Fortification of rice with vitamins and minerals for addressing micronutrient malnutrition

Abstract

Background

Rice fortification with vitamins and minerals has the potential to increase the nutrition in rice‐consuming countries where micronutrient deficiencies exist. Globally, 490 million metric tonnes of rice are consumed annually. It is the dominant staple food crop of around three billion people.

Objectives

To determine the benefits and harms of rice fortification with vitamins and minerals (iron, vitamin A, zinc or folic acid) on micronutrient status and health‐related outcomes in the general population.

Search methods

We searched CENTRAL, MEDLINE, Embase, CINAHL, and 16 other databases all up to 10 December 2018. We searched ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (ICTRP) on 10 December 2018.

Selection criteria

We included randomised and quasi‐randomised trials (with either individual or cluster randomisation) and controlled before‐and‐after studies. Participants were populations older than two years of age (including pregnant women) from any country. The intervention was rice fortified with at least one micronutrient or a combination of several micronutrients (iron, folic acid, zinc, vitamin A or other vitamins and minerals) compared with unfortified rice or no intervention.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Two review authors independently screened studies and extracted data.

Main results

We included 17 studies (10,483 participants) and identified two ongoing studies. Twelve included studies were randomised‐controlled trials (RCTs), with 2238 participants after adjusting for clustering in two cluster‐RCTs, and five were non‐randomised studies (NRS) with four controlled before‐and‐after studies and one cross‐sectional study with a control (8245 participants). Four studies were conducted in India, three in Thailand, two in the Philippines, two in Brazil, one each in Bangladesh, Burundi, Cambodia, Indonesia, Mexico and the USA. Two studies involved non‐pregnant, non‐lactating women and 10 involved pre‐school or school‐age children.

All 17 studies reported fortification with iron. Of these, six studies fortified rice with iron only; 11 studies had other micronutrients added (iron, zinc and vitamin A, and folic acid). One study had one arm each with vitamin A alone and carotenoid alone. Elemental iron content ranged from 0.2 to 112.8 mg/100 g uncooked rice given for a period varying from two weeks to 48 months.

Thirteen studies did not clearly describe either sequence generation or allocation concealment. Eleven studies had a low attrition rate. There was no indication of selective reporting in the studies. We considered two RCTs at low overall risk of bias and 10 at high overall risk of bias. One RCT was at high or unclear risk of bias for most of the domains. All controlled before‐and‐after studies had a high risk or unclear risk of bias in most domains. The included studies were funded by Government, private and non‐governmental organisations, along with other academic institutions. The source of funding does not appear to have altered the results. We used the NRS in the qualitative synthesis but we excluded them from the quantitative analysis and review conclusions since they provided mostly contextual information and limited quantitative information.

Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

Fortification of rice with iron (alone or in combination with other micronutrients) may make little or no difference in the risk of having anaemia (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.54 to 0.97; I² = 74%; 7 studies, 1634 participants; low‐certainty evidence) and may reduce the risk of iron deficiency (RR 0.66, 95% CI 0.51 to 0.84; 8 studies, 1733 participants; low‐certainty evidence). Rice fortification may increase mean haemoglobin (mean difference (MD) 1.83, 95% CI 0.66 to 3.00; I² = 54%; 11 studies, 2163 participants; low‐certainty evidence) and it may make little or no difference to vitamin A deficiency (with vitamin A as one of the micronutrients in the fortification arm) (RR 0.68, 95% CI 0.36 to 1.29; I² = 37%; 4 studies, 927 participants; low‐certainty evidence). One study reported that fortification of rice (with folic acid as one of the micronutrients) may improve serum or plasma folate (nmol/L) (MD 4.30, 95% CI 2.00 to 6.60; 215 participants; low‐certainty evidence). One study reported that fortification of rice with iron alone or with other micronutrients may slightly increase hookworm infection (RR 1.78, 95% CI 1.18 to 2.70; 785 participants; low‐certainty evidence). We are uncertain about the effect of fortified rice on diarrhoea (RR 3.52, 95% CI 0.18 to 67.39; 1 study, 258 participants; very low‐certainty evidence).

Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

One study had one arm providing fortified rice with vitamin A only versus unfortified rice. Fortification of rice with vitamin A (in combination with other micronutrients) may increase mean haemoglobin (MD 10.00, 95% CI 8.79 to 11.21; 1 study, 74 participants; low‐certainty evidence). Rice fortified with vitamin A may slightly improve serum retinol concentration (MD 0.17, 95% CI 0.13 to 0.21; 1 study, 74 participants; low‐certainty evidence).

No studies contributed data to the comparisons of rice fortification versus no intervention. The studies involving folic acid and zinc also involved iron in the fortification arms and hence we reported them as part of the first comparison.

Authors' conclusions

Fortification of rice with iron alone or in combination with other micronutrients may make little or no difference in the risk of having anaemia or presenting iron deficiency and we are uncertain about an increase in mean haemoglobin concentrations in the general population older than 2 years of age. Fortification of rice with iron and other micronutrients such as vitamin A or folic acid may make little or no difference in the risk of having vitamin A deficiency or on the serum folate concentration. There is limited evidence on any adverse effects of rice fortification.

Plain language summary

Fortification of rice with vitamins and minerals for addressing micronutrient malnutrition

What is the aim of this review?

The aim of this Cochrane Review was to assess whether rice fortification with one or more vitamins and minerals in the general population aged two years or older improves nutritional status.

Key messages

Fortification of rice with iron alone or in combination with other micronutrients may make little or no difference in the risk of having anaemia but probably reduces the risk of iron deficiency and increases mean haemoglobin concentrations in population aged two years or above. If vitamin A is added, it may reduce the risk of having vitamin A deficiency and when folic acid is added, fortified rice may slightly increase serum folate concentrations.

What was studied in this review?

Micronutrient malnutrition compromises the health and well‐being of populations in many low‐ and middle‐income countries. Fortification is the addition of nutrients to foods to improve their nutritional quality. Rice is widely consumed as a staple food and is suitable for adopting as a food vehicle for fortification. This review addresses the benefits and harms of rice fortification with vitamins and minerals on micronutrient status along with health‐related outcomes, among participants aged two years and above, in addition to outcomes relevant to deficiencies in iron, vitamin A, zinc and folate.

What are the main results of the review?

We identified 17 studies (involving 10,483 participants) from Bangladesh, Brazil, Burundi, Cambodia, India, Indonesia, Mexico, Philippines, Thailand and USA. Twelve were randomised studies (2238 participants); 10 involved children, and two studies involved non‐pregnant non‐lactating women. In addition to iron, some studies had vitamin A, zinc or folic acid as fortifying agents, alone or in combination. Five non‐randomised studies (8245 participants), were assessed to augment the information on implementation and impact of fortification. The included studies were funded by government, private and non‐governmental organisations, along with other academic institutions. The source of funding does not appear to have altered the results.

We are uncertain about whether rice fortification with iron and other micronutrients reduces the risk of having anaemia although this intervention may increase mean haemoglobin concentrations (a biomarker of anaemia). We are uncertain if fortification of rice with iron alone or in combination with other micronutrients as compared to without any fortification, reduces the risk of iron deficiency.

Furthermore, consumption of vitamin A in the fortified rice, may make little difference on haemoglobin and serum retinol concentrations (a biomarker of vitamin A nutrition). We do not know whether fortification of rice has any adverse effects, in the mid‐ or long‐term, as the evidence was very limited. We found that the overall certainty of the evidence ranged from very low to low. Also, all studies used iron to fortify rice, so the effect of isolated nutrients may be hidden. There was no significant publication bias across the studies.

How up‐to‐date is this review?

The review authors searched for studies that had been published up to 10 December 2018.

Summary of findings

Summary of findings for the main comparison. Rice fortified with iron alone or in combination with other micronutrients compared to unfortified rice (no micronutrients added) for addressing micronutrient malnutrition among the included studies.

Rice fortified with iron alone or in combination with other micronutrients compared to unfortified rice (no micronutrients added) for addressing micronutrient malnutrition
Patient or population: general population older than 2 years of age (including pregnant women) from any country Setting: Burundi, Cambodia, India, Indonesia, Mexico, Philippines, Thailand and USA Intervention: rice fortified with iron alone or in combination with other micronutrients Comparison: unfortified rice (no micronutrients added)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with unfortified rice (no micronutrients added)	Risk with rice fortified with iron alone or in combination with other micronutrients
Anaemia (defined as haemoglobin below the WHO cut‐off, adjusted for altitude as appropriate)	Study population		RR 0.72 (0.54 to 0.97)	1634 (7 RCTs)	⊕⊕⊝⊝ Low1	Included studies: Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Parker 2015 (C); Perignon 2016 (C); Radhika 2011; Thankachan 2012
	388 per 1000	279 per 1000 (209 to 376)
Iron deficiency (as defined by study authors, based on a biomarker of iron status)	Study population		RR 0.66 (0.51 to 0.84)	1733 (8 RCTs)	⊕⊕⊝⊝ Low2	Included studies: Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Moretti 2006b; Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012
	228 per 1000	150 per 1000 (116 to 191)
Haemoglobin concentration (in g/L)	The mean haemoglobin concentration (g/L) in the intervention groups was 1.83 higher (0.66 to 3.00 higher)		‐	2163 (11 RCTs)	⊕⊕⊝⊝ Low3	Included studies: Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012
Vitamin A deficiency (as defined by the study authors)	Study population		RR 0.68 (0.36 to 1.29)	927 (4 RCTs)	⊕⊕⊝⊝ Low4	Included studies: Hardinsyah 2016; Perignon 2016 (C); Pinkaew 2014; Thankachan 2012
	105 per 1000	71 per 1000 (38 to 135)
Serum or plasma folate (nmol/L)	The mean serum or plasma folate (nmol/L) in the intervention group was 4.30 higher (2.00 to 6.60 higher)		‐	215 (1 RCT)	⊕⊕⊝⊝ Low5	Included study: Hardinsyah 2016
Any adverse effects (hookworm infection risk)	Study population		RR 1.78 (1.18 to 2.70)	785 (1 RCT)	⊕⊕⊝⊝ Low6	Included study: Perignon 2016 (C)
	119 per 1000	211 per 1000 (140 to 320)
Diarrhoea (as defined by study authors)	Study population		RR 3.52 (0.18 to 67.39)	258 (1 RCT)	⊕⊝⊝⊝ Very Low7	Included study: Thankachan 2012
	0 per 1000	0 per 1000 (0 to 0)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; WHO: World Health Organization
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded 2 levels: one for serious limitations in study design or execution (risk of bias) and one for indirectness. The baseline characteristics were not similar in all groups and the method of randomisation was unclear in half of the studies. Also studies used different cut‐off levels of haemoglobin to define anaemia. Hardinsyah 2016; Parker 2015 (C); Perignon 2016 (C); Radhika 2011 used WHO cut‐off levels, Hotz 2008 used CDC criteria and Angeles‐Agdeppa 2008 and Thankachan 2012 did not name the criteria they used.
 ²Downgraded 2 levels: one for serious limitations in study design or execution (risk of bias) and one for indirectness as most of the studies, except one (Hotz 2008), were conducted in children. There was negligible inconsistency among the studies.
 ³Downgraded 2 levels: one for serious limitations in study design or execution (risk of bias) and one for indirectness. Most of the included studies (except Hotz 2008; Losso 2017) were carried out among children. Losso 2017 was carried out in USA, which is a different study setting as compared to all other studies included.
 ⁴Downgraded 2 levels: one for serious risk of bias and one for inconsistency. Findings from the studies crossed line of no effect except one study (Thankachan 2012), which showed clear benefit due to fortification.
 ⁵Downgraded 2 levels for risk of bias being serious in the included study (Hardinsyah 2016), having selection bias, reporting bias and presence of other bias.
 ⁶Downgraded 2 levels: one for inconsistency and one for indirectness. Only one study in children assessed this adverse effect of hookworm infection in an endemic setting to soil‐transmitted helminth infections among participating children (Perignon 2016 (C)).
 ⁷Downgraded 3 levels: one for inconsistency, one for indirectness and one for imprecision. Only one study in children reported on this outcome and assessed it through asking participating children about symptoms and signs during the previous week (Thankachan 2012). Wide confidence intervals.

Summary of findings 2. Rice fortified with vitamin A alone or in combination with other micronutrients compared to unfortified rice (no micronutrients added) for addressing micronutrient malnutrition.

Rice fortified with vitamin A alone or in combination with other micronutrients compared to unfortified rice (no micronutrients added) for addressing micronutrient malnutrition
Patient or population: general population older than 2 years of age (including pregnant women) from any country Setting: India Intervention: rice fortified with vitamin A alone or in combination with other micronutrients Comparison: unfortified rice (no micronutrients added)
Outcomes	Anticipated absolute effects* (95% CI)	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with rice fortified with vitamin A alone or in combination with other micronutrients
Haemoglobin concentration (g/L)	MD 10 higher (8.79 higher to 11.21 higher)	‐	74 (1 RCT)	⊕⊕⊕⊝ Low1	Included study: Hussain 2014
Serum or plasma retinol (µmol/L)	MD 0.17 higher (0.13 higher to 0.21 higher)	‐	74 (1 RCT)	⊕⊕⊕⊝ Low1	Included study: Hussain 2014
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded by 2 levels: one level for risk of bias and one level for indirectness. The only study was carried out in India with a small sample size (250 children aged 5‐8 years) attending a school with a subsidised lunch feeding programme (Hussain 2014).

Background

Description of the condition

Adequate vitamin and mineral nutrition is required for optimal growth and development of children and for the maintenance of adequate health and nutrition of adult populations. Vitamin and mineral deficiencies may result in conditions such as anaemia, blindness, birth defects, retarded growth, diminished mental development and other poor health outcomes (Howson 1998; Oakley 2004; Darnton‐Hill 2005; A2Z Project 2008). Micronutrient deficiencies have also long been demonstrated to increase the risk of morbidity and, in some cases, mortality, especially from infection (Bhaskaram 2002; Singhal 2002; Black 2003). They also significantly and negatively impact on socioeconomic development at the individual, community and national levels (Darnton‐Hill 2005). Iron, vitamin A, iodine and zinc deficiencies constitute the world’s most common micronutrient deficiencies (WHO 2009b).

Iron

The World Health Organization (WHO) estimates that approximately 1.6 billion people are anaemic worldwide with half being women and children under five years of age (WHO 2015a). It is estimated that in 2016, 41.7% of children, 40% of pregnant women and 32.5% of non‐pregnant women had anaemia (Stevens 2013; WHO 2015a; WHO 2019). Although anaemia can be caused by multiple factors, iron deficiency is estimated to account for up to 50% at least of the anaemia burden, making it the single most widespread nutritional deficiency in the world (Graham 2001; Rastogi 2002; Stoltzfus 2011). Other conditions such as parasitic infections, inherited haemoglobin disorders, or nutritional deficiencies such as of folate or vitamin B₁₂ can also cause anaemia (WHO 2017). Thus, low haemoglobin concentrations are indicators of both poor nutrition and poor health (WHO 2011a). Before birth and during the first years of life, iron deficiency affects growth, neurodevelopment and cognitive performance (Lozoff 2006; Carter 2010), and may increase susceptibility to infections (Scrimshaw 2010). In adults, iron deficiency and anaemia cause the loss of healthy and productive lives due to their effects on work and physical capacity (Haas 1996). Pregnant women with iron deficiency are at higher risk of suboptimal pregnancy outcomes, including complications at delivery, low birthweight infants and preterm births (Peña‐Rosas 2015).

Vitamin A

Vitamin A deficiency causes xerophthalmia, which leads to night blindness and weakens the immune system, thereby increasing the risk of childhood morbidity and mortality (Sommer 1996). Vitamin A deficiency may increase the risk of morbidity and mortality during infancy, pregnancy and in the postpartum period (Sommer 1996; West 1999). It is estimated that vitamin A deficiency results in 18 million disability‐adjusted life years (DALYs) lost, a measure of overall disease burden that is expressed as the number of years lost due to ill‐health, disability or early death (WHO 2002). Vitamin A deficiency occurs mostly after prolonged deprivation of this vitamin (WHO/FAO 2004), and is a significant public health problem in many low‐ and middle‐income countries, most seriously affecting young children, women of reproductive age and pregnant women. According to recent estimates, 190 million preschool‐age children (under five years of age) and 19.1 million pregnant women have inadequate concentrations of retinol. Roughly 45% of all preschool‐age children and pregnant women with vitamin A deficiency live in the WHO regions of South‐East Asia, while Africa accounts for another 30% of cases (WHO 2009b). An analysis of trends of vitamin A deficiency showed a decline in the overall prevalence from 39% to 29% from 1991 to 2013, but Africa and South Asia had the least decline (Stevens 2015). Vitamin A deficiency alone is responsible for almost 6% of child deaths under the age of five years in Africa and 8% in South‐East Asia (WHO 2009a). It was estimated that in 2013, 1.7% of all deaths in children younger than five years were attributable to vitamin A deficiency (Stevens 2015).

Zinc

Zinc deficiency is considered to be associated with morbidity and mortality in low‐ and middle‐income countries. Severe zinc deficiency in children may cause short stature, impaired immune function and other disorders, and is a significant cause of respiratory infections, malaria and diarrhoeal disease (WHO 2002). Adequate zinc nutrition is essential for human health because of zinc’s critical structural and functional roles in multiple enzyme systems that are involved in gene expression, cell division and growth, and immunologic and reproductive functions (Hess 2009). Although there is very limited national‐ or first administrative‐level survey data on the prevalence of zinc deficiency, it has been estimated that zinc deficiency is responsible for approximately 4% of child mortality and DALYs (Black 2008). An estimated 17.3% of the global population is at risk of inadequate zinc intake. The regional estimated prevalence of inadequate zinc intake ranged from 7.5% in high‐income regions to 30% in South Asia. These country‐specific prevalences of inadequate zinc intake were calculated based on the estimated absorbable zinc content of the national food supply (Wessells 2012).

Folate

Inadequate intake is a leading cause of folate deficiency and insufficiency in the population although increased requirements from pregnancy or neoplastic diseases, malabsorptive conditions, use of antifolate drugs or other metabolic inhibitors can also cause folate deficiency (Bailey 2015). Inadequate periconceptional folate status and folic acid intake are associated with congenital malformations including neural tube defects (IOM 2003). Folic acid is a synthetic form of folate used in supplements and fortified foods (like wheat and maize flour) to reduce the occurrence of neural tube defects (NTDs). These defects include spina bifida (or cleft spine), where there is an opening in one or more of the bones (vertebrae) of the spinal column and anencephaly where the head (cephalic) end of the neural tube fails to close. It has been demonstrated through controlled studies that the risk of neural tube defects can be substantially reduced (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.17 to 0.58; 5 studies, 6708 births; high‐certainty evidence) with daily folic acid supplementation, alone or in combination with other vitamins and minerals (De‐Regil 2015). The effectiveness of mandatory folic acid fortification in wheat flour programmes has also been documented by a decline in the prevalence of neural tube defects, in the USA, Canada, Costa Rica, Chile and South Africa (Berry 2010). In general, populations from lower socioeconomic status do not consume sufficient high‐folate‐content foods, and although their diets may be adequate in folate intake to preventing clinical deficiency (i.e. megaloblastic anaemia), they may be insufficient to reach red blood cell folate concentrations associated with optimal health and fetal development (i.e. greatest NTD risk reduction) in women of reproductive age, that is concentrations above 400 ng/mL (906 nmol/L) (WHO 2015b).

Other vitamins and minerals

In addition to iron, vitamin A, zinc and folate deficiencies, those of iodine, calcium, vitamin B₁₂ and vitamin D impair health and development. For example, iodine deficiency is a major threat to the health and development of populations worldwide, particularly in preschool children and pregnant women, resulting in goitre, stillbirth and miscarriage, hypothyroidism, and impaired growth (Andersson 2012). Vitamin D deficiency (defined as low concentrations of serum 25‐hydroxyvitamin D) may be a common health problem worldwide (Bandeira 2006; Palacios 2014). A recent review found an important proportion of infants, children, adolescents, adults and older persons living in different countries with low serum vitamin D concentrations (Palacios 2014). These low concentrations were seen in all age groups, but in particular in girls and women from the Middle East. Vitamin D deficiency and/or perturbations of vitamin D metabolism; very low chronic calcium intake or a combination of both vitamin D deficiency and low chronic calcium intake, can cause nutritional rickets. Rickets is mostly associated with very low calcium intake in older children while in adolescents, the studies suggest that nutritional rickets is more associated with vitamin D deficiency (Munns 2016).

Intervention strategies for micronutrient malnutrition

Current recommended intervention strategies for the prevention and treatment of micronutrient deficiencies include either one or a combination of supplementation, food‐based approaches such as dietary diversification, mass food fortification or point‐of‐use food fortification; other public health control measures include deworming, health and nutrition education (Howson 1998; Zimmermann 2007; WHO 2011c). These strategies can be delivered through at least four platforms, the health systems, agriculture, market‐based, and social protection programmes (Olney 2012). Supplementation is still the most widely practiced intervention to control iron (WHO 2011b; WHO 2011d; WHO 2016) and vitamin A deficiencies in high‐risk populations (WHO 2011e).

Some adverse effects observed with high‐dose supplements, as well as active participation from users, may affect compliance and the long‐term sustainability of such programmes. Supplementation programmes (Baltussen 2004; Alderman 2007), usually face logistical and human‐resource constraints, such as bad road networks and generally fragile institutions, which may hinder their effectiveness, especially in low‐ and middle‐income countries where the intervention is needed most (Zimmermann 2007). In such cases, mass fortification of staple foods becomes an important option to combat vitamin and mineral deficiencies. There are fewer concerns related to mass food fortification and it can be a complementary intervention to supplementation for efforts to reduce vitamin and mineral deficiencies.

Meeting the recommended dietary intakes (WHO/FAO 2004), through the daily diet is desirable but not always possible for many populations. Poor dietary diversity and dependence on cereal‐based diets, which are common in low‐ and middle‐income countries, are major contributing factors to the high prevalence of micronutrient deficiencies (Welch 1999). Cereals, in addition to being poor sources of vitamins and minerals, also contain high quantities of other dietary compounds, such as phytates, which decrease the absorption of certain micronutrients, often called 'anti‐nutrients' (Graham 2001). For instance, iron and zinc absorption is significantly inhibited by phytic acid, present in cereals and other grains; polyphenols, contained in red wine and chocolate; or calcium, abundant in dairy products (Gibson 1998; Hurrell 2010; Kim 2011). On this basis, dietary bioavailability of iron has been estimated to be in the range of 14% to 18% for mixed diets and 5% to 12% for vegetarian diets.

Cereals, however, are overwhelmingly the major source of food supplies for direct human consumption. In 2014, around 2.5 billion tonnes of cereals were produced with roughly 1.1 billion tonnes (43%) used as food; around 900 million tonnes (35%) used as animal feed and the remaining 500 million tonnes were diverted to industrial usage or seed, or were wasted (FAO 2016). While rice is produced in vast areas of the world, the physical requirements for growing this crop are limited to certain zones. Rice is the primary staple for more than half the world’s population. Production and consumption is greatest in Asia (Muthayya 2014), and in recent years, it has also become an important staple in Africa (FAO 2012). About 741 million tonnes of rice (paddy) were harvested in 2014 (FAOSTAT 2016). The milled equivalent of rice produced is 490 million tonnes (FAO 2016).

Description of the intervention

Fortification is “the addition of one or more essential nutrients to a food, whether or not it is normally contained in the food, for the purpose of preventing or correcting a demonstrated deficiency of one or more nutrients in the general population or specific population groups" (Codex Alimentarius 1994). This process usually takes place during food processing by the food industry at a central level so that it reaches the intended population en masse and does not require the active participation of end users. While there are some different definitions for enrichment, for the purposes of this review, we used enrichment and fortification interchangeably.

Results of a study in Vietnamese school children showed that iron‐fortified rice noodles are efficacious in reducing anaemia and improving haemoglobin and iron status indicators (Huong 2006). In places where rice is a staple food, iron fortification has been shown to reduce the prevalence of iron‐deficiency anaemia from 100% to 33% among preschool age children (Angeles‐Agdeppa 2008), particularly when there is strong political support and intensive social marketing activities as well as efforts to keep the cost affordable (Angeles‐Agdeppa 2011). Zinc fortification of cereals can boost total zinc consumed daily and absorbed zinc in infants, young children and adults (Brown 2007). Although less frequent, fortification of wheat and maize flours with vitamin A has the technological and biological potential to palliate this deficiency (Klemm 2010). Perhaps the most well known area of micronutrient fortification is that of folic acid, in both wheat and maize flours, and its effect on the prevention of birth defects (WHA 2010). Well conducted studies from several countries have documented decreases of 26% to 42% in the occurrence of neural tube defect (NTD)‐affected births after implementation of national regulations mandating wheat flour fortification with folic acid (WHO 2009b). Food fortification brings together the benefit of energy, fat and protein, and the complementary roles of vitamins and minerals to enhance the stability and bioavailability of vitamins and minerals used to fortify foods (Best 2011). In addition, this strategy has a dual advantage of reaching a wider and larger proportion of the population than supplementation without requiring radical changes in food consumption patterns (Howson 1998).

Food fortification practices vary nationally. The choice of nutrients (in this context also known as fortificants) varies according to their bioavailability. In the case of iron, for instance, many compounds such as ferrous sulphate, ferrous fumarate, ferric pyrophosphate and electrolytic iron powder can be used in food fortification (WHO/FAO 2006). However, many cereal foods are fortified with low‐cost iron powders with absorption of iron lower than 2% (Hurrell 2010). For vitamin A fortification, retinyl palmitate and acetate are frequently used while the synthetic form of folic acid is used to improve folate status.

A concern expressed by a few people about food fortification is related to the possible toxicity of excessive vitamins and minerals among all groups, particularly those that are not at risk of deficiencies (Garcia‐Casal 2019). This is especially so with iron excess (Gordeuk 1987), which may affect the risk of colonic adenomas and cancer (Muthunayagam 2009), and a potentially more pathogenic gut microbiota that is associated with higher gut inflammation (Zimmermann 2010). Excess and chronic vitamin A intake during pregnancy has been shown to increase the risk of teratogenicity (Rothman 1995), and hip fracture (Penniston 2003). A hypothetical association between the prolonged consumption of folic acid‐enriched cereals and the increase in the incidence of colorectal cancer in the USA and Canada (Mason 2007), has been challenged with other studies where such an association has not been demonstrated (EFSA 2009). Another concern may relate to the possibility of over‐consumption of rice given the potential benefits of additional vitamins and minerals. As a public health intervention, the use of a vehicle would imply not encouraging the population to consume greater amounts of the 'fortified' rice. Higher consumption of white rice is associated with a significantly increased risk of type 2 diabetes, especially in Asian (Chinese and Japanese) populations (Hu 2012).

Micronutrient deficiencies of public health significance are all widespread in most high rice‐consuming countries (Juliano 1993; MIcronutrient Initiative/UNICEF 2004), and rice fortification has the potential to fill an obvious gap in current nutrition programmes and help aid vulnerable populations that are currently out of reach. A fundamental requirement in the adoption of food fortification as a public health intervention is the selection of the most appropriate and suitable food that will serve as a vehicle for the extra nutrients. It needs to be eaten in large amounts by the target population and be affordable and available all year round (Dexter 1998; WHO/FAO 2006). Although almost all foods can be fortified, cereals are widely grown, produced and consumed in low‐ and middle‐income countries (Welch 1999), making them important vehicles for fortification. Improving the micronutrient content of cereals or their subproducts could provide a sustainable solution to the worldwide problem of micronutrient deficiencies, particularly in populations where there is a marked social characterisation of eating habits (Prättälä 2012), and where the fortified foods will be reaching those in need of the vitamins and minerals. Poor children and their mothers systematically lag behind the better‐off in terms of mortality, morbidity and undernutrition. Evaluations of the equity impact of health programmes and nutrition interventions are scarce. There are, however, some results suggesting that innovative approaches can effectively promote equity through, for example, employing appropriate delivery channels; removing financial barriers; and monitoring implementation, coverage and impact with an equity lens. Mandatory fortification of staple foods being consumed by the most vulnerable segments of the populations would potentially provide vitamins and minerals to those in a vulnerable situation (WHO 2010), although it is clear that tackling inequities requires the involvement of various programmes and stakeholders, both within and outside the health sector, that can help address social determinants (WHO 2010).

