeggi 2014,
(25) a) 2.5mg/d Fe enterobacteria/bifidobacteria ratio
2 RCTs with 4 months
Gp2: No iron (25) as NaFeEDTA (p=0.020), and Clostridium
2 arms each
RCT2 b) 12.5 mg/d Fe (p=0.030).
Gp1: MNP ferfumarate (25) as ferrous c) 27.3% in +12.5 mgFeMNP
Gp2: No iron (25) fumarate required treatment for diarrhoea
versus 8.3% in -12.5 mgFeMNP
(p=0.092);
a significant increase in the number
of enterobacteria (P < 0.005) and a
decrease in lactobacilli (P < 0.0001)
Children 6-14 years. increase in the mean fecal
20mg Fe as
Ivory Coast calprotectin concentration (P < 0.01)
Zimmermann electrolytic iron
Gp1: Fe fortified 6 months No significant difference in
2010, RCT (insoluble but
biscuits(70) 4d/wk gastrointestinal illness
with 2 arms bioavailable
Gp2: Anemic African children carry an
iron)
nonfortifiedbiscuits(69) unfavorable ratio of fecal
enterobacteria to bifidobacteria and
lactobacilli, which is increased by
iron fortification.
African children with a low
Children 6-11 years.
enteropathogen burden, Fe status and
South Africa
Dostal 2014, dietary Fe supplementation did not
Gp1: Fe deficient (22) 50 mg Fe as 9 months
RCT with 2 significantly affect the dominant
Gp2: Placebo (27) FeSO4 4d/wk
arms bacterial groups in the gut, faecal
Gp3: Fe sufficient (24)
SCFA concentration or gut
(microbiome comparison)
inflammation.

54
 Table 8. Systematic review: Beneficial effects of iron in Pregnant Women

No. of No. of
Adverse effect Measure of difference
trials participants
Pregnant Women 15–49 years
(Daily supplements containing iron 30-60 mg versus same supplements without
iron)
Any adverse effect 11 2423 RR 1.29 [0.83,2.02]
Diarrhoea 3 1088 RR 0.55 [0.32, 0.93]
Puerperal infection 4 4374 RR 0.68 [0.50, 0.92]
Any adverse effect vs Dose of Iron
≤ 30 mg 6 1533 RR 1 [0.86,1.16]
30-59 mg 2 225 RR 2 [0.66,6.02]
≥ 60 mg 5 665 RR 4.42 [0.61,30.67]
Any adverse effect 11 1777 RR 0.56 [0.37,0.84]
Intermittent vs Daily
dose

Table 9. Dietary iron intake and risk of diabetes mellitus

(Systematic review: Shahinfar, Jayedi, and Shab-Bidar 2022)
Number if
Risk factor
cohorts Relative effect
(Highest vs. lowest Outcome Certainty of evidence
sample (n) (95% CI)
category)
incident cases
GRADE = very low
7 Cohorts
Dietary total iron Type 2 RR 1.09 (downgrades for
n=197,672;
intake Diabetes (0.92, 1.28) imprecision and
Cases=19,175
inconsistency)
11 Cohorts
Dietary heme iron Type 2 RR 1.2
n=323,788; GRADE=moderate
intake Diabetes (1.07, 1.35)
Cases=28,837
6 Cohorts
Dietary non-heme Type 2 RR 0.96
n=135,893 GRADE=very low
iron intake Diabetes (0.81, 1.15)
Cases=8,978
2 cohorts
Type 2 RR 1.03
Supplemental iron n=120,729 GRADE=very low
Diabetes (0.86, 1.23)
Cases=6520

55
 Table 10. Dietary Iron Intake and Risk of Diabetes Mellitus
Systematic Review: Shahinfar, Jayedi, and Shab-Bidar 2022)(15)

Number if cohorts
Risk factor Relative effect
Outcome sample (n) Certainty of evidence
(dose response) (95% CI)
incident cases
7 Cohorts GRADE=very low
5 mg/day increment in Type 2 RR 0.99
n=197,672; (downgrades for imprecision
total iron intake Diabetes (0.97, 1.02)
Cases=19,175 and inconsistency)
11 Cohorts
1 mg/day increment in Type 2 RR 1.16
n=323,788; GRADE = moderate
heme iron intake Diabetes (1.03, 1.30)
Cases=28,837
6 Cohorts
5 mg/day increment in Type 2 RR 0.92
n=135,893 GRADE = very low
non-heme iron intake Diabetes (0.82, 1.03)
Cases=8,978
5 mg/day increment in 2 cohorts
Type 2 RR 1.02
supplemental iron n=120,729 GRADE = very low
Diabetes (0.96, 1.09)
intake Cases=6520

Table 11. Association between dietary iron intake and the risk of new-onset
Hypertension (Zhang et al. 2022) (21)
†
Iron intake, Events Adjusted model
N *
mg/day (rate ) HR (95% CI) P value
Total iron
Quintile
Q1 (<18.2) 2449 864(48.7) Ref
Q2 (18.2-<20.2) 2449 768(37.9) 0.80(0.72,0.88) <0.001
Q3 (20.2-<22.1) 2449 797(38.9) 0.80(0.71,0.89) <0.001
Q4 (22.1-<25.0) 2449 888(44.2) 0.89(0.80,0.99) 0.036
Q5 (≥25.0) 2449 987(58.0) 1.08(0.96,1.21) 0.189
Categories
Q1 (<18.2) 2449 864(48.7) 1.26(1.15,1.38) <0.001
Q2-3 (18.2-22.1) 4898 1565(38.4) Ref
Q4-5 (≥22.1) 4898 1875(50.5) 1.21(1.13,1.31) <0.001
Heme iron
Categories
Q1 (<0.25) 2448 1213(63.0) Ref
Q2-5 (≥0.25) 9797 3091(40.5) 0.71(0.65,0.78) <0.001
Non-heme iron
Categories
Q1 (<17.4) 2448 843(47.9) 1.33(1.21,1.46) <0.001
Q2-3 (17.4-21.3) 4899 1531(37.9) Ref
Q4-5 (≥21.3) 4898 1930(51.4) 1.24(1.15,1.34) <0.001

*Incident rate is presented per 1000 person-years of follow-up.

† Adjusted for age, sex, body mass index, smoking, systolic blood pressure, diastolic blood pressure, education, urban
or rural residence, region, occupations at baseline, as well as cumulative intake levels of carbohydrate, protein, fat,
red meats, grains, fruits and vegetables, and sodium to potassium intake ratio during the follow-up.
Mutual adjustment was performed for dietary heme and nonheme iron.

56