How the intervention might work

Rice is a globally produced, milled and traded staple food with an annual production and consumption worldwide of about 490 million tonnes. It is the dominant staple food crop of around three billion people worldwide, providing up to 50% to 60% of their daily energy and protein intake (IRRI 2010). Rice is cultivated in almost all parts of the world as it can grow in a wide range of soil and environmental conditions (Juliano 1993). It is estimated that 90% of the world's rice is produced in Asia (Juliano 1993; Muthayya 2014). China and India consume 50% of the world's rice and per capita consumption is highest in Asia (Muthayya 2014). High consumption has been reported in Latin America and Caribbean countries as well as in sub‐Saharan Africa (Muthayya 2014). With its popularity, reach and quantum of consumption, rice far exceeds the requirements for adoption as a vehicle for food fortification for the purposes of a population‐level intervention.

Globally, the main rice processing method is milling. The process is aimed at producing a maximum yield of unbroken milled rice compared to flour or meal in other cereals (Dexter 1998). The process involves cleaning the paddy or rough rice (un‐hulled rice grain) and de‐hulling (removing hull, germ and bran layers) to produce brown rice (Dexter 1998). Brown rice consists of an average weight of 6% to 7% bran, 90% endosperm and 2% to 3% embryo (Saunders 1979). Further milling to remove the bran layer yields white rice. On average, paddy rice produces 25% hulls, 10% bran, and 65% white rice (Chen 1998). In some countries the milled white rice is coated with talc and glucose to improve its appearance (Dexter 1998). The various forms of rice are presented in Table 3. Milled white rice is low in vitamins and minerals as these vitamins (B vitamins) and minerals (iron) are found predominately in the germ and bran layers (Dexter 1998). Parboiling is one of the ways by which nutrients in the rice grain can be partially preserved. The parboiling process of soaking the rough rice, applying heat, drying and milling results in the transfer of nutrients to the inner endosperm layer from the bran before milling (Dexter 1998). Parboiling is expensive and the end product, referred to as ‘golden colour rice’, may not be readily acceptable to consumers (Dexter 1998). The different types rice are depicted in Table 3.

1. Description of various forms of rice.

Forms of rice	Description of rice
Rough rice (paddy rice)	Rice kernels still enclosed in an inedible, protective hull
Brown rice	Rice with only the hull removed. Bran layers and rice germ remain, giving the rice a brown colour
Parboiled rice	Rice pressurised to gelatinise the starch within the rice kernel, resulting in a firmer, more separate grain that is more stable and less susceptible to overcooking than regular‐milled white rice
Regular‐milled white rice (milled rice)	Polished whole rice, or polished rice. Hull, bran layer and germ have all been removed
Precooked rice	Regular milled white rice, parboiled milled white rice, and brown rice can be precooked and dehydrated before packaging. Examples of precooked rice are quick‐cooking rice, instant rice, and boil‐in‐the‐bag rice
Individually quick frozen (IQF) rice	Cooked grains are individually frozen before packaging
Crisped/puffed/expanded rice	Kernels can be processed in a number of different ways and shapes to meet particular manufacturing need

Adapted from Dexter 1998.

Previous attempts to fortify rice by simply adding a micronutrient powder to the rice that adheres to the grains by electrostatic forces (dusting) have proven unsuccessful (Leon Guerrero 2009), due to the typical washing and cooking methods employed in most developing countries, which results in the rinsing away of the enrichment. Three more sophisticated methods have been developed to overcome this problem (A2Z Project 2008). Coating involves spraying of the surface of ordinary rice grains in several layers with a vitamin and mineral mix to form a protective coating that will not easily rinse off the surface when washed (Kyritsia 2011). The grains (fortified premix) contain high concentrations of vitamin and mineral fortificants and must be blended with natural rice (that is commonly 1 part fortified premix to 199 parts untreated milled rice) to produce fortified rice. The extrusion technology is a totally different concept in rice fortification. In hot extrusion, a dough made of rice flour, vitamin and mineral mix and water is passed through a single or twin screw extruder and shaped into partially precooked grain‐like structures resembling rice grains; that is then blended with natural polished rice at a ratio of about 1:200 to produce fortified rice. This process involves relatively high temperatures (70 to 110 °C) obtained by preconditioning or heat transfer through steam‐heated barrel jackets, or both. The cold extrusion follows a similar process at low temperature (below 70 °C) that does not primarily utilise any additional heat and produces uncooked, opaque fortified premix grains with a slightly softer consistency. This is then blended with natural polished rice at a ratio of about 1:200 to produce fortified rice.

Rice is a highly culturally‐sensitive commodity (Hariyadi 2011). Growing, selecting and cooking of rice grains are subject to regional, national and even local preferences. It is estimated that a large proportion of key vitamins and minerals are lost during milling (DSM/Buhler 2010). Additionally, rinsing and washing are common cooking methods which can potentially dissolve added or restored nutrients. There are many different ways of cooking rice. These are 1) soaking, and boiling with excess water; 2) boiling in excess water; 3) boiling without excess water; 4) rinsing and boiling without excess water; and 5) frying and boiling without excess water. The use of these cooking preparations could have different retentions of micronutrients in fortified rice kernels as some vitamins are sensitive to heat and others are water‐soluble (WHO/FAO 2006). Cultural preferences for specific types of rice characteristics may represent a barrier to mass fortification in some settings. A technical challenge is to produce fortified rice that resembles natural rice and resists normal meal preparation and cooking processes.

A study conducted as far back as 1948 in the Philippines demonstrated the effects of rice fortification in the prevention of beriberi (Salcedo 1950). In Brazil, a bioavailability study with vitamin A‐fortified rice showed an improvement in children's retinol levels (Flores 1994). Another study among young children from 6 to 24 months of age in Brazil found that rice fortified with micronized iron pyrophosphate was more effective than iron drops in decreasing anaemia from 100% to 62%, and iron deficiency from 69% to 25%, and improving iron status (Beinner 2010). In a study in India, fortified rice in school‐age children attending school showed a reduction of iron‐deficiency anaemia from 78% at baseline to 25% in the iron group (Moretti 2006a). In another setting, the feeding of rice fortified with microencapsulated, micronized iron pyrophosphate to improve the iron status of women in Mexico showed significant increases in plasma ferritin concentrations and estimated body iron stores as well as a significant decrease in plasma transferrin receptor concentrations. Fortified rice reduced the prevalence of anaemia by 80% and iron deficiency by 29% in Mexican women working in a factory (Hotz 2008).

This review attempts to evaluate, based on existing research, the effectiveness of rice fortification as a public health intervention. The World Health Organization and Centers for Disease Control and Prevention (WHO/CDC) logic model for micronutrient interventions in public health depicts the programme theory and plausible relationships between inputs and expected improvements in Sustainable Development Goals and can be adapted to different contexts (WHO/CDC 2016). The effectiveness of rice fortification in public health depends on several factors related to policies and legislation regulations; production and supply of the fortified rice; the development of delivery systems for the fortified rice; the development and implementation of external and internal food quality control systems; and the development and implementation of strategies for information, education and communication for behaviour change among consumers. A generic logic model for micronutrient interventions that depicts these processes and outcomes is presented in Figure 1.

1.

WHO/CDC logic model for micronutrients interventions in public health (with permission from WHO)

The high consumption of polished rice as a staple food in many settings has been associated with an increased risk of diabetes and other chronic diseases although the results of the studies have been conflicting. One systematic review and meta‐analysis has been published with respect to polished rice and diabetes studies (Hu 2012), and another has been published with respect to rice and the incidence of chronic diseases including diabetes (Saneei 2017). The earlier meta‐analysis included four prospective cohort studies and found that higher white rice consumption was associated with increased risk of developing type‐2 diabetes in comparison with lower intake levels (relative risk 1.27 (95% CI 1.04 to 1.54; Hu 2012). This association was stronger for Asian (Chinese and Japanese) populations, although the dose‐response relations indicated that even for Western populations with typically low intake levels, white rice consumption may still modestly increase risk of diabetes. A more recent meta‐analysis (Saneei 2017), did not show an increased risk of diabetes with higher rice consumption due to an additional study from Spain (Soriguer 2013), which showed that a negative association was found between white rice intake and the six‐year incidence of diabetes. No disaggregation of the estimates was done in Saneei 2017 for origin of population but both Hu 2012 and Saneei 2017 showed an increased risk of diabetes or chronic diseases among women who consumed more rice. Rice fortification policies may have to take into account the possible increased risk of diabetes and other diseases with rice consumption and identify fortification levels targeting existing rice consumption levels as has been done for salt iodisation and salt reduction policies (WHO 2014). Additionally, the fortification of this staple food may affect acceptability of the fortified rice and thus potentially change dietary patterns (Khanh 2014).

Why it is important to do this review

Vitamin and mineral deficiencies are important public health concerns worldwide. Among the options to address these deficiencies, mass fortification represents an appealing intervention as it takes advantage of the existing market and delivery systems, does not require the active participation of vulnerable populations to increase food intake or diversify the diet, and has few safety concerns. Rice represents a suitable vehicle for fortification as it is considered a staple food in most of the world, especially in regions where micronutrient deficiencies are most evident.

Wheat and maize flour fortification with iron alone, or in combination with folic acid and other micronutrients, has been implemented in more than 50 countries (CDC 2008; WHO 2009b) and is showing promising results in reducing anaemia and neural tube defects (Centeno Tablante 2019; Garcia‐Casal 2018). Based on this experience, an increasing number of countries across the world are rapidly adopting fortification of rice as a means to fight malnutrition. Mandatory fortification of rice has been adopted in some countries, such as the Philippines, Costa Rica, Papua New Guinea and Nicaragua (GAIN 2010). Fortified rice is sold in China using a multi‐micronutrient formula and in Japan enriched rice has been on the market since 1981. The USA has a mandatory food standard for 'enriched rice', prescribing levels of thiamin, niacin, riboflavin, folic acid and iron to be added to rice for enrichment. Although this requirement only applies in order for rice to be labelled as 'enriched' (FDA 2001), 70% of the rice eaten in the USA is enriched or fortified (American Rice Inc 2004; A2Z Project 2008). In India, Brazil and Colombia, fortified rice is currently being distributed through public safety net programmes (Tsang 2016).

Despite this interest, to date there has been no systematic assessment of the benefits and harms of this intervention to inform policymaking and assist countries in the design and implementation of appropriate food‐fortification programmes, except for one systematic review carried out on interventions among children between 6 to 59 months (Hijar 2015). Rice fortification was concluded to be effective for correcting and improving iron deficiency in children aged under five years of age.

Objectives

To determine the benefits and harms of rice fortification with vitamins and minerals (iron, vitamin A, zinc or folic acid) on micronutrient status and health‐related outcomes in the general population.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs). Such studies provide information on whether fortified rice is effective and can actually achieve changes in health and vitamin and mineral status for those receiving the intervention.

Food fortification is, however, an intervention that aims at reaching the entire population of a country or large sections of the population and is frequently delivered through the food system. Therefore we have also included data from other study designs.

In summary, we aimed to include the following study designs.

1. RCTs, with randomisation at either the individual or cluster level

2. Quasi‐RCTs (where allocation of treatment has been made, for example, by alternate allocation, date of birth, or alphabetical order)

3. Non‐randomised controlled trials

4. Observational studies that are prospective and report a kind of control group:

   1. cohort studies (prospective and retrospective);

   2. controlled before‐and‐after studies with at least two control and two intervention sites;

   3. interrupted time series with at least three measure points both before and after the intervention.

We analysed results from controlled non‐randomised and observational study designs separately from randomised and quasi‐randomised study designs.

We did not consider before‐and‐after studies without a control group for inclusion in this review. Results from these studies are presented in a table but are not included in a meta‐analysis and do not directly inform the conclusions of the review. Such studies provide information on the implementation, feasibility and other contextual factors relating to the interventions under review. We did not include cross‐over trials.

Types of participants

General population older than two years of age (including pregnant women) from any country. We excluded studies of interventions targeted toward participants with a critical illness or severe co‐morbidities.

Types of interventions

Interventions in the review were those in which rice had been fortified with at least one micronutrient or a combination of several micronutrients (iron, folic acid, zinc, vitamin A or other vitamins and minerals) irrespective of the method of fortification technology used. Fortified rice, for the purposes of this review, refers to the addition of a micronutrient premix to ordinary rice using any rice fortification technologies, such as hot extrusion, cold extrusion, coating or dusting (A2Z Project 2008). We included studies with co‐interventions, that is, fortified rice with education, if the comparison group also received the education component in addition to the unfortified rice.

Comparisons include the following.

1. Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

2. Rice fortified with iron alone or in combination with other micronutrients versus no intervention

3. Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

4. Rice fortified with vitamin A alone or in combination with other micronutrients versus no intervention

5. Rice fortified with zinc alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

6. Rice fortified with zinc alone or in combination with other micronutrients versus no intervention

7. Rice fortified with folic acid alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

8. Rice fortified with folic acid alone or in combination with other micronutrients versus no intervention

If studies examined the effects of two or more nutrients along with iron, we included them in the first comparison only to avoid duplication. If the studies had micronutrients in their fortification arms without iron, we included them in the further comparisons.

We excluded studies comparing rice fortification with other forms of micronutrient interventions (i.e. supplementation or dietary diversification) or the fortification of other food vehicles. We also excluded in‐vitro studies and those examining the effect of bio‐fortified rice (nutrient‐dense staple crops of rice using conventional breeding practices and modern biotechnology).

Types of outcome measures

Primary outcomes

The primary outcomes across all populations in this review were the presence of anaemia, iron deficiency, haemoglobin concentrations and adverse effects.

1. Anaemia (defined as haemoglobin (Hb) below the WHO cut‐off, adjusted for altitude as appropriate (WHO 2011a), or as defined by the study authors)

2. Iron deficiency (as defined by study authors, based on a biomarker of iron status)

3. Haemoglobin concentration (g/L)

4. Vitamin A deficiency (as defined by study authors, by using a biomarker; only for vitamin A‐fortified rice as intervention)

5. Serum or plasma folate (nmol/L) (only for folic acid‐fortified rice as intervention)

6. Any adverse effects (as defined by study authors)

Additional primary outcomes of interest differed by participant group, as listed below.

Children (2 to 11.9 years of age)

1. Diarrhoea (as defined by study authors)

2. Respiratory infections (as defined by study authors)

3. All‐cause death

Pregnant women

1. Congenital anomalies (neural tube defect, cleft lip, cleft palate, congenital cardiovascular defects and others as defined by study authors; only for folic acid‐fortified rice as intervention)

2. Miscarriage

Secondary outcomes

Secondary outcomes included the following.

1. Serum or plasma retinol (µmol/L) (only for vitamin A‐fortified rice as intervention)

2. Serum or plasma zinc (µmol/L)

3. Anthropometric measures (height‐for‐age Z‐score and weight‐for‐height Z‐score for children, body mass index (BMI) for adults)

4. Risk of iron overload (defined by serum ferritin higher than 150 µg/L in women and higher than 200 µg/L in men)

5. Clinical malaria (as defined by study authors)

6. Severe malaria (as defined by study authors)

7. Night blindness (defined as the reported inability to see after dusk by people who typically report having normal vision during the day; only for vitamin A‐fortified rice as intervention)

For those studies that delivered the intervention at the first administrative level or higher (i.e. non‐randomised studies) we examined the same variables at an ecological level (for example prevalence of anaemia or congenital anomalies rates).

Search methods for identification of studies

Electronic searches

We searched the following international and regional sources.

International databases

1. Cochrane Central Register of Controlled Trials (CENTRAL; Issue 7 2012 to Issue 12 2018) via Cochrane Register of Studies Online (CRSO)

2. MEDLINE (OVID; 1948 to 10 December 2018)

3. Embase (OVID; 1980 to 10 December 2018)

4. CINAHL EBSCOhost (1937 to 10 December 2018)

5. Web of Science (ISI) SCI, SSCI, CPCI‐exp & CPCI‐SSH (until 10 December 2018)

6. POPLINE (www.popline.org/; 10 December 2018)

7. AGRICOLA (Ebsco; 10 December 2018)

8. ClinicalTrials.gov (searched 10 December 2018)

9. WHO International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch; searched 10 December 2018)

10. BIOSIS (ISI; 2012 to 10 December 2018)

Regional databases

1. IBECS (ibecs.isciii.es; searched 10 December 2018)

2. SciELO (Scientific Electronic Library Online; www.scielo.br; searched 10 December 2018)

3. African Index Medicus (AIM; www.globalhealthlibrary.net/php/index.php?lang=en; searched 10 December 2018)

4. Index Medicus for the Eastern Mediterranean Region (IMEMR; www.globalhealthlibrary.net/php/index.php?lang=en; searched 10 December 2018)

5. LILACS (Latin American and Caribbean Health Sciences Literature; lilacs.bvsalud.org/en; searched 10 December 2018)

6. PAHO (Pan American Health Library; www1.paho.org/english/DD/IKM/LI/library.htm; searched 10 December 2018)

7. WHOLIS (WHO Library; dosei.who.int/; searched 10 December 2018)

8. WPRIM (Western Pacific Region Index Medicus; www.wprim.org/; searched 10 December 2018)

9. Index Medicus for the South‐East Asia Region (IMSEAR; imsear.hellis.org; searched 10 December 2018)

10. IndMED, Indian medical journals; medind.nic.in/imvw/; searched to 10 December 2018)

11. Native Health Research Database; hslic‐nhd.health.unm.edu; searched to 10 December 2018)

For these sources, we searched WorldCat, Networked Digital Library of Theses and Dissertations, DART‐Europe E‐theses Portal, Australasian Digital Theses Program, Theses Canada Portal and ProQuest‐Desertations and Theses.

We handsearched the five journals with the highest number of included studies in the last 12 months to capture any article that may not have been indexed in the databases at the time of the search. As rice fortification technologies are relatively novel we limited the search, from 1960 to present, for all databases, although some had no time restrictions.

We contacted Cochrane Public Health's Information Specialist to search the Cochrane Public Health Group Specialised Register. The search used keyword and controlled vocabulary (when available), using the search terms set out in the Appendices and adapting them as appropriate for each database (see Appendix 1).

We did not apply any language restrictions. If we identified articles written in a language other than English, we commissioned their translation into English. If this was not possible, we sought advice from Cochrane Public Health. We stored these articles in the 'Awaiting assessment' section of the review until a translation is available.

Searching other resources

For assistance in identifying ongoing or unpublished studies, we contacted the Department of Nutrition for Health and Development and WHO regional offices, the nutrition section of the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the US Centers for Disease Control and Prevention (CDC), US Agency for International Development (USAID) micronutrient programme, Nutrition International, the Global Alliance for Improved Nutrition (GAIN), Hellen Keller International (HKI), Sight and Life Foundation, PATH, the Wright Group, premix producers DSM and BASF, Food Fortification Initiative (FFI) and the Rice Fortification Resource Group (March 2019).

Data collection and analysis

Selection of studies

Two review authors (JPP, PM) independently screened the titles and abstracts of articles retrieved by each search to assess initial eligibility. After the initial screening, we then retrieved full copies of all eligible papers and screened them for eligibility as determined by the inclusion and exclusion criteria listed above. When we were unable to reject a title or abstract with certainty, we obtained the full text of the article for further evaluation. If we could not obtain full articles, we attempted to contact the study authors to obtain further details of  the study. Failing this, we classified studies as 'awaiting assessment' until further information is published or made available to us. We resolved disagreements at any stage of the eligibility assessment process through discussion and consultation with two other review authors (SN, LMR), where necessary.

Data extraction and management

Two review authors independently extracted data in duplicate using customised data extraction forms based on those from Cochrane Handbook (Higgins 2019), Cochrane Public Health (Cochrane PHG 2010), and Cochrane Effective Practice and Organisation of Care (EPOC 2017).

All review authors were involved in piloting the form using a subset of articles in order to enhance consistency amongst review authors; based on this, we modified the form as necessary. We collected information on study design, study setting, participants (number and characteristics) and provided a full description of the interventions examined. We extracted details of outcomes measured (including a description of how and when outcomes were measured) and results.

Two review authors (JPP, LMR) designed the form, so that we were able to record results for our prespecified outcomes as well as for other non‐specified outcomes, although we did not use such outcomes to underpin any of our conclusions. We also extracted additional items relating to study recruitment and the implementation of the intervention, including number of sites for an intervention, whether recruitment was similar at different sites, levels of compliance and use of rice in different sites within studies, resources required for implementation, and whether studies had conducted a process evaluation. We also recorded whether or not studies included specific strategies to address diversity or disadvantage. We used the PROGRESS (place of residence, race/ethnicity, occupation, gender, religion, education, socioeconomic status, capital) checklist to collect information on whether or not studies had reported data by sociodemographic characteristics known to be important from an equity perspective (Ueffing 2011).

Two review authors (JPP, JAS) entered data into Review Manager 5 software and checked for accuracy (Review Manager 2014).

Assessment of risk of bias in included studies

We used the EPOC 'RIsk of bias' tool for studies with a separate control group to assess the risk of bias of all studies at study level for primary outcomes (EPOC 2017). This tool includes five domains of bias: selection, performance, attrition, detection and reporting; as well as an 'other bias' category to capture other potential threats to validity.

Two review authors independently assessed risk of bias in duplicate (JPP, PM) for each study and resolved any disagreement by discussion or by involving an additional review author (SN).

Assessing risk of bias in randomised trials and quasi‐randomised trials

1. Sequence generation (checking for possible selection bias)

We assessed studies as:

1. low risk of bias if there is a random component in the sequence generation process (e.g. random number table; computer random number generator);

2. high risk of bias if a non‐random approach has been used (e.g. odd or even date of birth; hospital or clinic record number). Non‐randomised studies should be scored 'high';

3. unclear risk of bias if not specified in the paper.

2. Allocation concealment (checking for possible selection bias)

We assessed studies as:

1. low risk of bias if participants and investigators enrolling participants could not foresee assignment because an appropriate method was used to conceal allocation (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes). We gave this rating to studies where the unit of allocation was by institution and allocation was performed on all units at the start of the study;

2. high risk of bias if participants of investigators enrolling participants could possibly foresee assignments and potentially introduce selection bias (e.g. open random allocation; unsealed or non‐opaque envelopes);

3. unclear.   

3. Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)

We assessed studies as:

1. low risk of bias if outcomes were measured prior to the intervention, and no important differences were present across intervention groups;

2. high risk of bias if important differences in outcomes between groups were present prior to intervention and were not adjusted for in the analysis;

3. unclear risk of bias if there was no baseline measure of outcome (note: if 'high' or 'unclear' but there is sufficient information to do an adjusted analysis, the assessment should be 'low').

4. Similarity of baseline characteristics (checking for confounding, a potential consequence of selection bias)

We assessed studies as:

1. low risk of bias if baseline characteristics are reported and similar across intervention groups;

2. high risk of bias if baseline characteristics are not reported or if there are differences across groups;

3. unclear risk of bias if it is not clear (e.g. characteristics mentioned in text but no data presented).

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts and protocol deviations)

We assessed outcomes in each included study as:

1. low risk of bias due to incomplete outcome data, which could be either that there were no missing outcome data or the missing outcome data were unlikely to bias the results based on the following considerations: study authors provided transparent documentation of participant flow throughout the study, the proportion of missing data was similar in the intervention and control groups, the reasons for missing data were provided and balanced across the intervention and control groups, the reasons for missing data were not likely to bias the results (e.g. moving house).

2. high risk of bias if missing outcome data was likely to bias the results. Studies will also receive this rating if an 'as‐treated' (per protocol) analysis is performed with substantial differences between the intervention received and that assigned at randomisation, or if potentially inappropriate methods for imputation have been used;

3. unclear risk of bias.

6. Blinding (checking for possible performance and detection bias)

We assessed the risk of performance bias associated with blinding as:

1. low, high or unclear risk of bias for participants;

2. low, high or unclear risk of bias for personnel.

We assessed the risk of detection bias associated with blinding as:

1. low, high or unclear risk of bias for outcome assessors.

Whilst assessed separately, we combined the results in a single evaluation of risk of bias associated with blinding as follows:

1. low risk of bias if there was blinding of participants and key study personnel and it was unlikely to have been broken, or the outcomes are objective. This rating will also be given to studies where either participants and key study personnel were not blinded but outcome assessment was blinded and the non‐blinding of others was unlikely to introduce bias;

2. high risk of bias if there was no blinding or incomplete blinding or if there was blinding that was likely to have been broken and the outcome or outcome assessment was likely to be influenced by a lack of blinding;

3. unclear risk of bias.

7. Contamination (checking for possible performance bias)

We assessed studies as:

1. low risk of bias if allocation was by community, institution or practice and it is unlikely that the control group received the intervention;

2. high risk of bias if it is likely that the control group received the intervention;

3. unclear risk of bias if it is possible that contamination occurred but the risk of this happening is not clear.

8. Selective reporting bias

We assessed studies as:

1. low risk of bias if it is clear, either by availability of the study protocol or otherwise, that all prespecified outcomes that are of interest in the review have been reported;

2. high risk of bias if it is clear that not all of the study's prespecified outcomes have been reported, or reported outcomes were not prespecified (unless justification for reporting is provided), or outcomes of interest are reported incompletely and cannot be used, or where one or more of the primary outcomes is reported using measurements or analysis methods that were not prespecified, or finally if the study report fails to include an important outcome that would be expected to have been reported;

3. unclear risk of bias.

9. Other sources of bias

Other possible sources of bias were described for each included study and a rating of low, high or unclear risk of bias was given for this item.

In addition to the above criteria, we also assessed cluster‐RCTs with the following criteria:

1. Recruitment bias

We assessed studies as:

1. low risk of bias if individuals were recruited to the study before the clusters were randomised;

2. high risk of bias if individuals were recruited to the study after the clusters were randomised;

3. unclear risk of bias.

2. Baseline imbalance

We assessed studies as:

1. low risk of bias if baseline characteristics were reported and were similar across clusters or if study authors used stratified or pair‐matched randomisation of clusters;

2. high risk of bias if baseline characteristics were not reported or if there were differences across clusters;

3. Unclear risk of bias.

3. Loss of clusters

We assessed studies as:

1. low risk of bias if no complete clusters were lost or omitted from the analysis;

2. high risk of bias if complete clusters were lost or omitted from the analysis;

3. unclear risk of bias.

4. Incorrect analysis

We assessed studies as:

1. low risk of bias if study authors appropriately accounted for clusters in the analysis or provided enough information for review authors to account for clusters in the meta‐analysis;

2. High risk of bias if study authors did not appropriately account for clusters in the analysis or did not provide enough information for review authors to account for clusters in the meta‐analysis;

3. Unclear risk of bias.

5. Compatibility with individual RCTs

We assessed studies as:

1. low risk of bias if effects of the intervention were likely not altered by the unit of randomisation;

2. high risk of bias if effects of the intervention were likely altered by the unit of randomisation;

3. unclear risk of bias.

Overall risk of bias

For all included studies, we summarised the overall risk of bias by primary outcome within each study at the study level. Studies at high risk of bias were those with high or unclear risk of bias in the following domains: allocation concealment, similarity of baseline outcome measurements, and incomplete outcome data. We judged the overall risk of bias of each study as 'low' if we had assessed all three domains at low risk; and 'high' when we had assessed one or more of the domains at either high or unclear risk. Judgements took into account the likely magnitude and direction of bias and whether it was likely to impact on the findings of the study.  

Measures of treatment effect

For dichotomous outcomes we have presented proportions, and for two‐group comparisons we have presented results as average risk ratio (RR) with 95% confidence interval (CI). We have reported results for continuous outcomes as the mean difference (MD) with 95% CI if studies measured outcomes in the same way. Where some studies reported endpoint data and others reported changes from baseline data (with errors), we combined these in the meta‐analysis if the outcomes had been reported using the same scale. We used standardised mean difference (SMD) with 95% CI to combine studies that measured the same outcome (for example haemoglobin) but used different methods.

For studies with multiple arms reporting a continuous variable as an outcome, we calculated the weighted average for single pair‐wise results in the meta analysis.

Unit of analysis issues

Cluster‐randomised trials

We combined results from both cluster‐randomised and individually randomised studies if there was little heterogeneity between the studies. We labelled cluster‐randomised trials with a 'C'. If the authors of cluster‐randomised trials had conducted their analyses at a different level to that of allocation, and they had not appropriately accounted for the cluster design in their analyses, we calculated studies' effective sample sizes to account for the effect of clustering in the data. We utilised the intra‐cluster correlation coefficient (ICC) derived from the study (if available) or from another source (for example using the ICCs derived from other, similar studies) (Adams 2004; Gulliford 1999), and then calculated the design effect with the formula provided in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We reported this and undertook sensitivity analysis to investigate the effect of variations in ICC.

We made an adjustment in the number of participants for design effect for both the continuous outcome of haemoglobin concentrations and dichotomous outcomes of anaemia, iron deficiency and vitamin A deficiency in two studies (Parker 2015 (C); Perignon 2016 (C). We used the design effect calculated for anaemia for calculating the total number of participants in iron deficiency, vitamin A deficiency and haemoglobin concentration. We used the mean and standard deviations of haemoglobin concentration in the analysis without making any changes. The details of adjustments for design effect in each of the studies are provided in Characteristics of included studies.

Studies with more than two treatment groups

If we identified studies with more than two intervention groups (multi‐arm studies), where possible we combined groups to create a single pair‐wise comparison or used the methods set out in the Cochrane Handbook for Systematic Reviews of Interventions to avoid double counting study participants (Higgins 2011). If two or more study arms shared the control group, we divided the control group over the number of relevant subgroup categories to avoid double counting the participants (for dichotomous data, we divided the events and the total population while for continuous data we assumed the same mean and standard deviation but divided the total population). The details are described in the Characteristics of included studies tables.

Dealing with missing data

We noted missing outcome data and levels of attrition for included studies on the data extraction form. We explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. The denominator for each outcome in each study was the number randomised minus any participants whose outcomes we knew to be missing. For missing summary data, we contacted lead study authors for clarification or, if possible, we estimated missing summary data using other statistical information (for example confidence intervals, standard errors) provided in the primary paper and imputed the standard deviation either from other studies in the same systematic review or from studies in another systematic review.

Assessment of heterogeneity

We examined forest plots from a meta‐analysis to visually determine the level of heterogeneity (in terms of the size or direction of treatment effect) between studies. We used Tau², I² statistic (Higgins 2003) and Chi² statistic to quantify the level of heterogeneity among the studies in each analysis (Deeks 2017). We regarded substantial or considerable heterogeneity as Tau² greater than 0 and either I² statistic greater than 30% or a low P value (< 0.10) in the Chi² test. We noted this in the text and explored it using prespecified subgroup analyses mentioned below. Caution was taken in the interpretation of those results with high levels of unexplained heterogeneity.

Assessment of reporting biases

Where we suspected reporting bias (see 'Selective reporting bias' above) we attempted to contact study authors asking them to provide missing outcome data. Where this was not possible, and we thought that the missing data would introduce serious bias, we explored the impact of including such studies in the overall assessment of results by a sensitivity analysis.

We did not anticipate that there would be sufficient studies contributing data for any particular outcome for us to examine possible publication bias; if more than 10 studies reporting the same outcome of interest were available, we planned to generate funnel plots in Review Manager 2014 and visually examine them for asymmetry. Where we pooled studies in a meta‐analysis we ordered studies in terms of weight so that a visual examination of forest plots might allow us to assess whether the results from smaller and larger studies were similar or if there were any apparent differences according to study size.

Data synthesis

We carried out a meta‐analysis to provide an overall estimate of treatment effect when more than one study examined the same intervention, provided that studies used similar methods and measured the same outcome in similar ways in similar populations. We used a random‐effects model meta‐analysis for combining data as we anticipated that there might be natural heterogeneity between studies attributable to the difference. We used narrative synthesis, guided by the data extraction form in terms of the ways in which studies were grouped and summarised, to describe the outcomes, explore intervention processes, and describe the impact of interventions by sociodemographic characteristics known to be important from an equity perspective based on the PROGRESS framework, where this information was available.

We did not combine results from randomised and non‐randomised trials together in a meta‐analysis, and we have not presented pooled estimates for non‐randomised studies with different types of study design. We have reported the results of the controlled before‐and‐after studies in narrative form.

Assessing the certainty of evidence

For the assessment across studies, we used MECIR (Methodological Expectations of Cochrane Intervention Reviews) conduct standards (MECIR 2018), and we employed the GRADE approach to interpret findings (Langendam 2013). The GRADE profiler (GRADEpro GDT 2015) allowed us to import data from Review Manager 2014 to create 'Summary of findings' tables. For each of the outcomes, two review authors (JPP, MNGC) assessed the certainty of evidence of included studies independently, using the GRADE approach (Balshem 2011). We have listed the primary outcomes for each comparison with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. These tables provide outcome‐specific information concerning the overall certainty of evidence from studies included in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes we considered. We included only primary outcomes in the 'Summary of findings' tables. We prepared 'Summary of findings' tables for the comparisons including rice fortified with iron alone versus unfortified rice, vitamin A alone or in combination with other micronutrients versus unfortified rice, zinc alone or in combination with other micronutrients versus unfortified rice, and folic acid alone or in combination with other micronutrients versus unfortified rice. The outcomes included in these were anaemia, iron deficiency, haemoglobin concentration, vitamin A deficiency, diarrhoea, respiratory infections, all‐cause death, and any adverse effects (see Table 1; Table 2).

For assessments of the overall certainty of evidence for each outcome that included pooled data from included studies from RCTs only, we downgraded the evidence from 'high certainty' by one level for serious (or by two for very serious) study limitations (risk of bias), indirectness of evidence (due to the use of different cut‐offs, for example), serious inconsistency, imprecision of effect estimates or potential publication bias. Data from observational studies started at low certainty. This assessment was limited only to the studies included in this review and as we did not consider there was a serious risk of publication bias, we did not downgrade in this domain.

Subgroup analysis and investigation of heterogeneity

Where possible we conducted subgroup analysis to explore heterogeneity according to the following subgroups.

1. Micronutrient content: single nutrient versus two or more nutrients

2. Rice fortification method: hot extrusion versus cold extrusion versus coating versus dusting

3. Cooking method most commonly used in study setting (as reported): soaking, and boiling with excess water versus boiling in excess water versus boiling without excess water versus rinsing and boiling without excess water versus frying and boiling without excess water versus unknown/unreported

4. Public health significance of anaemia at baseline in the target group: not a problem (lower than 5%) versus mild and moderate (5% to 39.9%) versus severe (40% and more) versus mixed/unknown/unreported

5. Malaria endemicity at the time that the study was conducted: some malaria risk setting versus malaria‐free area versus unknown/unreported malaria setting.

We examined differences between subgroups by visual inspection of the CIs; non‐overlapping CIs suggesting a statistically significant difference in treatment effect between the subgroups. We also used the approach of Borenstein 2008 to formally investigate differences between two or more subgroups. We conducted analyses in RevMan 5 (Review Manager 2014). We limited this analysis to those outcomes for which three or more studies contributed data.

Sensitivity analysis

We carried out sensitivity analysis to examine the effects of removing studies at high risk of bias (those with high or unclear risk of bias for allocation concealment, similarity of baseline outcome measurements, incomplete outcome data) from the meta‐analysis. For cluster‐randomised trials, we carried out sensitivity analysis using a range of ICC on overall effect estimate and have reported these effects.

Results

Description of studies

Results of the search

Our search strategy identified 28,730 references (22,147 references after removing duplicates) for possible inclusion. We screened a total of 58 full‐text articles for potential inclusion for the analyses. We included 17 studies (28 records). We excluded 22 studies (28 records) with reasons and identified two ongoing or unpublished studies (NCT02714075; NCT03056625). All 17 included studies were reported in English. We have summarised the study selection process in Figure 2. Of the 17 studies, 12 RCTs contributed to the meta‐analysis.

2.

PRISMA study flow diagram

Included studies

We have presented the details of included studies, including participants, interventions, outcomes, source of funding, and results of contact with the study authors, in the Characteristics of included studies. We have given a summary of the general characteristics of the included studies in Table 4. Twelve studies were reported from Asian countries (Angeles‐Agdeppa 2008; Ara 2019; Gershoff 1977; Hardinsyah 2016; Hussain 2014; Moretti 2006b; Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Salcedo 1950; Thankachan 2012), two from Brazil (Della Lucia 2016; Nogueira Arcanjo 2013), one from Mexico (Hotz 2008), one from the USA (Louisiana; Losso 2017) and one study from Burundi (Parker 2015 (C)). The PROGRESS‐Plus framework characteristics are given in Table 5. Each of the 17 included studies had different levels of micronutrient concentrations per 100 grams of uncooked rice, and we have given details of the micronutrient fortification profile in Table 6.

2. Summary of characteristics of included studies.

Study and year (Country)	Participants	Type of rice fortification and dosage	Duration of intervention	Overall risk of bias
RCTs (individual randomisation)
Angeles‐Agdeppa 2008 (Philippines)	180 anaemic children aged 6‐9 years excluding severe anaemia (Hb < 70 g/L), history of blood disorders and other haemoglobinopathies	Participants were allocated to 3 groups of 60 each; receiving 160 g of cooked iron‐enriched rice with ferrous sulphate powder (ExFeSO4), micronized ferric pyrophosphate (ExFeP80); and cooked unfortified rice Interventions were given as 2‐week cycle with standard dishes during lunch, daily for 5 days/week as a supervised regimen.	6 months	High
Hardinsyah 2016 (Indonesia)	200 post‐menarchal adolescent girls 14‐18 years of age attending boarding school	Participants were randomly assigned to 2 groups: group 1 (n = 100) received meals containing fortified rice (iron, vitamin A, zinc, folic acid, thiamin, vitamin B12); group 2 (n = 100) received meals prepared with unfortified rice. All participants received the meals from the school kitchen. Every meal given to students always contained rice, side dish and vegetable soup (once a day); side dishes being rotated between egg, fish, chicken, tempe, or tofu.	4 months	High
Hotz 2008 (Mexico)	180 non‐pregnant, non‐lactating women 18‐49 years of age with moderate to low Hb concentrations from 6 factories	Participants were allocated to 2 groups of 90 each. Group 1 received iron‐formula UltraRice® and group 2 received unfortified rice. The iron fortificant was microencapsulated, micronized ferric pyrophosphate. The fortified rice was formulated to provide 20 mg of iron per daily portion. The fortified grains were mixed directly with dry, locally obtained rice. For first 3 months of the study, the fortified grains were added at 2:100 (weight/weight), and each daily portion of rice consisted of 75 g of dry rice For second half of the feeding period the blend rate was doubled to 4:100 and the daily quantity of dry rice was halved to 37 g per person, making the iron fortificant per daily portion same	6 months	High
Hussain 2014 (India)	222 iron‐ and vitamin A‐depleted children 5‐8 years of age attending a subsidised lunch feeding programme	Participants were randomly assigned to 1 of 6 groups: the group receiving fortified rice (n = 185) were randomly assigned to 5 subgroups based on the iron deficiency, iron‐deficiency anaemia and vitamin A deficient status at baseline. The subgroups that were divided from the fortified rice were: group 1 (n = 37) : children receiving iron‐fortified meals; group 2 (n = 37) : children receiving beta‐carotene‐fortified meals; group 3 (n = 37): children receiving retinyl palmitate‐fortified meals; group 4 (n = 37): children receiving iron + retinyl palmitate‐fortified meals; group 5 (n = 37): children receiving iron + beta‐carotene‐fortified meals. The meals were consumed under direct supervision, and the daily leftovers were weighed. All the children were dewormed at baseline.	6 months	High
Losso 2017 (USA)	17 menstruating women with iron‐deficiency anaemia	Participants were randomly assigned to 1 of 2 groups: group 1 (n = 9) received 100 g of rice (0.75 cups of cooked rice in 2 servings) per day in a 1:1 ratio of fortified rice containing 18 mg elemental iron/100 g rice); group 2 (n = 6) received unfortified rice (0.5 mg iron/100 g rice). The intervention lasted 2 weeks. The rice dishes were prepared in the Pennington metabolic kitchen and dispensed frozen in an insulated chest to the participants weekly in lots of 14 with instructions to heat and consume 1 rice dish twice a day.	2 weeks	High
Moretti 2006b (India)	184 iron‐depleted children aged 6‐13 years from a primary school serving the Rock‐Colony neighbourhood	Participants were allocated to 2 groups of 92 children each: group 1 received rice‐based lunch meal fortified with 20 mg elemental iron (as micronized ground ferric pyrophosphate); group 2 received an identical but unfortified control meal. Lunch was served 6 days/week (except for school holidays). 3 local recipes of rice cooked with different seasoning ingredients were presented in repeating sequence. At baseline and at the midpoint of the study, all participants were dewormed with 400 mg albendazole and were treated with vitamin A supplements (200000 IU) 4 months before the start of the study and study midpoint.	7 months	Low
Pinkaew 2013 (Thailand)	The study was conducted in 8 primary schools with children aged 4‐12 years and they were mainly from low‐income families.	School children with low serum zinc (n = 203) were randomised to 2 groups and group 1 received triple‐fortified rice (n = 101); group 2 received natural control rice (n = 102) as a component of school lunch meals. The fortification level of the extruded rice grains was 10 mg iron, 9 mg zinc and 1050 mg vitamin A/g of extruded rice.	5 months	High
Pinkaew 2014 (Thailand)	One primary school in the Muang district, of Thailand with children aged 8‐12 years, were the study participants	Schoolchildren with general good health and no major chronic diseases aged 8‐12 years (n = 50) were recruited for the study. Children who had consumed the triple‐fortified rice in a previous study or showed clinical symptoms of vitamin A deficiency (Bitot's spot or ocular signs of xerophthalmia) or serum retinol values of < 0.7mmol/L were excluded.	2 months	High
Radhika 2011 (India)	140 children aged between 5 and 11 years (with haemoglobin > 70 g/L)	Study participants were allocated to 2 groups of 70 children each. Group 1 received the fortified rice and group 2 received unfortified rice. Micronized ferric pyrophosphate was used to fortify the extruded rice kernels considering in vitro availability, and loss of iron during cooking consisting of 125 g rice (dry weight) with 19 mg iron (fortified rice); normal rice mixed with UltraRice® (extruded kernels containing MFPP of 3.14 µm mean particle size) in comparison with unfortified rice.	8 months	Low
Thankachan 2012 (India)	Total of 258 anaemic (Hb concentrations 115 g/L for 6–11 years and 120 g/L for 12 years) children attending 4 primary schools aged 6‐12 years	The children were assigned to 3 intervention groups of 86 children each to receive rice‐based lunch meals fortified with multiple micronutrients with either low‐iron (6.25 mg) or high‐iron (12.5 mg) concentrations or identical meals with unfortified rice. The fortified, artificially extruded‐rice kernels contained 6.25 mg iron/g as micronized ground ferric pyrophosphate and were mixed with local natural rice at a 1:99 ratio to obtain low‐iron fortified rice. To obtain high‐iron fortified rice, fortified artificially extruded rice, together with low‐iron fortified rice (prepared earlier) (6.25 mg iron/100 g raw rice) were mixed with natural rice at a 1:1:98 ratio to result in a fortification level of 12.5 mg iron/100 g natural raw rice. The 3 types of rice (high iron: 12.5 mg iron/100 g, low iron: 6.5 mg iron/100 g, and control; 100 g raw rice/meal) were used to prepare lunch meals daily in the kitchen.	6 months	High
RCTs (cluster randomisation)
Parker 2015 (C) (Burundi)	The study included 1071 children from 12 schools in Burundi aged between 7 and 11 years	12 schools in Burundi were assigned to 2 groups. 1 group received UltraRice® (fortified rice) and the other group received traditional rice. UltraRice® (UR) premix kernels were manufactured to contain 100% of the recommended nutrient intakes (RNI) for iron, zinc, thiamin, and folic acid, through the school feeding programme. Hb status was measured. Children attending the intervention group schools received fortified rice with iron (17.8 mg), zinc (8.5 mg), thiamine (1.8 mg), and folic acid (600 mg) for 5 days/week for 7 months and children in control group schools received an equivalent unfortified rice containing endogenous quantities of iron (1.2 mg), zinc (1.7 mg), thiamin (0.1 mg), and folate (14 mg).	7 months	High
Perignon 2016 (C) (Cambodia)	The study was a double‐blind cluster‐randomised, placebo‐controlled trial conducted among a total of 2440 school‐going children aged 6‐16 years.	20 primary schools in Cambodia were randomised to 5 arms (4 intervention + 1 control arm). The 4 intervention groups were fortified cold‐extruded rice (UltraRice® original formulation), fortified hot‐extruded rice (UltraRice® new formulation), fortified hot‐extruded rice Nutririce, non‐fortified rice (placebo) and a control group without the school feeding programme. The control schools were randomly selected from 16 primary schools participating in another programme of WFP (take‐home ration programme) not receiving a school meal. The UltraRice® original (URO) was produced by cold extrusion and the UltraRice new (URN) and NutriRice® by hot extrusion. Fortification process was carried out in such a way that every 100 g of URO provided 10.76 mg iron, 3.04 mg zinc; 170 folic acid, 1.06 vitamin B1, URN 7.55 mg iron, 2.02 mg zinc, 2140 IU vitamin A, 280 folic acid, 1.43 vitamin B1 and NutriRice® 7.46 mg iron, 3.68 mg zinc, 960 IU vitamin A, 140 folic acid and 0.69 vitamin B1	6 months	High
Non‐randomised studies (controlled before‐and‐after studies)
Ara 2019 (Bangladesh)	870 women aged 15‐49 years excluding severe anaemia (435/group) at baseline and 800 (400/group) at end line	Rice flour was fortified using hot extrusion technology and homogeneous blending of the same with unfortified rice. The intervention group received 30 kg fortified rice; the control group received 30 kg non‐fortified rice for every month from January 2013‐December 2013. After 12 months of fortified rice/non‐fortified rice consumption, the end line data were collected from December 2016‐April 2017. Follow‐up of the World Food Programme interventions was done on another group from the same area.	12 months	High
Della Lucia 2016 (Brazil)	131 non‐anaemic children between 2 and 6 years old, of both genders, participated in the study.	Participants from the selected preschools received either micronutrient fortified rice (UltraRice®) or unfortified polished rice, as part of school meals, 50 g daily, Monday through Friday.	4 months	High
Gershoff 1977 (Thailand)	2250 children aged 1.5‐9 years from 29 villages	The villages were divided into 5 groups: group 1 no intervention provided; group 2 placebo control, unfortified rice plus day­care centre food for preschool children; group 3, received fortified rice containing 0.087 3% thiamin naphthalene disulfonate, 0.0815% of retinol acetate, and 0.8% FeP04:4H20 (0.2% iron) plus day‐care centre food; group 4 received fortified rice containing 0.087 3% thiamin naphthalene disulfonate, 0.0815% of retinol acetate, 0.8% FeP04:4H20 plus 20% L‐lysine HCI and I 0% L‐threonine in addition to day‐care centre food; group 5 received fortified rice containing 0.087 3% thiamin naphthalene disulfonate, 0.0815% of retinol acetate, 0.8% FeP04:4H20 plus 20% L‐lysine HCI and I 0% L‐threonine, no day‐care centre food Before being mixed with the other ingredients. the rice was cooked by putting it in water and cooking under low heat for 15 minutes.	4 years	High
Nogueira Arcanjo 2013 (Brazil)	303 children 2‐5 years of age attending 2 public schools in City of Sobral‐Ceará, in the northeast of Brazil, between August and December 2010	Participants from 2 schools received the assigned intervention to the schools: children in group 1 (school A) (n = 138) received iron‐fortified rice (UltraRice®); children in group 2 (school B) (n = 165) received unfortified standard rice. The study rice was consumed with poultry, which was the customarily consumed meal for Tuesdays at the schools.	18 weeks	High
Non‐randomised studies (controlled cross‐sectional study)
Salcedo 1950 (Philippines)	574 children aged between 3 and 18 years 2188 Government employees with their families 1416 military personnel (clinical assessment limited to 350 in the experimental group and 116 in the control group)	Study participants were given 200‐250 g of fortified or unfortified rice. Both groups consumed between 200‐250 g of rice. Among military personnel, a total of 1300 were given fortified rice, but clinical assessment was limited to 350 participants serving as the experimental group and an additional 116 participants serving as the control. Fortification consisted of rice grains impregnated with premix and mixed at 1:200 to have a final fortified rice (per kg) with 4.4 mg thiamine, 33 mg niacin, 28.6 mg elemental (as iron pyrophosphate).	8 months	High
CBA: controlled before‐and‐after study; Hb: haemoglobin; RCT: randomised controlled trial

3. PROGRESS‐Plus equity checklist of included studies.

Study	Place	Race/ethnicity	Occupation	Gender	Religion/ culture/education	Socio‐economic status	Social status	Others/ disability/ age/ sexual orientation	Overall PROGRESS‐Plus
Angeles‐Agdeppa 2008	Metro Manila, Division Pasig; Philippines	No specific mention, apart from the locality of the school in the capital city	School children	Male 99 + female 81	No religion mentioned; children going to San Joaquin Elementary School (public)	Not mentioned	Not mentioned	Anaemic children; sexual orientation not mentioned	This study was carried out among 180 anaemic children going to a government elementary school.
Ara 2019	Vulnerable Group Development (VDG) beneficiaries in 5 districts of Bangladesh	Not mentioned specifically, however, they were the local resident women.	It included professional workers, unskilled workers, agricultural labourers, home servants and housewives. Most of the study population were housewives	Non‐pregnant women aged 15‐49 years	No religion mentioned; nearly 25% without any education	No direct estimate provided; however, most of the study participants were from lower socioeconomic strata	Not mentioned	Women with severe anaemia were excluded. Sexual orientation is not mentioned	The study was carried out among 870 women of reproductive age and local residents of Bangladesh
Della Lucia 2016	Brazil	Not specified	School‐going children		No religion mentioned, attending philanthropic schools	Not mentioned	Not mentioned	Children, 2‐6 years old	This study was carried out in 2 public schools among non‐anaemic children 2‐6 years of age during 4 consecutive months.
Gershoff 1977	Chiang Mai villages in tile valley of the Ping River, Thailand	Thai children	Children in the community	Male 1121 + female 1109	No religion mentioned. Children in the study villages	Not mentioned	Low/middle	Normal children; sexual orientation not mentioned	The study included 2230 children attending pre‐school and school from the low/middle social background
Hardinsyah 2016	Medan of North Sumatra Province, Indonesia	The majority of participants' ethnicity was Javanese and Bataknese	Teenage girls attending boarding school	Female	There is mention of the Ramadan fasting month during the second week of June	The family income ranges from 4.9 million to 5.5 million Rupiahs (Approximately 340 to 390 US Dollars)	Not mentioned	Age 14‐18 years of age	This study was carried out among post‐menarchal adolescent girls attending boarding school in Indonesia. The study lasted 4 months.
Hotz 2008	Morelos State, Mexico	Mexican women	Factory workers	Women only	No religion mentioned; 18‐49 years	Low/middle school	Low/middle	Anaemic women; sexual orientation not mentioned	This study included women with altitude‐adjusted Hb concentrations between 105 and 135 g/L from low/middle social background, non‐pregnant and non‐lactating.
Hussain 2014	India	Iron and vitamin A‐depleted 5‐8‐year‐old children attending a subsidised lunch feeding programme	Children attending a school‐based feeding programme	Not specified	Not reported	Not reported	Not mentioned, although programme is subsidised	5‐8 years of age	This study included 222 children aged 5‐8 years attending a school where there was a subsidised lunch feeding programme in India receiving a 200‐250 g meal of cooked rice daily.
Losso 2017	Baton Rouge, USA	In the iron‐fortified group: 4 white, 3 black or African‐American, 1 Asian, 1 other; in the unfortified rice group: 3 white, 2 black or African American, 1 Asian		Women only	Not reported	Not mentioned	Not mentioned	18‐50 years of age	This study included women with iron‐deficiency anaemia recruited through web and phone interviews and then in a clinic.
Moretti 2006b	Franciscan primary school serving the population of Rock‐Colony neighbourhood, in crowded urban slum of Bangaoore; India	Indian	School‐going children	Not mentioned	6‐13 years	Low	Low	Children with iron deficiency; sexual orientation not mentioned	Study included children having iron deficiency from an urban slum neighbourhood in India, belonging to low socioeconomic status and low social class
Nogueira Arcanjo 2013	Public schools in City of Sobral‐Ceará, in the northeast of Brazil	Not reported	School‐going children	Fortified rice group: 65 male: 73 female; unfortified rice group: 79 male: 86 female	2‐5 years of age	Not reported. Family income 300 USD or less (it is unclear if this is weekly or monthly income ‐ not reported). 126/138 participants from iron‐fortified group versus 154/165 participants from unfortified group.	Not mentioned	Children 2‐5 years of age. Other information not reported	This before‐and‐after study included children 2‐5 years of age from 2 public schools in northeast Brazil receiving the school lunch programme and the fortified/unfortified intervention once a week.
Parker 2015 (C)	The study was carried out in Muyinga Province in Burundi catering to mainly agrarian population	Burundians	School‐going children	Female: 51.1% in intervention arm, 55.3% in control arm	Religion was not mentioned. 7‐11 years	Mean socioeconomic status score quintile = 3.03 (1.45) for intervention arm and 2.97 (1.37) for control arm	Not mentioned	Children with Hb level 70‐110 g/L and those who had not taken any nutritional supplements during the past 1 month since commencement of the study were included. Sexual orientation is not mentioned.	This cluster‐RCT included 904 children who were mild to moderately anaemic from the selected schools of Burundi and mainly with an agricultural background.
Perignon 2016 (C)	The study was carried out in Kampung Speu Province of Cambodia	Cambodians	School‐going children	Male and female participants had equal representation (50% each)	6‐16 years	Not mentioned	Not mentioned	Excluding severely anaemic children. All in the eligible age group were included in the study. Sexual orientation not mentioned	The cluster‐RCT included children from selected schools of Cambodia in KamPong Speu province with rice farming as a predominant occupation and income source.
Pinkaew 2013	Satun province, west coast of southern Thailand	Thai Muslims	School children	Male, 98 + female 105	Majority Muslim, age group of 7‐12 years	Low	Low/middle	Children with zinc deficiency; sexual orientation not mentioned	This study included school‐going children from low socioeconomic status and having zinc deficiency in Thailand.
Pinkaew 2014	Muang District, Satun Province of southern Thailand	Thai Muslims	School Children	Males, 24 and females, 26	Majority Muslims in the age group 8‐12 years	Low	Low/middle	Children who had consumed the triple‐fortified rice before or showed clinical symptoms of VAD (Bitots spot or ocular signs of xerophthalmia) or serum retinol values of < 0.7m mol/L were excluded	This study included school‐going children from low socioeconomic status and having zinc deficiency in Thailand.
Radhika 2011	Village of Keesara; Andhra Pradesh State in India	Indian	School children	Male 56 + female 90	No mention of religion; age group of 5‐11 years	Low/middle	Low/middle	Anaemic children; sexual orientation not mentioned	The study included anaemic children from low‐middle socioeconomic background belonging to a rural area in India.
Salcedo 1950	Bataan, Philippines	Filipinos	Children and military personnel	Male and female, but proportions not reported	No mention of religion or education	Children lived in a welfare institution; military personnel were fully employed	Not mentioned	No exclusions were reported; sexual orientation was not mentioned	The study was conducted among children living in a welfare institution and among military personnel in the Philippines.
Thankachan 2012	Primary schools in Bangalore Urban District of Karnataka State; South India	Indians	School children	Male 47%, female 53%	Hindu > Christians > Muslim; 6‐12 years	Low/middle school	Low	Anaemic children; sexual orientation not mentioned	This study included anaemic school going children from low socioeconomic background from an urban area India.
Hb: haemoglobin; RCT: randomised controlled trial

4. Fortification profile per 100 grams of uncooked fortified rice in included studies.

Study	Elemental iron (mg)	Vitamin Aa (mg)	Zinc (mg)	Folic acid (µg)	Vitamin B1 (thiamin) (mg)	Vitamin B2 (riboflavin) (mg)	Vitamin B3 (niacin) (mg)	Vitamin B6 (pyridoxine) (mg)	Vitamin B12 (cobalamin) (µg)
Angeles‐Agdeppa 2008	6.25	‐	‐	‐	‐	‐	‐	‐	‐
Ara 2019 (CBA)	6	0.15	4.00	130	0.40				1.0
Della Lucia 2016 (CBA)	8.4	‐	4.20	144	0.72	‐	‐	‐	‐
Gershoff 1977 (CBA)	0.2	0.81			0.087	0.04
	0.2	0.81			0.087	0.04
	0.2	0.81			0.087	0.04
Hardinsyah 2016	10.8	0.28	5.20	145	‐				3.2
Hotz 2008	26.6	‐	‐	‐	‐	‐	‐	‐	‐
Hussain 2014	4		‐	‐	‐	‐	‐	‐	‐
	‐	1.20 (as beta‐carotene)	‐	‐	‐	‐	‐	‐	‐
	‐	0.18	‐	‐	‐	‐	‐	‐	‐
	4	0.18	‐	‐	‐	‐	‐	‐	‐
	4	1.20 (as beta‐carotene)	‐	‐	‐	‐	‐	‐	‐
Losso 2017	18	‐	‐	‐	‐	‐	‐	‐	‐
Moretti 2006b	20	‐	‐	‐	‐	‐	‐	‐	‐
Nogueira Arcanjo 2013 (CBA)	112.8	‐	‐	‐	‐	‐	‐	‐	‐
Parker 2015 (C)	11.9	‐	5.70	400	1.80	‐	‐	‐	‐
Perignon 2016 (C)	10.67	‐	3.04	170	1.06	‐	‐	‐	‐
	7.55	0.64	2.02	280	1.43	‐	12.57	‐	3.8
	7.46	0.29	3.68	140	0.69	‐	7.98	0.92	1.26
Pinkaew 2013	20	2.10	18	‐	‐	‐	‐	‐	‐
Pinkaew 2014	20	2.10	18	‐	‐	‐	‐	‐	‐
Radhika 2011	15	‐	‐	‐	‐	‐	‐	‐	‐
Salcedo 1950 (CBA)	2.86	‐	‐	‐	0.44	‐	0.33	‐	‐
Thankachan 2012	12.5	0.50	3	75	0.38	‐	5	0.38	0.75
	6.25	0.50	3	75	0.38	‐	5	0.38	0.75
C: cluster randomised; CBA: controlled before‐and‐after study

^aOne international unit (IU) vitamin A is equivalent to 0.0003 mg of retinol, 0.0006 mg of beta‐carotene and 0.0012 mg of other pro‐vitamin A carotenoids.

Study designs

Out of the 17 included studies (28 records), twelve were RCTs (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012), two of which were cluster‐randomised trials (Parker 2015 (C); Perignon 2016 (C). For distinguishing them from individual randomised trials, their names are denoted with '(C)'. Five studies were controlled before‐and‐after studies (Ara 2019; Della Lucia 2016; Gershoff 1977; Nogueira Arcanjo 2013; Salcedo 1950).

Overall, eight RCTs had 2‐arms (Hardinsyah 2016; Hotz 2008; Losso 2017; Moretti 2006b; Parker 2015 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011), two studies had three arms (Angeles‐Agdeppa 2008; Thankachan 2012), and one study had five arms (including a placebo and traditional feeding intervention) as a part of the FORISCA‐UltraRice+NutriRice study (Perignon 2016 (C)). One RCT had six arms with five fortification groups in addition to control group (Hussain 2014). The studies had various types of randomisation procedures, sequence generation, allocation concealment, blinding as described in Characteristics of included studies.

One before‐and‐after study had five arms (Gershoff 1977) and four had two arms (Ara 2019; Della Lucia 2016; Nogueira Arcanjo 2013; Salcedo 1950).

Settings

Twelve studies were carried out in Asia, four in the Americas and one in Africa. The studies in Asia were carried out in Bangladesh (Ara 2019), Cambodia (Perignon 2016 (C)), India (Hussain 2014; Moretti 2006b; Radhika 2011; Thankachan 2012), Indonesia (Hardinsyah 2016), Philippines (Angeles‐Agdeppa 2008; Salcedo 1950) and Thailand (Gershoff 1977; Pinkaew 2013; Pinkaew 2014). The four studies in the Americas were conducted in Brazil (Della Lucia 2016; Nogueira Arcanjo 2013), Mexico (Hotz 2008) and in the USA (Losso 2017). The study in Africa was conducted in Burundi (Parker 2015 (C)). The Indian studies had school children in an urban area (Thankachan 2012), urban slum (Moretti 2006b), and rural school setting (Radhika 2011). The Mexican study (Hotz 2008), recruited women from six factories without any specific mention of ethnicity or race. The studies from the Philippines had urban school children in Manila (Angeles‐Agdeppa 2008), and children from a welfare institution and military personnel (Salcedo 1950). The study in Burundi was conducted among rural school age children from Muyinga Province (Parker 2015 (C)). The study in Cambodia was among rural school children in Kampung Speu (Perignon 2016 (C)), while the Indonesian study included teenage girls from a boarding school in the area of Medan (Hardinsyah 2016).

Malaria endemicity

One study reported that it was conducted in a malaria‐endemic area (Parker 2015 (C)). Four studies reported to be from non‐endemic areas for malaria (Angeles‐Agdeppa 2008; Moretti 2006b; Perignon 2016 (C); Thankachan 2012). Other studies did not report on endemicity for malaria (Ara 2019; Della Lucia 2016; Gershoff 1977; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Nogueira Arcanjo 2013; Pinkaew 2013; Pinkaew 2014; Radhika 2011; Salcedo 1950).

Participants

The 17 included studies had a total of 10,483 participants. The controlled before‐and‐after studies were conducted in children aged two to six years of age (Della Lucia 2016; Nogueira Arcanjo 2013), 18 months to nine years of age (Gershoff 1977), and one was among women aged between 15 and 49 years (Ara 2019). One controlled before‐and‐after study was on infants to adults as it was prompted by clinical beriberi which cut across ages (Salcedo 1950). Among the RCTs, two were conducted among non‐pregnant, non‐lactating women 18 to 49 years of age (Hotz 2008; Losso 2017). All other included studies were carried out among preschool and school age children. RCTs involved children aged between 5 to 18 years of age (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hussain 2014; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012). There were no studies reporting data exclusively on adolescents beyond the age of 12 years, adult men or pregnant women.

Anaemia prevalence

The baseline prevalence of anaemia ranged from 5% to 62% in the studies in children (Angeles‐Agdeppa 2008; Hussain 2014; Moretti 2006b; Nogueira Arcanjo 2013; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2014; Radhika 2011; Thankachan 2012), and around 21% (intervention: 21.4 %; control: 20.4%) in one study among women (Hotz 2008), while the other study on women included women with iron deficiency as determined by serum ferritin or serum iron value, or both (Losso 2017). The study done on teenagers (Hardinsyah 2016), had a baseline anaemia level of 34%. Two studies from India had an anaemia prevalence of around 40% and above (Radhika 2011; Thankachan 2012). A third study from India reported iron‐deficiency anaemia of around 30% suggesting a much higher anaemia rate (Moretti 2006b). The two studies that included only anaemic children reported 38% (Parker 2015 (C)), and 45% (Angeles‐Agdeppa 2008), during screening. Three studies had an anaemia prevalence between 10% to 18% (Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014). The controlled before‐and‐after study Ara 2019 had a baseline level of anaemia of 42%.

Stunting

In total, five studies reported on stunting at baseline ranging from 12% to 40% (Angeles‐Agdeppa 2008; Perignon 2016 (C); Pinkaew 2014; Radhika 2011; Thankachan 2012), one study reported less than 10% stunting in both intervention and control arms (Hussain 2014). Two studies reported the height‐for‐age Z‐score (Moretti 2006b; Pinkaew 2013) as −1.3 and −0.8 respectively. One study (Perignon 2016 (C)), reported both: 40% stunting; −1.75 Z‐score). None of the studies restricted inclusion of participants or analysed their data based on stunting status.

Occupation

Thirteen studies had preschool or school‐going children as participants (Angeles‐Agdeppa 2008; Della Lucia 2016; Gershoff 1977; Hardinsyah 2016; Hussain 2014; Moretti 2006b; Nogueira Arcanjo 2013; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012). One study had women factory workers (Hotz 2008), and another did not mention the occupation of the participants (Losso 2017). The Ara 2019 study had mostly housewives (> 70% in each of the groups) followed by unskilled workers (˜7.82% to 11.26%).

Sex

Gender allocation was reported in all but three studies (Hussain 2014; Moretti 2006b; Salcedo 1950). All the three studies among adults included all women (Ara 2019; Hotz 2008; Losso 2017). There were no differences in gender between treatment groups at baseline in any study. Six studies had more female participants (Della Lucia 2016; Parker 2015 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012). One study was carried out among teenage girls (Hardinsyah 2016). Two studies had more male participants (Angeles‐Agdeppa 2008; Perignon 2016 (C)). One before‐and‐after study had roughly equal numbers (Gershoff 1977), while one had more women (Nogueira Arcanjo 2013).

Religion/culture

No specific mention was made about the religion of the study population in 12 studies (Angeles‐Agdeppa 2008; Ara 2019; Della Lucia 2016; Gershoff 1977; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Nogueira Arcanjo 2013; Perignon 2016 (C); Radhika 2011; Salcedo 1950). However one of these studies (Losso 2017), had mixed ethnic background participants. One study from India (Thankachan 2012), reported that the majority of the study participants were Hindus (74% in fortification groups and 65% in control groups). Two studies from Thailand had a predominantly Muslim population (Pinkaew 2013; Pinkaew 2014). The study from Indonesia had Javanese and Bataknese ethnic participants predominantly (Hardinsyah 2016).

Socioeconomic status

The studies were conducted mostly among those with low‐socioeconomic status. Three studies from India (Moretti 2006b; Radhika 2011; Thankachan 2012), and two studies from Thailand (Pinkaew 2013; Pinkaew 2014), were carried out among children from low socioeconomic backgrounds. One study from India was in an urban area (Thankachan 2012), urban slum (Moretti 2006b), and rural area (Radhika 2011). Other studies did not specify the socioeconomic status of their participants.

Education

Twelve studies (Angeles‐Agdeppa 2008; Della Lucia 2016; Hardinsyah 2016; Hussain 2014; Moretti 2006b; Nogueira Arcanjo 2013; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012), reported studies on pre‐school and school‐going children. One community‐based study (Salcedo 1950), and two other studies (Hotz 2008; Losso 2017), were on women whose educational status was not reported. One study included pre‐school children attending a day‐care centre (Gershoff 1977). In Ara 2019, nearly 25% of the study population did not have any education, the remaining participants all had primary school education and above.

Social capital

The studies did not report issues related to inequity, access to food or any particular instances of preferences of certain social classes. However, the included studies were carried out in predominantly lower socioeconomic settings.

Interventions

Micronutrient content

All studies fortified rice with iron and some studies added various additional combinations of micronutrients. Seven studies (Hardinsyah 2016; Hussain 2014; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Thankachan 2012), and four controlled before‐and‐after studies fortified with multiple micronutrients (Ara 2019; Della Lucia 2016; Gershoff 1977; Salcedo 1950). Among them, six studies (Hardinsyah 2016; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Thankachan 2012), compared the effectiveness of multiple‐micronutrient‐fortified rice with that of unfortified rice. One RCT reported different micronutrients and their effects on each arm, compared with the control arm, which received unfortified rice (Hussain 2014), in which out of five intervention arms, one arm each received iron alone, beta carotene, retinyl palmitate, iron plus retinyl palmitate and iron plus beta carotene. Five studies (Angeles‐Agdeppa 2008; Hotz 2008; Losso 2017; Moretti 2006b; Radhika 2011), and one controlled before‐and‐after study (Nogueira Arcanjo 2013), included iron alone for rice fortification (with various quantities of iron and its compounds).

For the RCTs with multiple micronutrients, two studies (Pinkaew 2013; Pinkaew 2014), reported rice fortified with three micronutrients (iron, zinc and vitamin A); one study (Parker 2015 (C)), with four micronutrients (iron, zinc, thiamine and folic acid) and two (Hardinsyah 2016; Perignon 2016 (C)), with four or more micronutrients. All the multiple micronutrient studies had an arm with at least iron and zinc. One study (Gershoff 1977), reported the field effect of consumption of rice fortified with lysine, threonine, thiamin, riboflavin, vitamin A and iron. One study (Thankachan 2012), compared the effectiveness of high iron (12.5 mg/100 g natural rice) with that of low iron (6.25 mg/100 g of natural rice) fortification, along with vitamin A, thiamine, niacin, vitamin B₆, vitamin B₁₂, folate, iron and zinc and no fortification of rice. Another study (Angeles‐Agdeppa 2008) compared the effectiveness of ferrous sulphate‐fortified rice and micronized dispersible ferric pyrophosphate‐fortified rice with that of unfortified rice, wherein each of the three arms received in 160 g (1 cup) of cooked rice, ferrous sulphate (ExFeSO4), micronized ferric pyrophosphate (ExFeP80) or no added fortificant (control).

In all the included studies, the amount of elemental iron per 100 g of rice ranged from 0.2 mg to 112.8 mg. Vitamin A was a fortificant in three studies. The amount of vitamin A per 100 g of rice ranged from 0.15 mg (Ara 2019) to 2.1 mg (Pinkaew 2013; Pinkaew 2014). The amount of zinc per 100 g of rice ranged from 2 mg (Perignon 2016 (C)) to 18 mg (Pinkaew 2013; Pinkaew 2014). One study carried out among women had ferrous sulphate 18 mg/100 g of fortified rice for the intervention arm and unfortified rice for the control arm (Losso 2017). Fortification details per 100 g of uncooked rice are given in Table 6.

Rice fortification method

One study reported using extrusion as a fortification method without indicating the temperature (Angeles‐Agdeppa 2008). Seven studies used hot‐extrusion process only (Ara 2019; Hardinsyah 2016; Moretti 2006b; Parker 2015 (C); Pinkaew 2013; Pinkaew 2014; Thankachan 2012), and three studies reported a cold extrusion process only (Della Lucia 2016; Hotz 2008; Radhika 2011). One study included 2 arms with hot extrusion and one arm with cold extrusion (Perignon 2016 (C)). Three studies reported using coating in the fortification (Gershoff 1977; Losso 2017; Salcedo 1950), and two studies did not report the method (Hussain 2014; Nogueira Arcanjo 2013).

Iron compounds

The included studies used three types of iron compounds. The before‐and‐after study (Gershoff 1977) used ferric phosphate tetrahydrate. One study (Angeles‐Agdeppa 2008), used ferrous sulphate as one of two iron fortificants. Nine studies that were part of the meta‐analysis used ferric pyrophosphate. Micronized iron reduces the particle size to promote absorption. Two studies used a micronized ferric pyrophosphate, which had a particle size of 0.3 μm and was encapsulated (Angeles‐Agdeppa 2008; Hotz 2008). One study, which used cold extrusion, reported a particle size of 3.1 μm (Radhika 2011). Five studies described the iron used as micronized ground ferric pyrophosphate (Moretti 2006b; Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Thankachan 2012), and three of these specified the particle size as 2.5 μm (Moretti 2006b; Pinkaew 2013; Pinkaew 2014). One study described the iron compound as ferric pyrophosphate without any reference to micronization or particle size (Parker 2015 (C)). Other studies had micronized ground ferric pyrophosphate with 4 mg iron (Hussain 2014), 10 mg iron (Pinkaew 2014), 11.8 mg per 100 g (Parker 2015 (C)); 10.6 mg per 11 g rice for cold‐extruded and 7.5 mg per 100 g rice for hot‐extruded (Perignon 2016 (C)), 20 mg iron (Moretti 2006b; Hotz 2008), 0.8% by weight (Gershoff 1977). One study on women reported ferrous sulphate as the iron compound used (Losso 2017). Two studies did not specify the iron compound (Ara 2019; Hardinsyah 2016).

Cooking methods

In three studies, rice was washed prior to cooking (Angeles‐Agdeppa 2008; Moretti 2006b; Radhika 2011). However, the manner of cooking was not described in sufficient detail to categorise based on the protocol for this review. In (Moretti 2006b), in addition to rice being washed in preparation for cooking, rice portions were cooked with seasoning ingredients in household pressure cookers for 8 min after reaching peak pressure, after which pressure was released. Test servings contained 35 g cooked rice.

One study used the absorption method of cooking rice (Perignon 2016 (C); author correspondence). Lunch menus were prepared in rotating order and usually consisted of rice together with chicken or fish and occasionally with vegetables. The schools also provided free milk (200 mL) daily to all children. Weekly iron supplementation, which had been given to the children by health officers or village health volunteers before the intervention, was not provided during the intervention. This was to improve the chance of showing an improvement in iron status even though it was not the primary outcome measure (Pinkaew 2014). In Burundi, parent committees performed all the cooking (Parker 2015 (C)). The other studies did not describe the manner of cooking rice.

All but one study (Parker 2015 (C)), described the accompanying dishes or menu. The study on female teenagers (Hardinsyah 2016), reported the cooking methods as pouring one sack of fortified rice into a plastic bucket to wash the rice, and steaming for about one hour until the rice was cooked well. One study (Losso 2017), was done as a pilot among women from the Baton Rouge area (Louisiana (LA), USA), wherein they tested the iron retention of fortified rice by several methods of cooking; however there was no description of the type cooking used for the clinical study. Similarly, Ara 2019 did not specify the method of cooking.
  

Comparisons

Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

Twelve studies (2201 participants) made this comparison.

Rice fortified with iron alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

One study (74 participants) made this comparison, having a vitamin A‐only arm versus a control arm.

Rice fortified with vitamin A alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Rice fortified with zinc alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

No studies contributed data to this comparison.

Rice fortified with zinc alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Rice fortified with folic acid alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

No studies contributed data to this comparison.

Rice fortified with folic acid alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Outcome

Of the 12 RCTs included in the meta‐analysis, seven reported on anaemia (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Parker 2015 (C); Perignon 2016 (C); Radhika 2011; Thankachan 2012). Five out of the twelve RCTs used WHO thresholds to define anaemia based on serum haemoglobin concentrations (Hb) (Hardinsyah 2016; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Radhika 2011), three used a cut‐off level but did not mention the cut‐off criteria (Angeles‐Agdeppa 2008, Pinkaew 2013Thankachan 2012), one RCT (Hotz 2008), used CDC 1989 criteria and three RCTs did not report the cut‐off used to define anaemia (Hussain 2014; Losso 2017; Pinkaew 2014). Among the included non‐randomised studies, three mentioned Hb cut‐off to define anaemia, but did not specify the criteria (Ara 2019; Della Lucia 2016; Gershoff 1977), one used WHO criteria (Nogueira Arcanjo 2013), and one study did not report a Hb cut‐off (Salcedo 1950). The details of the cut‐off used in each included study are given in Table 7. We used data from these studies in the meta‐analysis irrespective of the criteria used by them to define anaemia. Three studies reported iron‐deficiency anaemia (Moretti 2006b; Radhika 2011; Thankachan 2012); however we did not use these data in quantitative synthesis.

5. Haemoglobin thresholds used in the included studies to define anaemia.

Study	Haemoglobin threshold (g/L)	Criteria
Angeles‐Agdeppa 2008	Anaemia was defined as haemoglobin concentration in blood < 120 g/L	Not mentioned
Ara 2019	< 120 g/L in non‐pregnant and non‐lactating women	Not mentioned
Della Lucia 2016	≥ 110 g/L was used as a cut off for including children in the study. Anaemia was not defined	Not reported
Gershoff 1977	Haemoglobin levels were categorised as deficient < 100, low 100‐90 (g/L)	Not mentioned
Hardinsyah 2016	Severe anaemia: < 80 g/L; moderate anaemia: 80‐109 g/L; mild anaemia: 110‐119 g/L; non anaemia: ≥ 120 g/L	WHO (WHO 2011a)
Hotz 2008	< 122 g/L, adjusted for average altitude of the study sites (1100 m) with the use of an equation	CDC (CDC 1989)
Hussain 2014	< 110 g/L and severely anaemic (Hb < 75 g/L) were excluded	Not mentioned
Losso 2017	Not reported (iron‐deficiency anaemia was defined based on iron and ferritin levels in serum)	Not reported
Moretti 2006b	< 115 g/L in children aged 5–11 years	WHO (WHO 2001)
Nogueira Arcanjo 2013	< 110 g/L in children < 5 years of age	WHO (WHO 2001)
Parker 2015 (C)	For school‐aged children at 1500 m above sea level, mild anaemia was defined as Hb 115‐119 g/L, moderate anaemia Hb 85‐114 g/L, and severe anaemia Hb < 85 g/L	WHO (WHO 2011f)
Perignon 2016 (C)	< 115 g/L for children aged 6‐11 years, < 120 g/L for children aged 12‐14 years and girls aged ≥ 15 years and < 130 g/L for boys aged ≥ 15 years	WHO (WHO 2001)
Pinkaew 2013	< 120 g/L	Not mentioned
Pinkaew 2014	Not reported	Not reported
Radhika 2011	In children aged 5–11 years, anaemia (mild to moderate) was defined as Hb 70‐115 g/L.	WHO (WHO 2001)
Salcedo 1950	Not reported	Not reported
Thankachan 2012	< 115 g/L in children aged 6–11 years and < 120 g/L in participants aged ≥ 12 years	Not mentioned
CDC: Centers for Disease Control and Prevention; Hb: haemoglobin; WHO: World Health Organization

Nine studies reported iron deficiency (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Moretti 2006b; Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012); we included eight in the meta‐analysis. We did not include data from Hussain 2014 because the subgroup‐specific details were not available for further analysis.

To evaluate iron deficiency, seven studies used plasma ferritin concentrations (Angeles‐Agdeppa 2008; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006a; Radhika 2011; Thankachan 2012), four studies used serum transferrin receptor concentrations (Hotz 2008; Losso 2017; Moretti 2006bThankachan 2012), wherein two studies (Moretti 2006a; Thankachan 2012), used and reported both these parameters.

Eleven studies reported mean haemoglobin concentrations (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012), four studies evaluated vitamin A deficiency (Hardinsyah 2016; Perignon 2016 (C); Pinkaew 2014; Thankachan 2012), and one study reported plasma folate concentration (Hardinsyah 2016). One study reported the level of diarrhoea (Thankachan 2012). No studies compared the groups for respiratory infections (as measured by study authors) or all‐cause death in their outcomes. One study reported on hookworm infection (Perignon 2016 (C)). One study reported abdominal pain (Thankachan 2012). No studies reported congenital anomalies or miscarriage (no studies were carried out among pregnant women). Five studies reported serum retinol (Angeles‐Agdeppa 2008; Hardinsyah 2016; Pinkaew 2013; Pinkaew 2014; Thankachan 2012), three studies reported plasma zinc concentration (Hardinsyah 2016; Pinkaew 2014; Thankachan 2012).

One study (Moretti 2006b), reported anthropometric measurements (weight‐for‐age, height‐for‐age, weight‐for‐height in terms of Z‐score) whereas Angeles‐Agdeppa 2008 reported prevalence of wasting and stunting. No studies compared the risk of iron overload (defined by serum ferritin higher than 150 µg/L in women and higher than 200 µg/L in men), clinical and severe malaria, night blindness (defined as the inability to see after dusk by people who typically report having normal vision during the day; only for vitamin A fortified rice as an intervention), across the groups

The controlled before‐and‐after studies reported biochemical outcomes relevant to iron, vitamin A, zinc and folate in addition to clinical outcomes such as beriberi (Della Lucia 2016; Gershoff 1977; Nogueira Arcanjo 2013; Salcedo 1950). In Ara 2019, they included anaemia, mean haemoglobin (g/L), zinc deficiency (< 10.1 mmol/L), mean serum zinc (mmol/L), morbidity (last two weeks), diarrhoea, fever and inflammation (CRP >10.0 mg/L) as the outcomes. Gershoff 1977 study reported the effect of consumption of rice fortified with multiple vitamins, however they did not report the total number of outcomes in the entire study population, hence their report did not reach the stage of meta‐analysis.

Sources of funding

Most included studies were funded by one or more agencies from the government sector, private sector, academic organisations, or non‐government organisations. One study did not report the source of financial support (Losso 2017).

Angeles‐Agdeppa 2008 stated its source of funding was The International Life Sciences Institute Center for Health Promotion of Japan (ILSI CHP, Japan), and the ILSI CHP, Atlanta, USA. Taiyo Kagaku, Japan donated the necessary fortificant used in this study.

DSM Nutritional Products (India) provided fortified rice for Thankachan 2012. Another study, Gershoff 1977, reported that they were supported in part by the United States Agency for International Development and the Fund for Research and Teaching, Department of Nutrition, Harvard School of Public Health. Also, that Ajinomoto Company, Tokyo, Japan supplied the rice fortification grains.

Two RCTs (Pinkaew 2013; Pinkaew 2014), were supported by Medicor Foundation (Triesen, Liechtenstein), the Royal Thai Government Scholarship. Also, Pinkaew 2014 study was supported by the International Atomic Energy Agency (Vienna, Austria). The Micronutrient Initiative, Ottawa, Canada, along with the Swiss Federal Institute of Technology, Zurich, Switzerland, and St John’s Academy of Health Sciences, Bangalore, India supported Moretti 2006b and Dr. Paul Lohmann (GmbH, Emmerthal, Germany) provided the iron and zinc compounds, and DSM Nutritional Products Ltd. (Basel, Switzerland) provided the vitamin A compound for Moretti 2006b; Pinkaew 2013; and Pinkaew 2014. Radhika 2011 was funded by the Department of Biotechnology, New Delhi, India. The Program for Appropriate Technology in Health (PATH), Seattle, USA provided the Ultra Rice premix for them. United States Department of Agriculture (USDA) and the Open Road Alliance funded one study (Parker 2015 (C)). USDA, the World Food Programme‐DSM Consortium, and the Institut de Recherce pour le Development (IRD) supported Perignon 2016 (C).

A subcontract grant from PATH through an original grant from Bill & Melinda Gates Foundation provided the funding for Hotz 2008. The Food and Nutrition Society of Indonesia supported Hardinsyah 2016. Williams‐Waterman Fund Committee of the Research Corporation, New York City funded Salcedo 1950, and Hoffmann‐LaRoche, Inc., Nutley, New Jersey, USA donated the premix that they used. Della Lucia 2016 had financial support from O Programa Institucional de Bolsas de Iniciação Científica e Tecnológica da (PROBIC/FAPEMIG), PIBIC/CNPq and FAPEMIG and PATH donated the fortified rice. The United Nations World Food Programme (Grant # 1209) funded the study conducted in Bangladesh by Ara 2019

Excluded studies

We excluded 28 articles from 22 studies after assessing the full‐text articles. The details of excluded studies along with the reasons for exclusion are given in Characteristics of excluded studies.

See Figure 2 for reasons for excluding the articles. Nine studies were related to a different type of intervention or rice was not the medium of intervention (Arsenault 2010; Bagni 2009; Barboza 2011; Castro 2017; Finkelstein 2013; Graham 2007; Haskell 2005; Sridevi 2013; Vitolol 1998), six studies with participants outside the age range of interest (Beinner 2010; Ma 2016; Nogueira Arcanjo 2012; Pham 2012; Skau 2015; Walter 1993); five studies with different type of study design (Ando 2012; Angeles‐Agdeppa 2011; Florentino 1998; Huo 2014; Kagawa 2017), and two studies had insufficient information (Hyun 2015; Pham Van 2013).

We have provided details of two ongoing studies in Characteristics of ongoing studies table.

Risk of bias in included studies

We used standardised domains to assess the risk of bias of included studies (including individually and cluster‐randomised trials) (Higgins 2019). We assessed the primary outcomes for risk of bias at the study level. We considered additional domains for risk of bias among the cluster‐RCTs. We presented them in the 'Risk of bias' table in the Characteristics of included studies section, and give a summary of the ’Risk of bias’ analyses in Figure 3 and Figure 4. Among the 12 RCTs contributing to the meta‐analysis, two studies had a low overall risk of bias (Moretti 2006b; Radhika 2011), having low risk in allocation concealment, differences in baseline outcome measures, and incompleteness of outcome data. We assessed all other RCTS to be at high overall risk of bias. The five controlled before‐and‐after studies had high or unclear risk of bias for most domains (Ara 2019; Della Lucia 2016; Gershoff 1977; Nogueira Arcanjo 2013; Salcedo 1950). Two of these studies had a documented difference in baseline outcome measures (Della Lucia 2016; Nogueira Arcanjo 2013). Also, Ara 2019 had different baseline and end‐line populations.

3.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

Four studies were controlled before‐and‐after studies (Ara 2019; Della Lucia 2016; Gershoff 1977; Nogueira Arcanjo 2013), and one was a controlled cross‐sectional study (Salcedo 1950)

4.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies

Allocation

Sequence generation

We noted three studies adequately describing the sequence generation for the recruitment of study participants in their respective studies (Hotz 2008; Perignon 2016 (C); Thankachan 2012), and we graded them to be at low risk of bias. We assessed four studies at high risk of bias for not having random sequence generation (Ara 2019; Della Lucia 2016; Gershoff 1977; Salcedo 1950), and 10 studies to be at unclear risk (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hussain 2014; Losso 2017; Moretti 2006b; Nogueira Arcanjo 2013; Parker 2015 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011); all four studies at high risk of bias for random sequence generation were before‐and‐after comparison studies.

Allocation concealment

Five studies reported allocation concealment completely in their methods (Della Lucia 2016; Hardinsyah 2016; Moretti 2006b; Perignon 2016 (C); Radhika 2011), and we assessed them to be at low risk of bias. Six studies did not effectively conceal allocation (Angeles‐Agdeppa 2008; Ara 2019; Gershoff 1977; Pinkaew 2013; Pinkaew 2014; Salcedo 1950), and we assessed them at high risk of bias, and six studies were at unclear risk (Hotz 2008; Hussain 2014; Losso 2017; Nogueira Arcanjo 2013; Parker 2015 (C); Thankachan 2012).

Similarity of baseline characteristics

We assessed 13 studies to be at low risk of bias for similarity of baseline characteristics (Angeles‐Agdeppa 2008; Ara 2019; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Nogueira Arcanjo 2013; Pinkaew 2013; Pinkaew 2014; Radhika 2011; Salcedo 1950; Thankachan 2012). Two studies were at high risk of bias (Gershoff 1977; Perignon 2016 (C)), and two studies were at unclear risk (Della Lucia 2016; Parker 2015 (C)).

Overall, seven studies were at high risk of selection bias (Angeles‐Agdeppa 2008; Ara 2019; Gershoff 1977; Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Salcedo 1950) with high risk of bias in any one of the domains of selection bias.

For similarity of baseline outcome measurements, nine studies were at low risk of bias (Angeles‐Agdeppa 2008; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012), seven studies were at high risk of bias (Ara 2019; Della Lucia 2016; Gershoff 1977; Hardinsyah 2016; Nogueira Arcanjo 2013; Parker 2015 (C); Perignon 2016 (C)), and we assessed one study as unclear risk of bias (Salcedo 1950).

Blinding

Eight studies described the blinding process for the participants adequately and we graded them to be at low of bias in blinding the participants (Angeles‐Agdeppa 2008; Hardinsyah 2016; Losso 2017; Moretti 2006b; Nogueira Arcanjo 2013; Perignon 2016 (C); Radhika 2011; Thankachan 2012), five studies were at low risk of bias in blinding the outcome assessment (Angeles‐Agdeppa 2008; Moretti 2006b; Nogueira Arcanjo 2013; Radhika 2011; Thankachan 2012), and seven studies were at low risk in terms of contamination (Ara 2019; Hardinsyah 2016; Hussain 2014; Losso 2017; Nogueira Arcanjo 2013; Parker 2015 (C); Perignon 2016 (C)). Overall, four studies (Hardinsyah 2016; Losso 2017; Nogueira Arcanjo 2013; Perignon 2016 (C)), were at low risk of performance bias and five studies gave an account of blinding the outcome assessors which we assessed to be at low risk of detection bias (Angeles‐Agdeppa 2008; Moretti 2006b; Nogueira Arcanjo 2013; Radhika 2011; Thankachan 2012).

We assessed 13 studies at unclear risk of blinding. Two studies were at unclear risk of blinding the participants and personnel (Della Lucia 2016; Parker 2015 (C)), six studies for blinding of outcome assessment (Della Lucia 2016; Hardinsyah 2016; Hussain 2014; Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014), and nine studies for contamination (Della Lucia 2016; Gershoff 1977; Hotz 2008; Moretti 2006b; Pinkaew 2013; Pinkaew 2014; Radhika 2011; Salcedo 1950; Thankachan 2012).

Ten studies were at high risk of blinding. Seven studies were at high risk of blinding of the participants (Ara 2019; Gershoff 1977; Hotz 2008; Hussain 2014; Pinkaew 2013; Pinkaew 2014; Salcedo 1950), six studies for blinding of outcome assessment (Ara 2019; Gershoff 1977; Hotz 2008; Losso 2017; Parker 2015 (C); Salcedo 1950), and one study was at high risk of contamination (Angeles‐Agdeppa 2008).

Incomplete outcome data

We assessed 11 studies to be at low risk of bias for completeness of outcome data (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hussain 2014; Losso 2017; Moretti 2006b; Nogueira Arcanjo 2013; Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012), and they reported minimum loss to follow‐up rates among the study participants. Two studies were at high risk of bias (Hotz 2008; Salcedo 1950), because of high rates of dropout from the study, and we assessed four studies at unclear risk of bias due to inadequate description of attrition (Ara 2019; Della Lucia 2016; Gershoff 1977; Parker 2015 (C)).

Selective reporting

There was no indication of selective reporting by any of the studies from published records, however we did not have access to the study protocols. Ten studies reported all of their pre‐specified outcomes, including the insignificant ones, and we assessed them to be at low risk of bias (Angeles‐Agdeppa 2008; Ara 2019; Losso 2017; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012); one of these studies provided a study registration number for the protocol (Pinkaew 2014). We assessed one study at high risk of reporting bias because the study participants were given rewards for maintaining highest attendance in the schools in which the attendance rate was not steady (Hardinsyah 2016). We assessed six studies to be at unclear risk of bias (Della Lucia 2016; Gershoff 1977; Hotz 2008; Hussain 2014; Nogueira Arcanjo 2013; Salcedo 1950)

Other potential sources of bias

We could not identify other potential sources of bias in the included studies. For some studies, industry provided the fortificants or the rice fortification grains. We assessed three studies to be at low risk of bias (Angeles‐Agdeppa 2008; Parker 2015 (C); Perignon 2016 (C)), one study at high risk of bias (Hardinsyah 2016), and 13 studies at unclear risk of bias (Ara 2019; Della Lucia 2016; Gershoff 1977; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Nogueira Arcanjo 2013; Pinkaew 2013; Pinkaew 2014; Radhika 2011; Salcedo 1950; Thankachan 2012).

We evaluated and determined additional criteria for risk of bias in cluster‐randomised studies (i.e. recruitment bias, baseline imbalance, loss of clusters, incorrect analysis, compatibility with individual RCTs) for two studies (Parker 2015 (C); Perignon 2016 (C)). Among these criteria, Perignon 2016 (C) was at unclear risk for baseline imbalance because they did not describe clusters and did not report any process of statistical adjustment for clustering. For all remaining criteria, we judged both the studies to be at low risk of bias.

Effects of interventions

See: Table 1; Table 2

A summary of the effects of interventions is given in Table 1 and Table 2.

We included 12 RCTs in the meta‐analysis. All 12 RCTs contained at least one arm with iron and compared with unfortified rice. No RCT had a 'no intervention' arm in their study. Of the 12 RCTs, six RCTs fortified with iron only, five RCTs fortified with iron and other micronutrients and one RCT had several fortified groups including iron only, vitamin A only and multiple micronutrients. Few of the pre‐specified outcome measures in this review were not reported by any of the included studies. We analysed the results using a random‐effects model, since all the included studies had significant heterogeneity. See Data and analyses for a detailed description of pre‐specified outcomes and their results.

We carried out sensitivity analyses for two cluster‐randomised trials (Parker 2015 (C); Perignon 2016 (C)), with different values of ICC and examined their effect on the effect estimates (RR) for two outcomes: anaemia and mean haemoglobin concentration. We observed that ICC did not change the direction of effects of interventions significantly for any outcome. We have presented the details of these sensitivity analyses in Table 8. We also carried out sensitivity analysis by excluding the single RCT (Parker 2015 (C)), with a high/unclear risk of bias in eight out of 15 domains (including the additional domains for cluster‐RCTs) for two outcomes, anaemia and mean haemoglobin.

6. Sensitivity analysis of two cluster‐randomised trials using different intra‐cluster correlation on the outcomes anaemia and haemoglobin concentration.

Outcome (all studies included in the analysis)	Study (ICC)	RR (95% CI)	Tau²	Chi²	P value	I²
Anaemia (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Parker 2015 (C); Perignon 2016 (C); Radhika 2011; Thankachan 2012)	Parker 2015 (C) (0)	0.83 (0.64 to 1.08)	0.06	16.06	0.01	63%
	Parker 2015 (C) (0.001)	0.83 (0.64 to 1.08)	0.06	15.72	0.02	62%
	Parker 2015 (C) (0.002)	0.83 (0.64 to 1.08)	0.06	15.71	0.02	62%
	Parker 2015 (C) (0.005)	0.83 (0.64 to 1.07)	0.06	15.12	0.02	60%
	Parker 2015 (C) (0.01)	0.83 (0.64 to 1.08)	0.06	14.80	0.02	59%
	Parker 2015 (C) (0.02723)	0.83 (0.64 to 1.07)	0.05	13.08	0.04	54%
	Parker 2015 (C) (0.1)	0.81 (0.64 to 1.03)	0.04	10.03	0.12	40%
	Perignon 2016 (C) (0)	0.83 (0.67 to 1.03)	0.04	13.17	0.04	54%
	Perignon 2016 (C) (0.001)	0.83 (0.67 to 1.04)	0.04	13.15	0.04	54%
	Perignon 2016 (C) (0.002)	0.83 (0.66 to 1.04)	0.04	13.16	0.04	54%
	Perignon 2016 (C) (0.005)	0.83 (0.66 to 1.05)	0.04	13.12	0.04	54%
	Perignon 2016 (C) (0.01)	0.83 (0.65 to 1.05)	0.05	13.12	0.04	54%
	Perignon 2016 (C) (0.02723)	0.83 (0.64 to 1.07)	0.05	13.08	0.04	54%
	Perignon 2016 (C)( 0.1)	0.83 (0.63 to 1.09)	0.06	13.08	0.04	54%
Outcome (all studies included in the analysis)	Study (ICC)	MD (95% CI)	Tau²	Chi²	P value	I²
Haemoglobin concentration (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012)	Parker 2015 (C) (0)	1.69 (0.48 to 2.91)	1.82	24.15	0.007	59%
	Parker 2015 (C) (0.001)	1.70 (0.48 to 2.92)	1.81	23.90	0.008	58%
	Parker 2015 (C) (0.002)	1.71 (0.49 to 2.93)	1.81	23.69	0.008	58%
	Parker 2015 (C) (0.005)	1.73 (0.51 to 2.96)	1.80	23.18	0.01	57%
	Parker 2015 (C) (0.01)	1.77 (0.54 to 3.00)	1.79	22.62	0.01	56%
	Parker 2015 (C)) (0.02723)	1.85 (0.61 to 3.10)	1.77	21.73	0.02	54%
	Parker 2015 (C)) (0.1)	1.98 (0.71 to 3.25)	1.76	20.96	0.02	52%
	Perignon 2016 (C)) (0)	1.85 (0.61 to 3.09)	1.77	21.98	0.02	55%
	Perignon 2016 (C)) (0.001)	1.85 (0.61 to 3.09)	1.77	21.97	0.02	54%
	Perignon 2016 (C)) (0.002)	1.85 (0.61 to 3.09)	1.77	21.96	0.02	54%
	Perignon 2016 (C)) (0.005)	1.85 (0.61 to 3.10)	1.77	21.93	0.02	54%
	Perignon 2016 (C)) (0.01)	1.85 (0.61 to 3.10)	1.77	21.89	0.02	54%
	Perignon 2016 (C)) (0.02723)	1.85 (0.61 to 3.10)	1.77	21.73	0.02	54%
	Perignon 2016 (C)) (0.1)	1.86 (0.61 to 3.11)	1.78	21.15	0.02	53%
C: cluster‐randomised trial; CI: confidence interval; ICC: intra‐cluster correlation coefficient; MD: mean difference; RR: risk ratio

No studies looked at fortified rice versus no intervention, and we could not examine comparisons 2 and 4 to 8 because there were no studies looking at vitamin A, folic acid and zinc with other micronutrients that did not also include iron, and there were no studies with a 'no intervention' arm. However we undertook meta‐analysis for vitamin A versus unfortified rice since one study (Hussain 2014), reported an intervention arm with vitamin A only compared with unfortified rice. We included this in comparison 3.

Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice

There were 12 studies (2201 participants) included in this comparison (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Pinkaew 2014; Radhika 2011; Thankachan 2012). These studies comprise all the data included in the synthesis of this Review. We included five non‐randomised studies in this comparison (Ara 2019; Della Lucia 2016; Gershoff 1977; Nogueira Arcanjo 2013; Salcedo 1950) for qualitative assessment.

Primary outcomes

Anaemia (defined as haemoglobin (Hb) below the WHO cut‐off, adjusted for altitude as appropriate or as defined by the study authors)

We included seven studies in the analysis (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Parker 2015 (C); Perignon 2016 (C); Radhika 2011; Thankachan 2012). The studies had a duration of four months (Hardinsyah 2016), six months (Angeles‐Agdeppa 2008; Hotz 2008; Parker 2015 (C); Perignon 2016 (C); Thankachan 2012), and eight months (Radhika 2011). The detailed results are presented in Analysis 1.1. Overall, the children who consumed iron‐fortified rice had similar levels of anaemia to controls at the end of the follow‐up period (RR 0.72, 95% CI 0.54 to 0.97; 7 studies; 1634 participants; low‐certainty evidence). Heterogeneity was high (Tau² = 0.10; Chi² = 23.27, df = 6; P = 0.0007; I² = 74%) and the results have to be interpreted with caution. One study (Angeles‐Agdeppa 2008), reported direction of benefit favouring fortification, whereas Hotz 2008; Parker 2015 (C); Perignon 2016 (C); Radhika 2011 and Thankachan 2012 showed ambiguous direction. Exclusion of two studies, which clearly favoured fortification (Angeles‐Agdeppa 2008; Hardinsyah 2016), changed the effect such that there was no effect on anaemia (RR 0.92, 95% CI 0.76 to 1.12; 1248 participants) and reduced heterogeneity among studies (Tau² = 0.01; Chi² = 5.08, df = 4; P = 0.28; I² = 21%). Exclusion of Parker 2015 (C) revealed a slight reduction in anaemia with fortification of rice (RR 0.66, 95% CI 0.49 to 0.89; I² = 61%; 1336 participants) and it reduced the heterogeneity slightly.

1.1. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 1 Anaemia (defined as haemoglobin (Hb) below the WHO cut‐off, adjusted for altitude as appropriate).

There was no clear evidence of differences between subgroups in terms of reduction of anaemia in any of the following subgroup analyses.

1. Micronutrient content: iron alone (RR 0.63 95% CI 0.36 to 1.09; I² = 43%; 3 studies, 444 participants; Analysis 1.2); iron plus other nutrients (RR 0.95, 95% CI 0.82 to 1.11; I² = 0%; 4 studies, 1190 participants; Analysis 1.2).

2. Rice fortification method: hot extrusion (RR 0.72, 95% CI 0.52 to 1.01; I² = 80%; 5 studies, 1197 participants); cold extrusion (RR 0.75, 95% CI 0.41 to 1.38; I² = 31%; 3 studies, 437 participants; Analysis 1.3).

3. By cooking method most commonly used in study setting (as reported): rinsing and boiling without excess water (RR 0.40, 95% CI 0.26 to 0.63; 1 study; 215 participants; Analysis 1.4); unknown/unreported (RR 0.81, 95% CI 0.63 to 1.05; I² = 61%; 6 studies, 1419 participants; Analysis 1.4).

4. Public health significance of anaemia at baseline in the target group: mild and moderate, 5% to 39.9% (RR 0.69, 95% CI 0.44 to 1.06; I² = 85%; 4 studies, 1129 participants; Analysis 1.5); severe, 40% and more (RR 0.87, 95% CI 0.67 to 1.12; I² = 0%; 2 studies, 360 participants; Analysis 1.5); and mixed/unknown/unreported (RR 0.31, 95% CI 0.09 to 1.10; 1 study, 145 participants; Analysis 1.5).

5. Malaria endemicity at the time that the study was conducted: some malaria risk setting (RR 0.85, 95% CI 0.55 to 1.32; 1 study, 445 participants); malaria‐free area (RR 0.70, 95% CI 0.48 to 1.03; I² = 71%; 2 studies, 403 participants; Analysis 1.6); and unknown/unreported malaria setting (RR 0.67, 95% CI 0.34 to 1.31; I² = 84%; 4 studies, 786 participants; Analysis 1.6).

1.2. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 2 Anaemia (subgroup: by micronutrient content).

1.3. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 3 Anaemia (subgroup: by rice fortification method).

1.4. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 4 Anaemia (subgroup: by cooking method most commonly used in trial setting).

1.5. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 5 Anaemia (subgroup: by public health significance of anaemia at baseline ).

1.6. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 6 Anaemia (subgroup: by malaria endemicity).

Iron deficiency

We included eight studies in the analysis (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Moretti 2006b; Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012). We did not include data from Hussain 2014 in the meta‐analysis because the subgroup details (for each arm) related to iron deficiency were not available, since the study authors reported data only for overall fortification versus unfortified rice. The intervention in the included studies lasted four months (Hardinsyah 2016), five months (Pinkaew 2013), six months (Angeles‐Agdeppa 2008; Hotz 2008; Perignon 2016 (C); Thankachan 2012), seven months (Moretti 2006b) and eight months (Radhika 2011). Details are presented in Analysis 1.7. Participants consuming rice fortified with iron or in combination with other micronutrients may have slightly lower levels of iron deficiency compared to those consuming unfortified rice (RR 0.66, 95% CI 0.51 to 0.84; 8 studies, 1733 participants; low‐certainty evidence). Heterogeneity was low (Tau² = 0.02; Chi² = 8.60, df = 7; P = 0.28; I² = 19%). The pooled estimate favours fortification, in which direction of benefit was positive for fortification in Moretti 2006b and Radhika 2011. Also Hussain 2014 showed favourable effects towards fortification (48 out of 185 in the fortification arms together and 19 out of 37 in the control arm).

1.7. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 7 Iron deficiency (as defined by study authors, based on a biomarker of iron status).

There were no significant differences in iron deficiency due to consumption of iron‐fortified rice across the subgroups.

1. Micronutrient content: fortification with a single micronutrient (iron) resulted in lower risk of iron deficiency (RR 0.56, 95% CI 0.40 to 0.80; I² = 17%; 4 studies, 628 participants; Analysis 1.8), whereas fortification with multiple micronutrients showed no difference compared to the unfortified group (RR 0.78, 95% CI 0.57 to 1.06; I² = 0%; 4 studies, 1105 participants; Analysis 1.8).

2. Rice fortification method: hot extrusion (RR 0.66, 95% CI 0.51 to 0.87; I² = 4%; 6 studies, 1283 participants; Analysis 1.9), cold extrusion (RR 0.65, 95% CI 0.38 to 1.09; participants = 450; studies = 3; I² = 40%; Analysis 1.9).

3. Cooking method most commonly used in study setting (as reported): rinsing and boiling without excess water (RR 0.79, 95% CI 0.51 to 1.21; 1 study, 215 participants; Analysis 1.10) and unknown/unreported (RR 0.63, 95% CI 0.46 to 0.84; I² = 22%; 7 studies, 1518 participants; Analysis 1.10).

4. Public health significance of anaemia at baseline in the target group: mild and moderate, 5% to 39.9% (RR 0.77, 95% CI 0.55 to 1.07; I² = 0%; 4 studies, 1046 participants; Analysis 1.11); severe, 40% and more (RR 0.57, 95% CI 0.26 to 1.27; I² = 59%; 2 studies, 358 participants; Analysis 1.11) and mixed/unknown/unreported (RR 0.63, 95% CI 0.39 to 1.01; I² = 47%; 2 studies, 329 participants; Analysis 1.11).

5. Malaria endemicity at the time that the study was conducted: some malaria risk setting (RR 0.86, 95% CI 0.48 to 1.53; 1 study, 485 participants; Analysis 1.12); malaria‐free area (RR 0.58, 95% CI 0.41 to 0.84; I² = 0%; 3 studies, 585 participants; Analysis 1.12); and unknown/unreported malaria setting (RR 0.61, 95% CI 0.39 to 0.96; I² = 46%; 4 studies, 663 participants; Analysis 1.12).

1.8. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 8 Iron deficiency (subgroup: by micronutrient content).

1.9. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 9 Iron deficiency (subgroup: by rice fortification method).

1.10. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 10 Iron deficiency (subgroup: by cooking method most commonly used in trial setting).

1.11. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 11 Iron deficiency (subgroup: by public health significance of anaemia at baseline ).

1.12. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 12 Iron deficiency (subgroup: by malaria endemicity).

Haemoglobin concentration (g/L)

We included 11 studies in the analysis (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hotz 2008; Hussain 2014; Losso 2017; Moretti 2006b; ; Parker 2015 (C); Perignon 2016 (C); Pinkaew 2013; Radhika 2011; Thankachan 2012). The duration of the intervention varied between two weeks (Losso 2017), and eight months (Radhika 2011). The other included studies provided the intervention for four months (Hardinsyah 2016), five months (Pinkaew 2013), six months (Angeles‐Agdeppa 2008; Hotz 2008; Hussain 2014; Perignon 2016 (C); Thankachan 2012) and seven months (Moretti 2006b; Parker 2015 (C)). Details are presented in Analysis 1.13. Consuming rice fortified with iron or in combination with other micronutrients may increase haemoglobin concentrations (g/L) in comparison to consuming unfortified rice (MD 1.83, 95% CI 0.66 to 3.00; 11 studies, 2163 participants; low‐certainty evidence). Heterogeneity was substantial (Tau² = 1.58; Chi² = 21.86, df = 10; P = 0.02; I² = 54%) and results should be interpreted with caution. The direction of benefit was towards fortification in three studies (Angeles‐Agdeppa 2008; Hardinsyah 2016; Perignon 2016 (C)). Exclusion of Parker 2015 (C) did not change the direction of the effect or the heterogeneity.

1.13. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 13 Haemoglobin concentration (g/L).

There were no clear differences between other subgroups, or any obvious asymmetry in the funnel plot (Figure 5).

5.

Funnel plot of comparison 1. Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added), outcome 1.13, haemoglobin concentration (g/L)

1. Micronutrient content: rice fortified with iron alone showed a significant increase in mean haemoglobin (MD 3.93, 95% CI 1.24 to 6.62; I² = 57%; 6 studies, 698 participants; Analysis 1.14); whereas the studies giving iron in combination with other micronutrients did not increase mean haemoglobin (MD 1.06, 95% CI 0.15 to 1.98; I² = 24%; 6 studies, 1465 participants; Analysis 1.14).

2. Rice fortification method: hot extrusion (MD 1.93, 95% CI 0.53 to 3.32; I² = 68%; 7 studies, 1563 participants; Analysis 1.15); cold extrusion (MD 1.54, 95% CI 0.58 to 2.51; I² = 11%; 3 studies, 437 participants; Analysis 1.15);coating (MD 8.20, 95% CI −12.14 to 28.54; 1 study, 15 participants; Analysis 1.15); and mixed/unknown/unreported (MD −4.00, 95% CI −11.72 to 3.72; 1 study, 148 participants; Analysis 1.15).

3. Cooking method most commonly used in study setting (as reported): rinsing and boiling without excess water (MD 3.80, 95% CI 0.86 to 6.74; 1 study, 215 participants; Analysis 1.16); and unknown/unreported (MD 1.62, 95% CI 0.43 to 2.81; I² = 51%; 10 studies, 1948 participants; Analysis 1.16).

4. Public health significance of anaemia at baseline in the target group: mild and moderate, 5% to 39.9% (MD 1.67, 95% CI −0.10 to 3.44; I² = 70%; 6 studies, 1459 participants; Analysis 1.17); severe, 40% and more (MD 1.07, 95% CI −0.84 to 2.98; I² = 0%; 2 studies, 360 participant; Analysis 1.17); and mixed/unknown/unreported (MD 3.42, 95% CI 1.10 to 5.73; I² = 0%; 3 studies, 344 participants; Analysis 1.17).

5. Malaria endemicity at the time that the study was conducted: some malaria risk setting (MD 0.90, 95% CI 0.65 to 1.15; 1 study, 445 participants; Analysis 1.18); malaria‐free area (MD 3.15, 95% CI 0.98 to 5.31; I² = 53%; 3 studies, 587 participants; Analysis 1.18); and unknown/unreported malaria setting (MD 1.33, 95% CI −0.48 to 3.14; I² = 34%; 7 studies, 1131 participants; Analysis 1.18).

1.14. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 14 Haemoglobin concentration (subgroup: by micronutrient content).

1.15. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 15 Haemoglobin concentration (subgroup: by rice fortification method).

1.16. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 16 Haemoglobin concentration (subgroup: by cooking method most commonly used in trial setting).

1.17. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 17 Haemoglobin concentration (subgroup: by public health significance of anaemia at baseline).

1.18. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 18 Haemoglobin concentration (subgroup: by malaria endemicity).

Vitamin A deficiency (as defined by the study authors)

Four studies contributed data for vitamin A deficiency (Hardinsyah 2016; Perignon 2016 (C); Pinkaew 2014; Thankachan 2012). Details are provided in Analysis 1.19. Consumption of fortified rice may make little or no difference to vitamin A deficiency (RR 0.68, 95% CI 0.36 to 1.29; 927 participants; 4 studies, low‐certainty evidence). Heterogeneity was marginally high (Tau² = 0.16; Chi² = 4.77, df = 3; P = 0.19; I² = 37%) and results have to be interpreted with caution. We did not include data from Hussain 2014 in the meta‐analysis, since the study authors reported vitamin A deficiency for the fortified rice group overall versus unfortified rice (37 out of 185 in the fortified arm and 22 out of 37 in the control arm). However their overall estimates had significant decrease in vitamin A deficiency in the fortified arm compared to control arm at the end of the six‐month intervention period.

1.19. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 19 Vitamin A deficiency (as defined by study authors, by using a biomarker of vitamin A).

There are no significant differences in the risk ratio across the subgroups. The details of subgroup analyses are presented below.

1. Micronutrient content: all the studies contributing data to this analysis compared iron plus other micronutrients with unfortified rice (RR 0.68, 95% CI 0.36 to 1.29; I² = 37%; 4 studies, 927 participants; Analysis 1.20).

2. Rice fortification method: hot extrusion (RR 0.70, 95% CI 0.35 to 1.39; I² = 34%; 4 studies, 765 participants; Analysis 1.21); and cold extrusion (RR 0.61, 95% CI 0.24 to 1.54; 1 study, 162 participants; Analysis 1.21).

3. Cooking method most commonly used in study setting (as reported): rinsing and boiling without excess water (RR 1.10, 95% CI 0.47 to 2.60; 1 study, 215 participants; Analysis 1.22); and unknown/unreported (RR 0.55, 95% CI 0.25 to 1.22; I² = 34%; 3 studies, 712 participants; Analysis 1.22).

4. Public health significance of anaemia at baseline in the target group: mild and moderate, 5% to 39.9% (RR 0.60, 95% CI 0.29 to 1.24; I² = 47%; 3 studies, 695 participants; Analysis 1.23) and severe, 40% and more (RR 1.46, 95% CI 0.30 to 7.07; 1 study, 232 participants; Analysis 1.23).

5. Malaria endemicity at the time that the study was conducted: some malaria risk setting (RR 0.57, 95% CI 0.30 to 1.08; 1 study, 442 participants; Analysis 1.24); malaria‐free area (RR 1.46, 95% CI 0.30 to 7.07; 1 study, 232 participants; Analysis 1.24); and unknown/unreported malaria setting (RR 0.55, 95% CI 0.12 to 2.59; I² = 72%; 2 studies, 253 participants; Analysis 1.24).

1.20. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 20 Vitamin A deficiency (subgroup: by micronutrient content).

1.21. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 21 Vitamin A deficiency (subgroup: by rice fortification method).

1.22. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 22 Vitamin A deficiency (subgroup: by cooking method most commonly used in trial setting).

1.23. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 23 Vitamin A deficiency (subgroup: by public health significance of anaemia at baseline ).

1.24. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 24 Vitamin A deficiency (subgroup: by malaria endemicity).

Serum or plasma folate (nmol/L)

One study reported the level or comparison of serum folate (Hardinsyah 2016). The direction of benefit in this study was slightly towards fortified rice (MD 4.30, 95% CI 2.00 to 6.60; 1 study, 215 participants; low‐certainty evidence). The details are given in Analysis 1.25.

1.25. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 25 Serum or plasma folate (nmol/L).

Any adverse effects (hookworm infection risk)

One study (Perignon 2016 (C)), reported that children given fortified rice were more likely to have hookworm infection compared to those given unfortified rice (RR 1.78, 95% CI 1.18 to 2.70, 1 study, 785 participants; low‐certainty evidence; Analysis 1.26).

1.26. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 26 Any adverse effects.

Any adverse effects (abdominal pain more than three days)

One study (Thankachan 2012), reported that children given fortified rice were just as likely to have abdominal pain compared to those given unfortified rice (average RR 0.77, 95% CI 0.42 to 1.42; Analysis 1.26).

Diarrhoea (as defined by study authors; for studies among children aged 2 to 11.9 years of age)

One study reported the comparison of diarrhoeal episodes across the fortified and unfortified groups (Thankachan 2012). There was no difference in the risk of diarrhoea (average RR 3.52, 95% CI 0.18 to 67.39; 1 study, 258 participants, very low‐certainty evidence; Analysis 1.27).

1.27. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 27 Diarrhoea (as defined by study authors).

Respiratory infections (for studies among children aged 2 to 11.9 years of age)

The included studies mentioned the episodes of respiratory infections in intervention and control groups during the study period, however, none reported the differences across the groups following rice fortification.

All‐cause death (for studies among children aged 2 to 11.9 years of age)

None of the included studies reported deaths.

Congenital anomalies (for studies among pregnant women with folic acid‐fortified rice as intervention)

No studies involved pregnant women.

Miscarriage (for studies among pregnant women)

No studies involved pregnant women.

Secondary outcomes

Serum or plasma retinol (µmol/L)

Five studies reported the outcome of serum retinol (µmol/L) across the iron‐fortified and unfortified groups (Angeles‐Agdeppa 2008; Hardinsyah 2016; Hussain 2014; Pinkaew 2014; Thankachan 2012). Details are presented in Analysis 1.28. Participants consuming rice fortified with iron alone or other micronutrients had a marginally higher plasma retinol compared to those consuming unfortified rice (MD 0.04, 95% CI −0.13 to 0.21; 5 studies; 727 participants). Heterogeneity was high (Tau² = 0.03; Chi² = 60.39, df = 4 P < 0.00001; I² = 93%). Two studies favoured fortification (Angeles‐Agdeppa 2008; Hussain 2014), and three had ambiguous results (Hardinsyah 2016; Pinkaew 2014; Thankachan 2012). Heterogeneity was explained by one study (Hardinsyah 2016), and its removal showed a higher mean difference favouring fortification (MD 0.20, 9% CI 0.18 to 0.22). This study had seven micronutrients.

1.28. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 28 Serum or plasma retinol (µmol/L).

Serum or plasma zinc (µmol/L)

Three studies reported the effectiveness of multiple micronutrient‐fortified rice on the level of serum or plasma zinc among children (Hardinsyah 2016; Pinkaew 2014; Thankachan 2012). See Analysis 1.29 for details (MD 0.38, 95% CI −0.08 to 0.83; I² = 28%; 3 studies, 618 participants).

1.29. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 29 Serum or plasma zinc (µmol/L).

Anthropometric measures

One study (Moretti 2006b), contributed data to the outcome height‐for‐age Z‐score and weight‐for‐height Z‐score. The mean difference for height‐for‐age Z‐score was 0.02 (95% CI −0.32 to 0.36; 1 study, 184 participants; Analysis 1.30) and for weight‐for‐height Z‐score mean difference was 0.13 (95% CI −0.19 to 0.45; 1 study, 184 participants; Analysis 1.31). For both these outcomes, fortification may or may not make a difference.

1.30. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 30 Height‐for‐age Z‐score.

1.31. Analysis.

Comparison 1 Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)., Outcome 31 Weight‐for‐height Z‐score.

Risk of iron overload (defined by serum ferritin higher than 150 µg/L in women and higher than 200 µg/L in men)

No studies reported the aspects of iron overload.

Clinical and severe malaria

None of the included studies had details on malaria across any of the study groups. Few studies had declared they were conducted in malaria non‐endemic areas.

Night blindness (defined as the inability to see after dusk by people who typically report having normal vision during the day; only for vitamin A‐fortified rice as an intervention)

No studies with vitamin A reported night blindness.

Rice fortified with iron alone or in combination with other micronutrients versus no intervention

No studies contributed data for this outcome.

Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice

We included one study in this comparison (Hussain 2014).

Primary outcomes

Anaemia (defined as haemoglobin (Hb) below the WHO cut‐off, adjusted for altitude as appropriate)

No studies contributed data for this outcome.

Iron deficiency

No studies contributed data for this outcome.

Haemoglobin concentration (g/L)

One study contributed data for this analysis (Hussain 2014). The study had five intervention arms; we included the retinyl palmitate arm with the fortification arm and the arm without fortification as the control arm for this comparison. The study authors reported a significant increase in the haemoglobin concentration in the vitamin A‐fortified arm compared to the unfortified control arm (MD 10.00, 95% CI 8.79 to 11.21; 1 study, 74 participants; low‐certainty evidence; Analysis 2.1).

2.1. Analysis.

Comparison 2 Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added), Outcome 1 Haemoglobin concentration (g/L).

Vitamin A deficiency (as defined by study authors, by using a biomarker)

We did not include any studies in this meta‐analysis. One study (Hussain 2014), reported vitamin A deficiency; however there were no data on vitamin A deficiency status in the arm fortified with vitamin A only. Their estimates are reported for the fortification arms in total. Details of their findings are in comparison 1.

Diarrhoea (as defined by study authors; for studies among children aged 2 to 11.9 years of age)

No studies contributed data for this outcome.

Respiratory infections (for studies among children aged 2 to 11.9 years of age)

No studies contributed data for this outcome.

All‐cause death (for studies among children aged 2 to 11.9 years of age)

No studies contributed data for this outcome.

Serum or plasma retinol (µmol/L)

One study contributed data to this analysis (Hussain 2014). Fortification of rice with vitamin A probably increases the serum retinol concentration compared to unfortified rice (MD 0.17, 95% CI 0.13 to 0.21; 1 study, 74 participants; low‐certainty evidence; Analysis 2.2).

2.2. Analysis.

Comparison 2 Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added), Outcome 2 Serum or plasma retinol (µmol/L).

Any adverse effects (hookworm infection risk)

No studies contributed data for this outcome.

Any adverse effects (abdominal pain more than 3 days)

No studies contributed data for this outcome.

Rice fortified with vitamin A alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Rice fortified with zinc alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

No studies contributed data to this comparison.

Rice fortified with zinc alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Rice fortified with folic acid alone or in combination with other micronutrients versus unfortified rice (no micronutrients added)

No studies contributed data to this comparison.

Rice fortified with folic acid alone or in combination with other micronutrients versus no intervention

No studies contributed data to this comparison.

Summary of non‐randomised studies

The value of the controlled before‐and‐after studies was mixed. Salcedo 1950 documented a reduction in clinical beriberi. Gershoff 1977 reported on the changes in amino acid intake and weight and length but did not make any formal estimates of change. One of the more recent studies, Nogueira Arcanjo 2013, comparing iron‐fortified rice versus unfortified rice showed no change in mean haemoglobin but with an increase in anaemia in the unfortified group. The study comparing multiple micronutrient‐fortified rice with unfortified rice compared outcomes relative to baseline values within the fortified group and the unfortified group (Della Lucia 2016). In the fortified group, there was an improvement in folic acid, thiamine and serum zinc, but not for haemoglobin or ferritin. In the unfortified group, there was an improvement in thiamine and ferritin concentrations. The groups were unbalanced with respect to ferritin levels, being significantly higher in the fortified group at baseline.

In Nogueira Arcanjo 2013, the groups were different in the prevalence of anaemia at baseline: 8.9% (11/120 were anaemic) in the group receiving iron‐fortified rice, and 20.8% (30/144 were anaemic) in the group receiving unfortified rice (P = 0.009). At the end of the study, the groups remained different, 10.5% (13/120) among the participants receiving iron‐fortified rice, and 37.5% (54/144) among those receiving unfortified rice (P < 0.001). There was a statistically significant increase in anaemia prevalence in the control group receiving standard unfortified rice; however, the iron‐fortified rice group did not present a statistically significant change in the number of anaemic children after the intervention. Also, the groups were similar for haemoglobin concentration: 120.6 ± 10.1 g/L in the fortified rice group versus 124.0 ± 41.4 g/L in the unfortified rice group, P = 0.38; but after intervention, there was no significant difference between the groups, P = 0.56. The after intervention period haemoglobin concentrations were 121.4 ± 10.6 g/L in the fortified rice group and 122.9 ± 24.8 g/L. Among only anaemic participants, in the group receiving iron‐fortified rice before intervention, mean haemoglobin value was 101.2 ± 8.5 g/L (n = 11) and 115.6 ± 8.6 after intervention, P = 0.0003; in the control group receiving unfortified rice (n = 30), mean haemoglobin concentrations changed from 108.3 ± 11.1 g/L at baseline to 109.4 ± 11.8 g/L after intervention, P = 0.18. For the standard rice school: baseline mean haemoglobin was 124.0 ± 41.4 g/L, and after intervention 122.9 ± 24.8, P = 0.78. Considering only anaemic participants, there was a significant increase in haemoglobin means before and after intervention, P = 0.003 in the fortified rice school.

In the other controlled before‐and‐after study (Gershoff 1977), the average haemoglobin concentration among those children consuming less than 10% or no fortified rice for all ages (5 to 9 years of age) was 114.6 g/L ± 6.6 (n = 135) in 1971 and changed to 119.8 g/L ± 12.6 (n = 135) in 1975. On the other hand, the average haemoglobin concentration among those children consuming more than 66% of fortified rice for all ages (5 to 9 years) was 117.7 g/L ± 8.8 (n = 61) in 1971 and 122.5 g/L ± 11.8 (n = 61) in 1975. These changes were not significant.

Discussion

Summary of main results

We have summarised the findings here and in Table 1 and Table 2. We included 17 studies in this review, 12 of which were RCTs. Two of the RCTs were cluster‐randomised trials. Five studies had a before‐and‐after study design that compared micronutrient‐fortified rice with unfortified rice. All the included studies had unfortified rice in the control arm. There were no studies comparing fortified rice with no intervention arm.

We considered 12 RCTs for the meta‐analysis. Ten RCTs were conducted in children and two were among non‐pregnant and non‐lactating women. All studies included in this review had unfortified rice as the control. All the studies included iron in their intervention arms (one study by Hussain 2014 with multiple arms had one fortification group with vitamin A only). Five studies included rice fortified with iron alone and one study had one arm with iron alone as the intervention. Seven studies used multiple micronutrients (six in children; one in women). Vitamin A, zinc, folate and vitamin B were the additional micronutrients. Four studies fortified with vitamin A, five studies fortified with zinc and three studies fortified with folic acid. The fortification profile of the included studies is shown in Table 6.

Participants consuming rice fortified with iron alone or in combination with other micronutrients were just as likely to be anaemic as those taking unfortified rice (7 RCTs, low‐certainty evidence); however, fortification of rice may reduce the risk of iron deficiency (8 RCTs, low‐certainty evidence). Considering the low level of certainty, rice fortification may make an improvement in the mean haemoglobin levels (g/L; 11 RCTs). Consumption of fortified rice may make little or no difference to vitamin A deficiency (4 RCTs, low‐certainty evidence), it may improve serum or plasma folate (1 RCT). Two studies reported on three adverse effects of diarrhoea, hookworm infection risk and abdominal pain of more than three days' duration. We are uncertain about the risk of diarrhoea (1 RCT, very low‐certainty evidence). Children given fortified rice may have a higher risk of hookworm infection compared to those given unfortified rice (1 RCT, low‐certainty evidence) and there may not be any difference in terms of abdominal pain of more than three days.

We noted a slight improvement in serum or plasma retinol (µmol/L) concentration among the participants consuming fortified rice (5 RCTs). There is no difference in serum zinc concentration (µmol/L; 3 RCTs), height‐for‐age Z‐score (1 RCT) and weight‐for‐height Z‐score (1 RCT) with fortification.

We included one RCT under the comparison of vitamin A alone or in combination with other micronutrients versus unfortified rice, since all other RCTs that included vitamin A in their fortification arm, also had iron. So they were only included in the first comparison, to avoid duplication.

Participants consuming rice fortified with vitamin A alone tend to have higher mean haemoglobin levels (1 RCT) and serum retinol levels (1 RCT).

The controlled before‐and‐after studies were significant in showing the first evidence of a clinical outcome attributable most likely to rice fortification (Salcedo 1950), and the extent by which dietary content is improved (Gershoff 1977). The limitations of unbalanced groups, most likely due to the absence of random allocation into treatment groups, limits our interpretation of the two studies in Brazil (Della Lucia 2016; Nogueira Arcanjo 2013), however both provide a foundation for planning studies on zinc and folate, both of which have very few studies.

Overall completeness and applicability of evidence

The review includes studies on preschool and school‐age children, and non‐pregnant, non‐lactating women. We found no studies for adolescents only (except one study that included adolescent girls), pregnant or lactating women or adult males. All but one study were from low‐ and middle‐income countries, where anaemia prevalence among children aged 6 to 59 months of age ranged between 26% to 59% (WHO 2015a). The studies with serum retinol as outcomes were conducted in countries where the prevalence of vitamin A deficiency among preschoolers ranged from 16% to 62% (WHO 2009a).

Almost all randomised clinical trials used micronized ferric pyrophosphate and the hot extrusion method, with three studies including either a cold or warm extrusion arm. Of the four vitamins and minerals identified for review, studies were found to have investigated four (iron, vitamin A, folate and zinc). All but one study had haemoglobin data but not all studies reported the mean haemoglobin or anaemia rates. Although three studies included folic acid as one of the fortificants, folate status was reported in only one. Also, most of the included RCTs were conducted in school settings. The certainty of evidence for anaemia and iron deficiency was low. For haemoglobin concentration, it was very low‐certainty evidence. This being a closed and controlled set up, generalising the findings of such studies becomes a challenge for the present systematic review. There could also be an interplay of co‐interventions like other added micronutrients to the same fortified rice, dosage and absorption of iron and consumption of other nutritive items, which would alter the overall estimate of effect.

Another potential aspect of the rice fortification and its effect on malnutrition is the duration of intervention. The included studies had a duration of follow‐up from two weeks to four years. However in the included RCTs, one study had a follow‐up of two weeks, other studies ranged from four months to eight months. Thus there could be a role played by the duration of intervention and follow‐up.

Quality of the evidence

Among the RCTs that contributed to the meta‐analysis, we assessed two studies as having overall low risk of bias and one study as having a high or unclear risk of bias in most of the domains. Excluding this study favoured fortification and altered the conclusion for anaemia (from no effect to a reduction of anaemia) and the conclusion for the multiple micronutrient subgroup in comparison 1 for mean haemoglobin (from no effect to an increased mean difference). Most of these studies inadequately described their randomisation sequence generation. Close to half had an unclear description of allocation concealment and blinding of outcomes. Most of the studies had low attrition rate.

The GRADE assessment of the certainty of evidence was low for anaemia (no effect), iron deficiency (favours fortification), vitamin A deficiency (no effect), serum or plasma folate (one included study favouring fortification), and adverse events (one study reported hookworm infection risk higher with fortification) in the comparison of iron alone or in combination with other micronutrients versus no fortification. The certainty of the evidence was also low for mean haemoglobin (may favour). We rated the outcome diarrhoea (no effect) as very low‐certainty evidence. We mainly downgraded studies due to inconsistency and imprecision in the estimates. In the comparison of vitamin A alone versus no fortification, one RCT contributed data and we graded the certainty of evidence for haemoglobin concentration and serum retinol concentration as low.

Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the results.

Potential biases in the review process

Two review authors independently carried out the review process, with the same data extraction sheet and tools to assess risk of bias in the included studies. Many studies had minimum information regarding the randomisation procedure, allocation concealment and blinding. In the absence of precise details, we considered mutual discussion among review authors as final in this review, since these included subjective components. We also extensively searched grey literature and trials registries, along with contacting agencies involved in carrying out RCTs and subject experts; thus minimising publication bias in this review. Also there was no language limit set in this systematic review for searches as well as obtaining abstracts/full‐text articles. We sought the help of translators to convert non‐English‐language articles to English. This would minimise the language bias in this review.

Agreements and disagreements with other studies or reviews

Our review is the first systematic review and meta‐analysis specific to rice as a vehicle to fortification as a public health intervention. There are systematic reviews and meta‐analyses of micronutrient fortification of staples, condiments and processed foods including all age groups, but these do not include a subgroup analysis specifically for rice (Das 2013; Gera 2012). Only two of the 12 studies included in our review were included in Das 2013 and our review did not include infants and young children under two years of age. In Das 2013, staple foods fortified with iron were found to improve mean haemoglobin and serum ferritin concentrations, and reduce the risk of anaemia. Staple foods fortified with vitamin A improved mean haemoglobin and serum retinol concentrations. Cereals fortified with zinc improved zinc serum levels. Staple foods fortified with iron had no impact on iron indicators among women. The two reviews agreed that fortification with iron improved mean haemoglobin concentrations. Our review showed a reduction of iron deficiency, while Das 2013 showed an improvement in serum ferritin concentrations. There was no agreement between Das 2013 and this review on the impact on anaemia, vitamin A and zinc concentrations or deficiency. The systematic review by Gera 2012 included only apparently healthy individuals and examined the effect of fortified food items on haematological outcomes. They concluded that food items fortified with iron led to improvement in haemoglobin, serum ferritin and iron status and there by reduced the risk of anaemia.

Another systematic review and meta‐analysis evaluated the effect of fortification of staples with zinc on serum zinc levels and zinc deficiency (Shah 2016). Zinc‐fortified staples were compared with food without zinc. None of the studies included in our review were included in Shah 2016. Shah 2016 showed that fortification of foods with zinc alone, but not in combination with other micronutrients, improved serum zinc levels. Our review did not have a comparison of rice fortified with zinc alone with unfortified rice, but rice fortified with zinc and other micronutrients did not improve zinc levels. In both reviews, the certainty of evidence was low for zinc.

A systematic review of rice fortification included seven studies among children aged 6 to 59 months (Hijar 2015). They did not carry out a meta‐analysis and the search strategy was more limited than that used in our review. The population also included children less than two years, who we excluded from our review. None of the studies in our review were included in the review by Hijar 2015. They reported that rice fortification was effective in correcting iron deficiency among children aged less than five years. The improvement was not significant for vitamin A‐fortified rice.

Another systematic review of rice fortification with no age restrictions included 12 studies that fortified rice with iron, four studies that fortified with vitamin A and two that included other micronutrients (De Pee 2017). They gave a description of the direction of the effects, but did not perform a meta‐analysis. The review by De Pee 2017 concluded that with the available evidence of efficacy, stability and needs, rice should be fortified with multiple micronutrients including iron, zinc, and vitamins A, B₁ (thiamin), B₃ (niacin) B₆ (pyridoxine), B₉ (folic acid) and B₁₂ (cobalamin). The meta‐analysis in our review shows evidence of an effect of iron on mean haemoglobin and iron deficiency; of vitamin A fortification on vitamin A deficiency; and of folate fortification on folate deficiency. Another review on issues related to rice fortification in correcting micronutrient deficiency compiled the evidence from available primary studies to conclude that rice fortification is an effective strategy (Piccoli 2012).

Authors' conclusions

Implications for practice.

Fortification of rice has been recommended as an effective strategy for reducing micronutrient deficiencies. This review shows that fortification of rice may make no difference on anaemia and there are probable effects on blood haemoglobin concentration (an indicator used in diagnosis of anaemia). However, the review suggests that fortification of rice with iron may reduce iron deficiency. There is some evidence that these effects may be greater in single nutrient fortification than multiple micronutrient fortification. There is also evidence that fortification of rice with iron, vitamin A and other micronutrients may improve serum retinol concentrations, may not reduce the risk of vitamin A deficiency, and it may improve plasma folate. There is no evidence that fortification improves zinc levels.

This review may provide enough evidence supporting the effectiveness of fortification for anaemia and iron status. However, more evidence is needed for other micronutrients. Moreover, more thought may have to be given to the number of micronutrients added as this appears to have some bearing on the effect of fortification of rice.

Implications for research.

The certainty of evidence for the outcome of anaemia and iron deficiency was low. The certainty of outcome change in mean haemoglobin was also low. There were considerable differences in the effects of single and multiple nutrient fortification. Single nutrient fortification with iron compound was found to be superior to multiple micronutrient interventions in terms of improvement in iron deficiency and haemoglobin concentration. A similar observation could be made when exploring heterogeneity in serum retinol results, with heterogeneity mainly due to one study with multiple micronutrients. Very few studies reported adverse effects, and a substantial number did not report the manner of cooking or malaria endemicity. There were only a handful of studies that used cold extrusion. We identify the following areas of research.

1. More, high‐quality randomised controlled trials (RCTs) with anaemia as a reported outcome. Given that anaemia, rather than iron deficiency or mean haemoglobin is a more common indicator of national nutrition programmes, it is important to have better evidence on this outcome.

2. RCTs that directly compare the efficacy or effectiveness of iron‐fortified rice, and iron and other micronutrient‐fortified rice with unfortified rice would inform policymakers on whether the reduced effect of the multiple micronutrient‐fortified rice described in this review happens in a controlled setting with the same population.

3. RCTs directly comparing cold extrusion with unfortified rice would increase the evidence base for evaluating the effect of the cold extrusion method.

4. RCTs should be encouraged to include the recording of solicited and unsolicited adverse effects and data relevant to rice fortification (e.g. manner of cooking) and iron metabolism (e.g. malaria and other parasitic infections like hookworm infection).

5. RCTs with zinc and folate as outcomes would increase the evidence base as very few studies reported these.

Appendices

Appendix 1. Search strategy for electronic databases

Cochrane Central Register of Controlled Trials (CENTRAL) (CRSO)

#1 MESH DESCRIPTOR Micronutrients EXPLODE ALL TREES

#2 MESH DESCRIPTOR iron compounds

#3 MESH DESCRIPTOR zinc compounds

#4 MESH DESCRIPTOR iron, dietary EXPLODE ALL TREES

#5 ((micronutrient* or micro‐nutrient*)):TI,AB,KY

#6 ((multinutrient* or multi‐nutrient*)):TI,AB,KY

#7 ((multinutrient* or multi‐nutrient* or multi* nutrient* or multimicronutrient*)):TI,AB,KY

#8 ((multivitamin* or multi‐vitamin* or multi* vitamin*)):TI,AB,KY

#9 ( (multimineral* or multi‐mineral* or multi* mineral*)):TI,AB,KY

#10 ((trace adj (element* or mineral* or nutrient*))):TI,AB,KY

#11 ((iron or Fe or ferric* or ferrous* or zinc or Zn or vitamin* or retinol* or folate* or folic* or folacin*)):TI,AB,KY

#12 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11

#13 MESH DESCRIPTOR Food, Fortified EXPLODE ALL TREES

#14 (((fortifi* or enrich* or enhanc*) adj2 (food* or rice))):TI,AB,KY

#15 MESH DESCRIPTOR Oryza sativa EXPLODE ALL TREES

#16 #13 OR #14 OR #15

#17 #12 AND #16

#18 11/07/2012 TO 08/11/16

#19 #17 AND #18

MEDLINE and Medline in Process (OVID)

1 exp Micronutrients/ or iron compounds/ or zinc compounds/ or exp iron, dietary/

2 (micronutrient$ or micro‐nutrient$).ti,ab.

3 (multinutrient$ or multi‐nutrient$).ti,ab.

4 (multinutrient$ or multi‐nutrient$ or multi$ nutrient$ or multimicronutrient$).ti,ab.

5 (multivitamin$ or multi‐vitamin$ or multi$ vitamin$).ti,ab.

6 (multimineral$ or multi‐mineral$ or multi$ mineral$).ti,ab.

7 (trace adj (element$ or mineral$ or nutrient$)).ti,ab.

8 (iron or Fe or ferric$ or ferrous$ or zinc or Zn or vitamin$ or retinol$ or folate$ or folic$ or folacin$).ti,ab.

9 or/1‐8

10 exp Food, Fortified/

11 ((fortifi$ or enrich$ or enhanc$) adj2 (food* or rice)).ti,ab.

12 rice/

13 Oryza sativa/

14 or/10‐13

15 9 and 14

16 exp animals/ not humans.sh.

17 15 not 16

18 (201206* or 201207* or 201208* or 201209* or 201210* or 201211* or 201212* or 2013* or 2014* or 2015* or 2016*).ed.

19 17 and 18

Embase (OVID)

1 exp Micronutrients/ or iron compounds/ or zinc compounds/ or exp iron, dietary/

2 (micronutrient$ or micro‐nutrient$).ti,ab.

3 (multinutrient$ or multi‐nutrient$).ti,ab.

4 (multinutrient$ or multi‐nutrient$ or multi$ nutrient$ or multimicronutrient$).ti,ab.

5 (multivitamin$ or multi‐vitamin$ or multi$ vitamin$).ti,ab.

6 (multimineral$ or multi‐mineral$ or multi$ mineral$).ti,ab.

7 (trace adj (element$ or mineral$ or nutrient$)).ti,ab.

8 (iron or Fe or ferric$ or ferrous$ or zinc or Zn or vitamin$ or retinol$ or folate$ or folic$ or folacin$).ti,ab.

9 or/1‐8

10 exp Food, Fortified/

11 ((fortifi$ or enrich$ or enhanc$) adj2 (food* or rice)).ti,ab.

12 rice/

13 Oryza sativa/

14 or/10‐13

15 9 and 14

16 (animal/ or nonhuman/) not human/

17 15 not 16

18 (201206* or 201207* or 201208* or 201209* or 201210* or 201211* or 201212* or 2013* or 2014* or 2015* or 2016*).dd.

19 17 and 18

CINAHL (EBSCO)

June 2012 to Nov 2016 (n=152)

S20 S18 AND S19

S19 EM 20120601‐20151130

S18 S11 AND S16 Limiters ‐ Human

S17 S11 AND S16

S16 S12 OR S13 OR S14 OR S15

S15 Oryza sativa

S14 (MH "Rice")

S13 ((fortifi* or enrich* or enhanc*) N2

(food* or rice))

S12 (MH "Food, Fortified")

S11 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR

S7 OR S8 OR S9 OR S10

S10 (iron or Fe or ferric* or ferrous* or

zinc or Zn or vitamin* or retinol* or

folate* or folic* or folacin*)

S9 (trace N1 (element* or mineral* or

nutrient*))

S8 (multimineral* or multi‐mineral* or

multi* mineral*)

S7 (multivitamin* or multi‐vitamin* or

multi* vitamin*)

S6 (multinutrient* or multi‐nutrient* or

multi* nutrient* or multimicronutrient*)

S5 (multinutrient* or multi‐nutrient*)

S4 (micronutrient* or micro‐nutrient*)

S3 (MH "Zinc Compounds")

S2 (MH "Iron Compounds+")

S1 (MH "Micronutrients")

BIOSIS & Web of Science (ISI) SCI, SSCI, CPCI‐exp & CPCI‐SSH

2012 to 7/11/16 (n=1)

#10 #9 AND #8

#9 TOPIC: (((fortifi* or enrich* or enhanc*) N2 (food* or rice)))

#8 #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1

#7 TOPIC: ((iron or Fe or ferric* or

ferrous* or zinc or Zn or vitamin* or

retinol* or folate* or folic* or

folacin*))

#6 TOPIC: ((trace N (element* or mineral*

or nutrient*)))

#5 TOPIC: ((multimineral* or multi‐

mineral* or "multi* mineral*"))

#4 TOPIC: ((multivitamin* or multi‐

vitamin* or "multi* vitamin*"))

#3 TOPIC: ((multinutrient* or multi‐

nutrient* or "multi* nutrient*" or

multimicronutrient*))

#2 TOPIC: ((multinutrient* or multi‐

nutrient*))

#1 TOPIC: ((micronutrient* or micro‐

nutrient*))

Popline & SCIELO

(micronutrient* OR micronutrient* OR multinutrient* OR multinutrient* OR multinutrient* OR multinutrient* OR multi* nutrient* OR multimicronutrient* OR multivitamin* OR multivitamin* OR multi* vitamin* OR multimineral* OR multimineral* OR multi* mineral* OR trace element* OR trace mineral* OR trace nutrient* OR iron OR Fe OR ferric* OR ferrous* OR zinc OR Zn OR vitamin* OR retinol* OR folate* OR folic* OR folacin*)

AND

((fortifi* OR enrich* OR enhanc*) AND (food* OR rice))

LIMIT BY

2012‐2015

IBECS, PAHO, WHOLIS, AFRO and LILACS (BIRME)

(micronutrient$ or micro‐nutrient$) or (multinutrient$ or multi‐nutrient$) or (multinutrient$ or multi‐nutrient$ or multi$ nutrient$ or multimicronutrient$) or (multivitamin$ or multi‐vitamin$ or multi$ vitamin$) or (multimineral$ or multi‐mineral$ or multi$ mineral$) or trace element$ or trace mineral$ or trace nutrient$ or (iron or Fe or ferric$ or ferrous$ or zinc or Zn or vitamin$ or retinol$ or folate$ or folic$ or folacin$) [Words] and ((fortifi$ or enrich$ or enhanc$) and (food$ or rice)) [Words] and 2012 or 2013 or 2014 or 2015 [Country, year publication]

IMSEAR and EMRO (GLOBAL INDEX MEDICUS)

rice

fortification

INMED & Native Health Research database

Rice AND fortify OR fortified OR enrich OR enriched

AGRICOLA (Ebsco)

#1 (ZU "micronutrients") OR (ZU "micronutrients concentration") OR (ZU "micronutrients uptake") OR (ZU "micronutrition") OR (ZU "micronycteris minuta")) OR ((ZU "iron compounds") OR (ZU "iron compounds‐congresses") OR (ZU "iron compounds‐structure") OR (ZU "iron concentration") OR (ZU "iron concretions") OR (ZU "iron consumption") OR (ZU "iron content") OR (ZU "iron contents"))) OR ((ZU "zinc compounds") OR (ZU "zinc contamination") OR (ZU "zinc content") OR (ZU "zinc coordination") OR (ZU "zinc deficiencies") OR (ZU "zinc deficiency") OR (ZU "zinc deficiency diseases") OR (ZU "zinc deficiency diseases‐congresses") OR (ZU "zinc deficiency diseases‐epidemiology") OR (ZU "zinc deficiency diseases‐united states") OR (ZU "zinc deficiency states‐congresses"))) OR ((ZU "dietary iron")) OR TI (multinutrient* OR multi‐nutrient* OR multinutrient* OR “multi‐nutrient*” OR “multi* nutrient*” OR multimicronutrient* OR multivitamin* OR multi‐vitamin* OR multi* vitamin* OR multimineral* or multi‐mineral* or multi* mineral* OR iron or Fe or ferric* or ferrous* or zinc or Zn or vitamin* or retinol* or folate* or folic* or folacin*) OR AB (multinutrient* OR multi‐nutrient* OR multinutrient* OR multi‐nutrient* OR multi* nutrient* OR multimicronutrient* OR multivitamin* OR multi‐vitamin* OR multi* vitamin* OR multimineral* OR multi‐mineral* OR multi* mineral* OR iron OR Fe OR ferric* OR ferrous* OR zinc OR Zn OR vitamin* OR retinol* OR folate* OR folic* OR folacin*)

#2 (fortified food) or (ZU "fortified food") or (ZU "fortified foods") or (ZU "fortified fruit beverages") or (ZU "fortified instant asian noodles") or (ZU "fortified milk") or (ZU "fortified musts") or (ZU "fortified seaweed extract") or (ZU "fortified soy protein powder") or (ZU "fortified vegetables") or (ZU "fortified vitamin juices") or (ZU "fortified water") or (ZU "fortifying agents") OR (ZU "rice") or (ZU "rice ( <i>oryza sativa</i> l.)") or (ZU "rice (<i>oryza sativa</i> l.)") or (ZU "rice (oriza sativa l.)") or (ZU "rice (oryza sativa cv tainung 67) suspension cells") or (ZU "rice (oryza sativa l)") or (ZU "rice (oryza sativa l. var. nipponbare)") or (ZU "rice (oryza sativa l.)") or (ZU "rice (oryza sativa l.) crop") or (ZU "rice (oryza sativa ssp. japonica)") or (ZU "rice (oryza sativa)") or (ZU "rice (oryza sativa) cells") or (ZU "rice (oryzae sativa l.)") or (ZU "rice (oryzae sativa)") or (ZU "rice (orzya sativa)") or (ZU "rice (qryza sativa l.)") or (ZU "rice act1 genes") or (ZU "rice aging") or (ZU "rice agriculture") or (ZU "rice agro‐residues") or (ZU "rice and rice products") or (ZU "rice as feeding stuff") or (ZU "rice as food") or (ZU "rice bibliography") or (ZU "rice blends") or (ZU "rice bran") or (ZU "rice bran protein") or (ZU "rice byproducts") or (ZU "rice cake") or (ZU "rice cake machines") or (ZU "rice cakes") or (ZU "rice cereals") or (ZU "rice consumption") or (ZU "rice cookie") or (ZU "rice cooking") or (ZU "rice council for market development") or (ZU "rice cracker") or (ZU "rice crackers") or (ZU "rice development") or (ZU "rice drink") or (ZU "rice economy") or (ZU "rice enrichment") or (ZU "rice exploitation") OR ((TI (fortifi* or enrich* or enhanc*) OR AB (fortifi* or enrich* or enhanc*)) N2 (TI (food* or rice) OR AB (food* or rice))) OR ((TI (fortifi* or enrich* or enhanc*) OR AB (fortifi* or enrich* or enhanc*) ) AND ((TI (food* or rice) OR AB (food* or rice)))

#3 ZU (rabbit* OR bird* OR chicken* OR soil* OR insect* OR Mice OR rat OR goat* OR sheep OR animal* OR livestock* OR cow*) OR ((ZE "animals") or (ZK "animal breeding and genetics") or (ZK "animal diseases (bacterial)") or (ZK "animal diseases (fungal)") or (ZK "animal diseases (general)") or (ZK "animal diseases (physiological)") or (ZK "animal diseases (viral)") or (ZK "animal disorders and injuries") or (ZK "animal ecology and behavior") or (ZK "animal nutrition") or (ZK "animal physiology and biochemistry") or (ZK "animal production") or (ZK "animal reproduction") or (ZK "animal science") or (ZK "animal structure") or (ZK "animal taxonomy and geography") or (ZK "pests of animals (general)") or (ZK "pests of animals (helminths)") or (ZK "pests of animals (insects and other arthropods)"))

#4 (#1 AND #2) NOT #3

#5 Limited to up to January 2017

Clinicaltrials.gov

"rice AND fortification", "rice AND enrichment","fortified rice" OR "enriched rice".

WHO International Clinical Trials Registry Platform (ICTRP)

"rice AND fortification", "rice AND enrichment","fortified rice" and "enriched rice". Duplicates were removed.

Data and analyses

Comparison 1. Rice fortified with iron alone or in combination with other micronutrients versus unfortified rice (no micronutrients added).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anaemia (defined as haemoglobin (Hb) below the WHO cut‐off, adjusted for altitude as appropriate)	7	1634	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.54, 0.97]
2 Anaemia (subgroup: by micronutrient content)	7	1634	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.66, 1.04]
2.1 Iron alone	3	444	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.36, 1.09]
2.2 Iron + other micronutrients	4	1190	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.82, 1.11]
3 Anaemia (subgroup: by rice fortification method)	7	1634	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.55, 0.97]
3.1 Hot extrusion	5	1197	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.52, 1.01]
3.2 Cold extrusion	3	437	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.41, 1.38]
3.3 Coating	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Dusting	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 Mixed/unknown/unreported	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Anaemia (subgroup: by cooking method most commonly used in trial setting)	7	1634	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.54, 0.97]
4.1 Soaking, and boiling with excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Boiling without excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Rinsing and boiling without excess water	1	215	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.26, 0.63]
4.4 Frying and boiling without excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.5 Unknown/unreported	6	1419	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.63, 1.05]
5 Anaemia (subgroup: by public health significance of anaemia at baseline )	7	1634	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.54, 0.97]
5.1 Not a problem (lower than 5%)	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Mild and moderate (5% to 39.9%)	4	1129	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.44, 1.06]
5.3 Severe (40% and more)	2	360	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.67, 1.12]
5.4 Mixed/unknown/unreported	1	145	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.09, 1.10]
6 Anaemia (subgroup: by malaria endemicity)	7	1634	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.54, 0.97]
6.1 Some malaria risk setting	1	445	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.55, 1.32]
6.2 Malaria‐free area	2	403	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.48, 1.03]
6.3 Unknown/unreported	4	786	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.34, 1.31]
7 Iron deficiency (as defined by study authors, based on a biomarker of iron status)	8	1733	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.51, 0.84]
8 Iron deficiency (subgroup: by micronutrient content)	8	1733	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.51, 0.84]
8.1 Iron alone	4	628	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.40, 0.80]
8.2 Iron + other micronutrients	4	1105	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.57, 1.06]
9 Iron deficiency (subgroup: by rice fortification method)	8	1733	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.52, 0.83]
9.1 Hot extrusion	6	1283	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.51, 0.87]
9.2 Cold extrusion	3	450	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.38, 1.09]
9.3 Coating	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9.4 Dusting	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9.5 Mixed/unknown/unreported	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10 Iron deficiency (subgroup: by cooking method most commonly used in trial setting)	8	1733	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.51, 0.84]
10.1 Soaking, and boiling with excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.2 Boiling without excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.3 Rinsing and boiling without excess water	1	215	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.51, 1.21]
10.4 Frying and boiling without excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.5 Unknown/unreported	7	1518	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.46, 0.84]
11 Iron deficiency (subgroup: by public health significance of anaemia at baseline )	8	1733	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.51, 0.84]
11.1 Not a problem (lower than 5%)	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11.2 Mild and moderate (5% to 39.9%)	4	1046	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.55, 1.07]
11.3 Severe (40% and more)	2	358	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.26, 1.27]
11.4 Mixed/unknown/unreported	2	329	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.39, 1.01]
12 Iron deficiency (subgroup: by malaria endemicity)	8	1733	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.51, 0.84]
12.1 Some malaria risk setting	1	485	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.48, 1.53]
12.2 Malaria‐free area	3	585	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.41, 0.84]
12.3 Mixed/unknown/unreported	4	663	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.39, 0.96]
13 Haemoglobin concentration (g/L)	11	2163	Mean Difference (IV, Random, 95% CI)	1.83 [0.66, 3.00]
14 Haemoglobin concentration (subgroup: by micronutrient content)	11	2163	Mean Difference (IV, Random, 95% CI)	2.09 [0.75, 3.44]
14.1 Iron alone	6	698	Mean Difference (IV, Random, 95% CI)	3.93 [1.24, 6.62]
14.2 Iron + other micronutrients	6	1465	Mean Difference (IV, Random, 95% CI)	1.06 [0.15, 1.98]
15 Haemoglobin concentration (subgroup: by rice fortification method)	11	2163	Mean Difference (IV, Random, 95% CI)	1.60 [0.81, 2.38]
15.1 Hot extrusion	7	1563	Mean Difference (IV, Random, 95% CI)	1.93 [0.53, 3.32]
15.2 Cold extrusion	3	437	Mean Difference (IV, Random, 95% CI)	1.54 [0.58, 2.51]
15.3 Coating	1	15	Mean Difference (IV, Random, 95% CI)	8.20 [‐12.14, 28.54]
15.4 Dusting	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
15.5 Mixed/unknown/unreported	1	148	Mean Difference (IV, Random, 95% CI)	‐4.0 [‐11.72, 3.72]
16 Haemoglobin concentration (subgroup: by cooking method most commonly used in trial setting)	11	2163	Mean Difference (IV, Random, 95% CI)	1.83 [0.66, 3.00]
16.1 Soaking, and boiling with excess water	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
16.2 Boiling without excess water	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
16.3 Rinsing and boiling without excess water	1	215	Mean Difference (IV, Random, 95% CI)	3.80 [0.86, 6.74]
16.4 Unknown/unreported	10	1948	Mean Difference (IV, Random, 95% CI)	1.62 [0.43, 2.81]
17 Haemoglobin concentration (subgroup: by public health significance of anaemia at baseline)	11	2163	Mean Difference (IV, Random, 95% CI)	1.83 [0.66, 3.00]
17.1 Not a problem (lower than 5%)	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
17.2 Mild and moderate (5% to 39.9%)	6	1459	Mean Difference (IV, Random, 95% CI)	1.67 [‐0.10, 3.44]
17.3 Severe (40% and more)	2	360	Mean Difference (IV, Random, 95% CI)	1.07 [‐0.84, 2.98]
17.4 Mixed/unknown/unreported	3	344	Mean Difference (IV, Random, 95% CI)	3.42 [1.10, 5.73]
18 Haemoglobin concentration (subgroup: by malaria endemicity)	11	2163	Mean Difference (IV, Random, 95% CI)	1.83 [0.66, 3.00]
18.1 Some malaria risk setting	1	445	Mean Difference (IV, Random, 95% CI)	0.90 [0.65, 1.15]
18.2 Malaria‐free area	3	587	Mean Difference (IV, Random, 95% CI)	3.15 [0.98, 5.31]
18.3 Mixed/unknown/unreported	7	1131	Mean Difference (IV, Random, 95% CI)	1.33 [‐0.48, 3.14]
19 Vitamin A deficiency (as defined by study authors, by using a biomarker of vitamin A)	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.29]
20 Vitamin A deficiency (subgroup: by micronutrient content)	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.29]
20.1 Iron alone	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
20.2 Iron + other micronutrients	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.29]
21 Vitamin A deficiency (subgroup: by rice fortification method)	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.41, 1.14]
21.1 Hot extrusion	4	765	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.35, 1.39]
21.2 Cold extrusion	1	162	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.24, 1.54]
21.3 Coating	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
21.4 Dusting	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
21.5 Mixed/unknown/unreported	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
22 Vitamin A deficiency (subgroup: by cooking method most commonly used in trial setting)	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.29]
22.1 Soaking, and boiling with excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
22.2 Boiling without excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
22.3 Rinsing and boiling without excess water	1	215	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.47, 2.60]
22.4 Frying and boiling without excess water	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
22.5 Unknown/unreported	3	712	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.25, 1.22]
23 Vitamin A deficiency (subgroup: by public health significance of anaemia at baseline )	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.29]
23.1 Not a problem (lower than 5%)	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
23.2 Mild and moderate (5% to 39.9%)	3	695	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.29, 1.24]
23.3 Severe (40% and more)	1	232	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.30, 7.07]
23.4 Mixed/unknown/unreported	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
24 Vitamin A deficiency (subgroup: by malaria endemicity)	4	927	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.29]
24.1 Some malaria risk setting	1	442	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.30, 1.08]
24.2 Malaria‐free area	1	232	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.30, 7.07]
24.3 Unknown/unreported	2	253	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.12, 2.59]
25 Serum or plasma folate (nmol/L)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
26 Any adverse effects	2	1019	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.53, 2.76]
26.1 Hookworm infection risk	1	785	Risk Ratio (M‐H, Random, 95% CI)	1.78 [1.18, 2.70]
26.2 Abdominal pain more than 3 days	1	234	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.42, 1.42]
27 Diarrhoea (as defined by study authors)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
28 Serum or plasma retinol (µmol/L)	5	727	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.13, 0.21]
29 Serum or plasma zinc (µmol/L)	3	618	Mean Difference (IV, Random, 95% CI)	0.38 [‐0.08, 0.83]
30 Height‐for‐age Z‐score	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
31 Weight‐for‐height Z‐score	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 2. Rice fortified with vitamin A alone or in combination with other micronutrients versus unfortified rice (no micronutrients added).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Haemoglobin concentration (g/L)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Serum or plasma retinol (µmol/L)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Angeles‐Agdeppa 2008.

Methods	Double‐blinded, RCT with 3 arms
Participants	A total of 180 anaemic (Hb < 120 g/L) children aged 6‐9 years of age attending San Joaquin Elementary School in Metro Manila, in the Division of Pasig City, Philippines with no severe anaemia (Hb < 70 g/L), nor history of blood disorders and other haemoglobinopathies.
Interventions	Participants were randomly allocated to 1 of 3 groups: group 1 (n = 60) received 160 g (1 cup) of cooked iron‐FFR with extruded iron premix rice using ferrous sulphate powder as fortificant (ExFeSO4) providing 12.88 mg elemental iron/160 g; group 2 (n = 60) received 160 g (1 cup) of cooked iron‐FFR with extruded iron premix rice using micronized ferric pyrophosphate as fortificant (ExFeP80) providing 12.24 mg elemental iron/160 g; and group 3 (n = 60) received 160 g (1 cup) of cooked non‐FFR (control) providing 0.10 mg elemental iron/160 g. It is estimated that 160 mg cooked rice is equivalent to 66.72 g of uncooked rice. Rice was served during a 2‐week cycle with standard dishes during lunch, daily for 5 days a week for 120 days (6 months) under a supervised regimen. The separate mixtures for groups 1 and 2 were subjected to extrusion to form iron/rice‐like grains premix. This premix was blended with ordinary rice at a ratio of 2.5:100, aiming to provide 10 mg elemental iron per day. All participants received a 400 mg chewable albendazole tablet at baseline and a second dose was given at 12th week of the feeding.
Outcomes	Hb, plasma ferritin, plasma retinol, and C‐reactive protein, anaemia at baseline, at 3 months and at 6 months. Weight, height, weight‐for‐age Z‐score, height‐for‐age Z‐score, weight‐for‐height Z‐score at 6 months of the intervention
Notes	Micronutrient content: single nutrient Rice fortification method: extrusion but not specified if hot, warm or cold Cooking method most commonly used in study setting (as reported): soaking, and boiling with excess water Public health significance of anaemia at baseline in the target group: moderate (5% to 39.9%) Iron compound: comparable bioavailability in group 1 (as ferrous sulphate) and (as micronized dispersible ferric pyrophosphate) in group 2 Malaria endemicity at the time that the study was conducted: malaria‐free area Source of funding: International Life Sciences Institute Center for Health Promotion of Japan (ILSI CHP, Japan), the ILSI CHP, Atlanta, Georgia, USA. Taiyo Kagaku, Japan donated the fortificant used in this study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Reported as randomised but method unclear
Allocation concealment (selection bias)	High risk	Colour‐coded packages of uncooked rice were placed in respective colour‐coded kettles by a staff at the catering service.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	The 3 groups showed similar mean values of Hb, weight and height
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	Participants were similar at baseline for all the variables measured.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The dropout rate was 5%. It was similar across all the 3 arms of the study.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The school officials and the researchers were blinded as to the type of rice the children were eating.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The school officials and the researchers were blinded as to the type of rice the children were eating.
Contamination (performance bias)	High risk	The packing of allocation of cooked rice into the lunch boxes was done by colour codes, hence, there was no point of comparison with the other cooked rice. However, after the study and data analysis, a thorough scrutiny was conducted by the researchers and noticed that brown‐coloured rice grains were visible in the uncooked rice fortified with ferrous sulphate.
Selective reporting (reporting bias)	Low risk	Study authors reported both significant and insignificant outcomes
Other bias	Low risk	There are insufficient problems with the study design to put it at high risk of bias.
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Ara 2019.

Methods	This was a community‐based CBA conducted in Bangladesh, done to evaluate the intervention provided by the WFP on the VGD beneficiaries. The 2 groups included 870 (435 in each group) women aged 15‐49 years; VGD beneficiaries receiving the FFR in 5 sub district‐level units called upazilas and a control group of the same age group receiving non‐FFR. These upazilas for both the groups were selected by the WFP from 5 districts across the country by using systematic random sampling method. The study was carried out between January and December 2013. A total of 400 women in each group were available for the end‐line survey. Quote "Participants for FFR group were drawn from the total list of approximately 15,000 VGD beneficiaries from 40 unions under the 5 upazilas. Similarly, participants for non‐FFR group were selected from enlisted approximately 15,000 VGD women from 53 unions of the 5 upazilas. During the end line evaluation, similar sampling approach was employed, and participants were allocated to FFR and non‐FFR group from the same sampling frame."
Participants	Women aged 15–49 years‐old with possession of the VGD programme card. Those with either known/suspected chronic or congenital disease, pregnant and those with severe anaemia were excluded from the study. Advice was given to severe cases of anaemia to visit the government health facility.
Interventions	The intervention group received 30 kg FFR; the control group received 30 kg non‐FFR for every month during the study period.
Outcomes	Anaemia (defined as Hb level < 120 g/L in non‐pregnant and non‐lactating women), zinc deficiency (serum zinc level of < 10.10 mmol/L) and elevated CRP (> 10.0 mg/L) were measured
Notes	The sampling was done among the VGD beneficiaries who received either FFR in 5 upazilas namely Kaligonj, Sarankhola, Tungipara, Dacope and Shyamnagar in the FFR group and non‐FFR rations in the non‐FFR group. The 5 FFR upazilas were selected by the WFP from 5 districts in different geographic locations across the country. Micronutrient content per 100 g of rice: vitamin A 150 µg, iron 6 mg, vitamin B1 0.4 mg, folic acid 130 µg, zinc 4 mg, vitamin B12 1 µg Rice fortification method: hot extrusion method Cooking method: not specified Public health significance of anaemia at baseline in the target group: prevalence of anaemia in the study population at the baseline was 42%. Iron compound: not specified Malaria endemicity at the time that the study was conducted: not reported Source of funding: this research was supported by the UN WFP Grant # 1209, www1.wfp.org/countries/bangladesh
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	There was no random sequence generation, since this was CBA
Allocation concealment (selection bias)	High risk	There was no mechanism for allocation concealment. The study participants were selected using systematic random sampling
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	The difference in the baseline prevalence of anaemia differed across the FFR and non‐FFR groups by 4.8% (38.8% in FFR versus 34% in non‐FFR).
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	The demographic characteristics were similar among the FFR and non‐FFR groups.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The baseline and end‐line study population was different.
Blinding of participants and personnel (performance bias) All outcomes	High risk	There was no blinding of study participants, data collectors or any person involved in the research
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of the outcome assessment done in the study
Contamination (performance bias)	Low risk	Since the allocation was in community and also the baseline and end‐line populations were different.
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes were reported.
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Della Lucia 2016.

Methods	CBA with 2 arms
Participants	143 male and female children 2‐6 years of age, with Hb concentrations ≥ 110 g/L attending 2 philanthropic preschools in Brazil were considered and 131 were eligible. Of these only 112 received parental consent to participate and underwent biochemical assessment. A total of 99 children completed all stages of the study. Children diagnosed with iron‐deficiency anaemia, who received ferrous sulphate supplementation or other nutritional supplements after evaluation by a qualified doctor of the city Health Department, were excluded from the study.
Interventions	Participants from the selected preschools received, as part of school meals: group 1 (n = 49) received micronutrient‐FFR UltraRice® containing elemental iron (as micronized ferric pyrophosphate), zinc (as zinc oxide), thiamine (as thiamine mononitrate) and folic acid, mixed with polished rice (test group); group 2 (n = 50) received non‐FFR "polished rice". Rice portions (50 g) were served daily, Monday‐Friday. The intervention study lasted 4 months. Rice grains extruded from rice flour (Ultra Rice® (UR® )), produced and provided by a pasta manufacturer after authorisation by the Program for Appropriate Technology in Health (PATH).
Outcomes	Erythrocytes, Hb, hematocrit, mean corpuscular volume, mean corpuscular Hb, mean corpuscular Hb concentration, folate, thiamine, ferritin, serum zinc, C‐reactive protein concentrations
Notes	Micronutrient content: multiple nutrient Rice fortification method: cold extrusion (personal communication with study author) Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: unknown/unreported Iron compound: comparable bioavailability (as micronized ferric pyrophosphate) Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: Programa de Bolsas de Iniciação Científica e Tecnológica Institucional da Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Programa Institucional de Bolsas de Iniciação Científica/CNPq and Fundação de Amparo à Pesquisa do Estado de Minas Geraisprovided financial support and PATH donated the FFR.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	"Quote; The preschools were randomly selected as “control” or “test”.
Allocation concealment (selection bias)	Low risk	Quote: "The preschools were randomly selected as “control” or “test”."
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	Quote: "At the beginning of the study, children in the test group showed higher concentrations of erythrocyte thiamin (p = 0.012) and ferritin (p <0.001) Table 1."
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Unclear risk	There was no comparison of the baseline characteristics between groups.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Figure 1 shows that 13 out of 112 children at baseline "did not attend the dietetic and anthropometric assessment". The distribution between groups is not reported.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding is not reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding is not reported.
Contamination (performance bias)	Unclear risk	This study was conducted in 2 schools only and either FFR or non‐FFR was used in that school. Quote: "The preschools were randomly selected as "control" or "test"."
Selective reporting (reporting bias)	Unclear risk	No protocol was found on clinical trials.gov
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Gershoff 1977.

Methods	CBA with 2 arms
Participants	2250 children aged 1.5‐9 years from 29 villages in the province of Chiang Mai, Thailand from January 1971‐July 1975
Interventions	The villages were divided into 5 groups: group 1‐raw control, no intervention provided; group 2 placebo control, non‐FFR plus day­care centres for preschool children; group 3, received FFR containing 0.087 3% thiamin naphthalene disulfonate (equivalent to 0.05% thiamin nitrate), 0.0815% of retinol acetate, and 0.8% FeP04:4H20 (0.2% iron) plus day‐care centres; group 4 received FFR containing 0.087 3% thiamin naphthalene disulfonate (equivalent to 0.05% thiamin nitrate), 0.0815% of retinol acetate, 0.8% FeP04:4H20 (0.2% iron) plus 20% L‐lysine HCI and I 0% L‐threonine in addition to day‐care centres; group 5 received FFR containing 0.087 3% thiamin naphthalene disulfonate (equivalent to 0.05% thiamin nitrate), 0.0815% of retinol acetate, 0.8% FeP04:4H20 (0.2% iron) plus 20% L‐lysine HCI and I 0% L‐threonine, no day‐care centres Before being mixed with the other ingredients the rice has been cooked by putting it in water, bringing the water to boil and then cooking under low heat for 15 mins, by which time the rice becomes soft and the water absorbed. The fortification occurred at the mills. In some villages the rice was not fortified.
Outcomes	Length, weight, hand‐wrist X‐rays, head, arm and chest circumferences, triceps and subscapular skinfold measurements, Hb and hematocrit concentrations and morbidity evaluations
Notes	Micronutrient content: ≥ 2 nutrients Rice fortification method: coating Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: mixed/unknown/unreported Iron compound: comparable bioavailability Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: USAID
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Observational study with no random allocation
Allocation concealment (selection bias)	High risk	No allocation concealment
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	Groups were different.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	High risk	Groups were different.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All outcomes	High risk	This was not purposely done.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open.
Contamination (performance bias)	Unclear risk	it is possible that contamination occurred but the risk of this happening is not clear.
Selective reporting (reporting bias)	Unclear risk	Unclear
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Hardinsyah 2016.

Methods	RCT with 2 arms
Participants	215 post‐menarchal anaemic and non‐anaemic adolescent girls 14‐18 years of age, with symptoms of anaemia (i.e. lethargy, weakness) assessed through self‐administered questionnaire from January‐September 2016, attending boarding school in Medan of North Sumatra Province, Indonesia. Participants with history of chronic diseases, obese, or having donated blood during the last 3 months, and practice regular fasting (intermittent fasting, and fasting on Monday and Thursday) were excluded.
Interventions	Participants were randomly assigned to 1 of 2 groups: group 1 (n = 108) received the school meals containing FFR, side dish and vegetable soup with side dishes rotated in the schedule of 1 of the following dishes: egg, fish, chicken, tempe, or tofu for 4 months; group 2 (n = 107) received the school meals using non‐FFR. The FFR contained iron, zinc, thiamin, folic acid, vitamin B12, niacin, and vitamin A. The duration of intervention was about 4 months from March‐June 2016. FFR was produced by mixing rice kernel and rice with the ratio 2:100 using mixer machine. The menu cycle was changed every 2 weeks. The school meal was cooked and prepared centrally by the school kitchen.
Outcomes	Hb, ferritin, serum folate, serum retinol, serum zinc, C‐reactive protein, weight, height, food intake, absenteeism, morbidity and cognitive score
Notes	Micronutrient content: multiple micronutrients Rice fortification method: hot extrusion Cooking method most commonly used in study setting (as reported): rinsing and boiling without excess water. Quote: "Rice washed as usual in the kitchen but only for once. The fortified rice which had been washed, put into a steamer of hot water. The kitchen staff stirred the rice cooked in a steamer as usually done in the kitchen until the rice is cooked well, about one hour." Public health significance of anaemia at baseline in the target group: mild and moderate (5% to 39.9%). Quote: "the researcher’s assume that the prevalence of anaemia similar to the national prevalence". Iron compound: not reported Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: Food and Nutrition Society of Indonesia, Better Rice Initiative Asia (BRIA), a larger Public Private Partnership and Deutsche Gesellschaft fur Internationale Zusammenarbeit (GIZ)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study reported as individually randomised but method unclear.
Allocation concealment (selection bias)	Low risk	Quote: "A total of 18 sacks of rice fortification was coded to show the intervention week and the serial number of sacks. For example the sack code is M1‐H3‐W2, it means the fortified rice sack is for the first week intervention (M1), on the third day of the week that is Thursday (H3) and for lunch time (W2)."
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	A total of 81.3 % of participants in the control group were not anaemic at baseline; while in the intervention group 50% were non‐anaemic. In terms of rice consumption the groups were similar. Quote: "There is no difference in the mean consumption of rice for both groups, which ranges from 147 grams to 150 grams served".
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	Quote: "During the baseline survey, the mean age of subjects were around 16.1 years old. Both groups have an average of normal nutrition status with mean weight 49,4 kg and height 151,5 cm. Most of the subject’s parents are high school graduates and above."
Incomplete outcome data (attrition bias) All outcomes	Low risk	No attrition reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Both fortified and non‐fortified rice with the dishes and vegetables in a sealed container was taken by car to the dining room (canteen) as usual. The meaning of colours of the basket only known by kitchen staff and servants."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Unclear
Contamination (performance bias)	Low risk	Quote: "Quality checks of the nutrients content of the rice kernel and fortified rice were performed by an accredited laboratory analysis, namely in Laboratory Saraswanti in Bogor."
Selective reporting (reporting bias)	High risk	Researchers provided rewards for participants with the highest attendance to increase the compliance of participants in the second week, even though they report that the attendance was not consistent throughout the study.
Other bias	High risk	Quote: "Every week during the four months, the intervention subjects was given fortified cooked rice from Tuesday to Sunday (six days). Monday is a fasting day for students as suggested by the principal of the school." "Friday is a free day for the students of Ar Raudhatul Hasanah, hence parents are allowed to visit their children. They often bring in food from outside of the school, causing the subjects to be absent during meal times in the canteen."
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Hotz 2008.

Methods	RCT with 2 arms
Participants	A total of 201 nonpregnant, non lactating women 18‐49 years of age with moderate‐low altitude‐adjusted Hb concentrations (between 105 and 135 g/L) working in 6 factories in Morelos State, Mexico. Women who were currently taking, or were planning to take, iron supplements in the next 6 months or were planning to discontinue employment at their workplace in the next 6 months were excluded.
Interventions	Participants were randomly assigned to 1 of 2 groups: group 1 (n = 98) received iron‐FFR; group 2 (n = 103) received non‐FFR. The iron fortificant used in this study was microencapsulated, micronized ferric pyrophosphate, which is marketed as SunActive® iron. The FFR was formulated to provide 20 mg of elemental iron per daily portion during 6 months. The fortified grains were mixed directly with dry, locally obtained rice. For the first 3 months of the study, the fortified grains were added at a proportion of 2:100 (weight/weight), and each daily portion of rice consisted of 75 g of dry rice. Rice was prepared daily in a central kitchen with a standard recipe that was varied from day to day by using different combinations of 1‐3 cooked vegetables (broccoli, carrot, cauliflower, garlic, green bean, onion, parsley, pea, pepper, potato, sweet corn, and tomato) and seasonings. Portions were weighed by project personnel and packed in individual plastic containers labelled with the participant’s name and study identification number.
Outcomes	Blood Hb concentration, plasma ferritin, soluble transferrin receptors, C‐reactive protein, anaemia, iron deficiency and iron body stores
Notes	Micronutrient content: single nutrient (iron) Rice fortification method: cold extrusion Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: mixed/unknown/unreported (intervention 21.4 %, control 20.4%) Iron compound: comparable bioavailability (as microencapsulated, micronized ferric pyrophosphate) Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: PATH through an original grant by the Bill & Melinda Gates Foundation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Upon enrolment, each woman was assigned a unique, consecutive identification number. These numbers were then randomly assigned by computer to 1 of 2 groups.
Allocation concealment (selection bias)	Unclear risk	Unclear. There was no mention as to how the allocation was concealed.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	Baseline characteristics are reported and similar across intervention groups.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	There were no differences in characteristics of the enrolled women between the treatment and control groups at baseline.
Incomplete outcome data (attrition bias) All outcomes	High risk	There were 33 out of 103 (32%) lost to follow‐up from the non‐FFR, and 23 out of 98 (23%) from the iron‐FFR group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	The women did not know to which group they were assigned.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Only participants were blinded to the intervention groups.
Contamination (performance bias)	Unclear risk	Because of the large number of different lunch shifts, it was not feasible for project staff to monitor consumption of the rice. It is possible that contamination occurred but the risk of this happening is not clear.
Selective reporting (reporting bias)	Unclear risk	Unclear
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Hussain 2014.

Methods	RCT with 6 arms
Participants	250 children aged 5‐8 years attending a school with a subsidised lunch feeding programme in India receiving a 200‐250 g meal of cooked rice daily
Interventions	Participants were randomly assigned to 1 of 6 groups. The group receiving FFR (n = 185 in total) were randomly assigned to 5 subgroups based on their iron deficiency, iron‐deficiency anaemia and vitamin A deficient status at baseline. They received a lunch meal containing FFR for 6 months. The subgroups that were divided from the FFR were: group 1 (n = 37): children receiving iron‐fortified meals; group 2 (n = 37): children receiving beta‐carotene fortified meals; group 3 (n = 37): children receiving retinyl palmitate fortified meals; group 4 (n = 37): children receiving iron + retinyl palmitate fortified meals; group 5 (n = 37): children receiving iron + beta‐carotene fortified meals; and the control was group 2 (n = 37): received the lunch meal using non‐FFR during 6 months. The meals were consumed under direct supervision, and the daily leftovers were weighed. All the children were dewormed at baseline. Thus some children received iron‐FFR, others vitamin A‐FFR or beta‐carotene FFR and others a combination.
Outcomes	Hb, serum ferritin, serum retinol, total iron binding capacity at baseline and after 6 months
Notes	The data are disaggregated in this study to isolate the effect of iron alone, iron+retinyl palmitate, iron + beta‐carotene, beta‐carotene alone, retinyl palmitate alone in comparison with non‐FFR meals. For the vitamin A‐FFR comparisons we used only the group fortified with vitamin A and not the one with beta‐carotene, if the data were disaggregated. Micronutrient content: variable. There was a group using FFR in comparison with non‐FFR meal. However the fortified group was divided in several subgroups that included 1 or more micronutrients. Rice fortification method: extrusion, but the temperature not reported Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: mild and moderate (5% to 39.9%) Iron compound: comparable bioavailability. Micronized ferric pyrophosphate was used as iron source Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: the study is reported to have been made under the auspices of the public health agencies, but there is no mention of the specific agencies. The Directorate of Rice Research, Rajendranagar, Hyderabad is mentioned as provider of a sensory scale used in the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Reported as randomised but method not reported.
Allocation concealment (selection bias)	Unclear risk	Unclear
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	Quote: "The intervention groups did not differ significantly in baseline characteristics for Hb, serum ferritin, total; iron binding capacity, iron deficiency, iron‐deficiency anaemia, and vitamin A deficiency. At baseline 6.4 and 9.7 percent children were mildly stunted (HAZ < ‐1.0), 3.3 and 6.8 percent were mildly under weight (WAZ < ‐1.0) and 2.8 and 1.4 percent were mildly wasted (WHZ < ‐1.0) in fortified and control group respectively".
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	Quote: "The baseline characteristics of the two groups did not differ significantly after the randomisation".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Out of 250 subjects enrolled, 222 completed the study. Twenty four of 28 subjects, who discontinued the study, were in micronutrient fortification group and 4 were in control group".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "The distinguished colour of beta‐carotene fortified premix could not match the white colour of natural rice which also affected the taste and elongation score of such samples". Also less than a third of the panellists doing the sensory assessment part of the study could detect any difference between fortified and natural rice during sensory evaluations.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	The study is reported as double‐blind, but it is unclear if outcome assessors were aware of the group assignments.
Contamination (performance bias)	Low risk	Quote: "The meals were consumed under the direct supervision, and the daily left overs were weighed".
Selective reporting (reporting bias)	Unclear risk	Unclear
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Losso 2017.

Methods	RCT with 2 arms
Participants	A total of 17 menstruating women 18‐50 years of age with iron‐deficiency anaemia (low iron and/or low ferritin) and otherwise healthy living in Baton Rouge, USA. Women who were pregnant, nursing, taking an iron supplement or taking a chronic medication that had not been stable for ≥ 1 month were excluded. The study was halted due to slow recruitment, the blind was broken and analysis performed after randomisation of 17 participants and completion of 15.
Interventions	Participants were randomly assigned to 1 of 2 groups: group 1 (n = 9) to receive 100 g of rice (0.75 cups of cooked rice in 2 servings) per day in a 1:1 ratio of FFR containing 18 mg elemental iron/100 g rice); group 2 (n = 6) received non‐FFR (0.5 mg iron/100 g rice). The intervention lasted 2 weeks. The rice dishes were prepared in the Pennington metabolic kitchen and dispensed frozen in an insulated chest to the participants weekly in lots of 14 with instructions to heat and consume 1 rice dish twice a day. The participants were asked to return the dishes with any remaining food with the insulated chest each week. The coated iron FFR kernels were added to the regular rice at a 1:200 ratio (1 g of coated iron FFR kernels was added to 199 g of regular rice). The iron content in the finished iron‐FFR is 18 mg/100 g.
Outcomes	Hb, hematocrit, serum ferritin, compliance, any adverse events (i.e. mild fatigue, mild insomnia, severe migraine, mild sinus congestion)
Notes	Micronutrient content: single nutrient (iron) Rice fortification method: coating Cooking method most commonly used in study setting (as reported): rinsing and boiling without excess water Public health significance of anaemia at baseline in the target group: not a problem (< 5%) in this target group, however in the study, 12/15 participants were anaemic Iron compound: comparable bioavailability (as ferrous sulphate) Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: rice samples including control (non‐FFR) and iron‐fortified samples were provided by The Wright Group (Crowley, USA).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study did not report the method of random sequence generation.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	Recruitment was based on serum hematocrit values and only those women who were anaemic were included. Quote: "Originally 20 women with iron deficiency determined by a serum ferritin (Siemens Immulite 2000) and/or a serum iron value (Beckman Coulter DXC600) below the lower limits of normal for the local laboratory (5 ng/mL and 40μg/mL, respectively) but otherwise healthy between the ages of 18 and 50 years of age were to be recruited".
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	Quote: "All subjects were menstruating women and the two groups were well‐matched."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Seventeen subjects were randomised to the study and 15 completed. One subject changed her mind about participating in the trial. Another subject did not return and could not be contacted."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study reported a double‐blinding to both investigators and the participants. The process of rinsing did not alter the colour or taste of rice to be consumed.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Study reports a break in the blind at the time of slow down in recruitment and performance of the analysis of those participants who completed the interventions at that time.
Contamination (performance bias)	Low risk	Since the study was double‐blinded and both intervention arms had the same appearance of rice and container, chances of contamination were minimal.
Selective reporting (reporting bias)	Low risk	The women who completed the intervention were included in the analysis and all the parameters for all the 9 in intervention arm and 6 in control arm were reported.
Other bias	Unclear risk	Not clear. Quote: "Women who were pregnant, nursing, taking an iron supplement or taking a chronic medication that had not been stable for 1 month or longer were excluded. Although subjects were initially recruited from a study of women with irregular menses, recruitment eventually slowed."
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Moretti 2006b.

Methods	RCT with 2 arms
Participants	The study included 184 iron‐depleted children aged 6‐13 years in a primary school serving the population of the Rock‐Colony neighbourhood, an urban slum in Bangalore, India. A subsidised lunch feeding programme is in place that provides the students with a 200–300‐g meal of cooked rice daily.
Interventions	Participants were randomly assigned to 1 of 2 groups: group 1 (n = 92) received either a rice‐based lunch meal fortified with 20 mg elemental iron (as micronized ground ferric pyrophosphate); group 2 (n = 92) received an identical but unfortified control meal. The intervention lasted 7 months. Lunch was served 6 days/week (except for school holidays). 3 local recipes of rice cooked with different seasoning ingredients were presented in repeating sequence to maintain interest. The main seasoning ingredients of the 3 recipes were as follows: for tomato rice, onions and tomatoes; for lemon rice, groundnuts, roasted lentils, and lemon juice; and for vegetable pulao, french beans, beetroot, cauliflower, carrots, and onions. At baseline and at the midpoint of the study, all participants were dewormed with 400 mg albendazole (Low‐Cost Pharmaceuticals®, Bangalore, India). As part of the current Indian national supplementation campaign, children in the study were treated with vitamin A supplements (200000 IU) 4 months before the start of the study and near the study midpoint. Quote: "Rice was washed in preparation for cooking. Rice portions were cooked with seasoning ingredients in household pressure cookers for 8 min after reaching peak pressure, after which pressure was released. Test servings contained 35 g cooked rice."
Outcomes	Serum transferrin receptor, serum ferritin, Hb, C‐reactive protein at 3.5 and 7 months post‐intervention, height, weight, weekly morbidity
Notes	Micronutrient content: single nutrient (iron only) Rice fortification method: hot extrusion  Cooking method most commonly used in study setting (as reported): method not specified except for "washed before cooking" Public health significance of anaemia at baseline in the target group: unknown/unreported. Iron deficiency reported as 78% in the fortification group and 79% in the control group. Iron deficiency‐anaemia was 30% and 28% respectively. Iron compound: comparable bioavailability (as micronized ground ferric pyrophosphate) Malaria endemicity at the time that the study was conducted: malaria‐free area Source of funding: Micronutrient Initiative, Ottawa, Canada; the Swiss Federal Institute of Technology, Zurich, Switzerland; and St John’s Academy of Health Sciences, Bangalore, India. Paul Lohmann GmbH (Emmerthal, Germany) provided the iron fortification compound.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Reported as randomised but method unclear.
Allocation concealment (selection bias)	Low risk	The iron‐FFR and non‐FFR were packaged in colour‐coded 10‐kg polyethylene bags.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	The baseline characteristics of the 2 groups are reported and do not differ.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	The baseline characteristics of the 2 groups did not differ significantly after the randomisation step.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Of the 184 participants enrolled, 170 completed the study. 12 of the 14 participants who discontinued the study were in the iron‐fortification group and 2 were in control group. The main reasons for dropping out were leaving school (n = 9) and loss of interest in the study (n = 5). 3 participants who dropped out because of lack of interest were in the iron group and 2 were in the control group.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The participants were blinded and were informed about the procedures of the test only after completion of the entire study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The study was double‐blind.
Contamination (performance bias)	Unclear risk	It is possible that contamination occurred but the risk of this happening is not clear.
Selective reporting (reporting bias)	Low risk	The study protocol was approved by the institutions, that all prespecified outcomes that are of interest in the review have been reported.
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Nogueira Arcanjo 2013.

Methods	CBA
Participants	303 children aged 2‐5 years in Brazil from 2 public schools in City of Sobral‐Ceará, in the northeast of Brazil, between August and December 2010. The mean Hb values for the groups were 120.6 ± 10.1 g/L for group receiving FFR and 124.0 ± 41.4 g/L for those receiving non‐FFR; P = 0.38; anaemia prevalence was 8.9% and 20.8%, in these groups, respectively, P = 0.009.
Interventions	Participants from the 2 selected schools received: group 1 (n = 138) iron‐FFR (UltraRice®) once weekly in schools meals; group 2 (n = 165) received standard non‐FFR. The menus at the 2 schools were equal in content; the study rice was consumed with poultry, which was the customarily consumed meal for Tuesdays at the schools. "This proportioned a weekly ingestion of 56.4 mg of elemental iron as ferric pyrophosphate per 50 g uncooked individual portion."
Outcomes	Hb and anaemia
Notes	Micronutrient content: single nutrient (iron) Rice fortification method: not specified Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: 15% overall Iron compound: comparable bioavailability (as non‐encapsulated, micronized ferric pyrophosphate) Malaria endemicity: not reported Source of funding: Secretariat of Education and Secretariat of Health at the Municipal City Hall‐Sobral‐CE; Program for Appropriate Technology in Health (PATH) donated the rice to the Secretariat of Education at the Municipal City Hall‐Sobral‐CE
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Schools were chosen and participants later invited to participate. "Prior to the study, each school was identified to receive one type of rice to avoid contamination between the different groups".
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	Anaemia was higher in the school receiving non‐FFR.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	The baseline characteristics of the 2 groups are reported and do not differ.
Incomplete outcome data (attrition bias) All outcomes	Low risk	13% attrition, but balanced between groups.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Staff at the schools were not aware of the rice that was being served (fortified or standard) as the rice was provided by the study team in non‐identifying packages. Data collection team was also unaware of intervention and control groups."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Data collection team was also unaware of intervention and control groups."
Contamination (performance bias)	Low risk	Schools were chosen and only 1 intervention given.
Selective reporting (reporting bias)	Unclear risk	Protocol not available.
Other bias	Unclear risk	Unclear
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Parker 2015 (C).

Methods	Single‐blind, cluster randomised, placebo‐controlled trial
Participants	904 anaemic (Hb concentration 70‐120 g/L) school children aged 7‐11 years from 12 primary schools in the Muyinga Province, Burundi
Interventions	The study team randomised 12 schools to receive either FFR or milled non‐FFR, wherein 904 participants were enrolled and received 150 g dry ration of rice: group 1 (n = 461) received FFR providing 17.8 mg elemental iron, 8.5 mg zinc, 1.8 mg vitamin B1 (thiamine), and 0.6 mg (600 µg) folic acid 5 days/week for 7 months; group 2 (n = 443) received non‐FFR. All children received beans prepared with vitamin A‐fortified oil and iodised salt as co‐intervention in both groups. All children were dewormed 2 weeks prior to the start of the study. Children did not receive the intervention in the 2 study holiday periods (December and April) consisting of 2 weeks per period and during a 2‐week period in March due to procurement problems. Milled non‐FFR or FFR was delivered every 2 weeks to the schools and parents prepared the meals under supervision of study staff.
Outcomes	Change in Hb concentration expressed as change in Hb between baseline and follow‐up. Anemia improvement based on a change from mild to no anaemia or moderate anaemia to mild or no anaemia
Notes	Anaemia classification was based on WHO criteria for children at 1500 m above sea level; moderate and severe anaemia was combined as 1 group in the analysis because of the few participants who had Hb < 8.5 g/L (severe). Sample size estimated not reported. The study did not report on malaria smear positivity nor presence of soil‐transmitted helminths, but malaria and hookworm infections are endemic in the area. It is indicated in the article that "Almost 80 % of the population of Burundi lives in malaria‐endemic areas, and one‐quarter lives in areas of particularly high incidence." Micronutrient content: multiple Rice fortification method: hot extrusion Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: moderate (37.5% anaemic on screening). Only anaemic children included; 43.8 % in intervention and 35.1 % in non‐intervention; participants only: 79% moderate severe in intervention versus 72%) Iron compound: not reported in methodology Malaria endemicity at the time that the study was conducted: malaria endemic.  In this cluster‐randomised trial, we made adjustment towards design effect while presenting the outcomes anaemia and Hb concentration by estimating the effective sample size. This included 6 clusters each receiving FFR and non‐FFR. The total number of participants who provided complete outcome data was 904 (461 + 443), and therefore mean cluster size was 75.33. With ICC as 0.02723, from ICC for postal code reported in other studies for outcome Hb (Adams 2004; Gulliford 1999), the computed design effect was 3.024. For anaemia, in the intervention arm receiving iron‐FFR, sample size adjustment was made to 84 events (from n = 254) out of 152 participants (from n = 461) and in control arm with non‐FFR, numbers were adjusted to 77 events (from n = 234) out of 146 participants (from n = 443). However, for Hb concentration, only the total numbers in both intervention and control groups were adjusted as above without changing the mean and SD, thus making total number of participants in FFR group as 152 and control group as 146. Source of funding: USDA and Open Road Alliance
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Reported as randomised but random sequence generation was not reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported. The study team transported non‐FFR or FFR to the schools.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	Participants from intervention schools had a significantly lower Hb level and a higher proportion of children with moderate or severe anaemia.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Unclear risk	The baseline characteristics (age, dietary diversity score) are reported in the text as different between groups, but the table shows only the frequency or mean, but not the P values. Calculation for the P values confirm that these are < 0.05.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Of the 1071 participants, 904 (15% attrition) completed the study. From the intervention group, 81 were lost to follow‐up and from the control group, 86 were lost to follow‐up. There was no description of the reasons for attrition.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	This is reported as a "single‐blind" study with participants receiving the food through the school canteen and parent volunteers using the rice allocated. However, study team food monitors on site supervised the programme and it is unclear whether these monitors were blinded.
Blinding of outcome assessment (detection bias) All outcomes	High risk	This is reported as a "single‐blind" study and the study team measured Hb on site.
Contamination (performance bias)	Unclear risk	It is possible that contamination occurred but the risk of this happening is not clear. Each school received either FFR or non‐FFR coming from a central location.
Selective reporting (reporting bias)	Low risk	All outcomes stated in the methods section were reported. This study was approved by the Comité National d’Ethique du Burundi and the PATH Research Ethics Committee.
Other bias	Low risk	There are no other clear signs of bias. Source of funding was declared as "Funding for this study was provided by the United States Department of Agriculture (USDA) grant #2010‐38418‐21635 with supplemental funding from Open Road Alliance."
Recruitment Bias	Low risk	Reported randomisation of the schools (clusters) into intervention and control arms was done after the screening of children and their recruitment into the study.
Baseline imbalance	Low risk	Clusters were reported to be similar in terms of demographic, social and dietary characteristics. However there was significant difference across the arms with respect to baseline outcome measurements (Hb concentration and level of anaemia). Study authors also report "The primary models were not adjusted for any additional covariates, although we did conduct a sensitivity analyses to assess whether the results differed after adjustment for characteristics that were found to be imbalanced between the intervention groups at baseline. "
Loss of clusters	Low risk	No clusters were lost at the follow‐up.
Incorrect analysis	Low risk	"Linear mixed model" was used in the analysis to account for clustering by school.
Compatibility with individual RCTs	Low risk	It is unlikely that cluster design would effect the outcomes in this study.

Perignon 2016 (C).

Methods	Cluster‐randomised, double‐blind trial
Participants	2440 school‐age children from 20 schools with Hb ≥ 70 g/L. 16 schools in Cambodia were randomly allocated into 4 groups: 3 with FFR and 1 placebo. From another 16 schools 4 schools were randomly selected to be a no‐intervention group. From each of the 20 schools, 132 children were selected after stratification by age and grade. A total 528 participants were selected per group, including the no intervention group. Of the 2640 children, 200 were not recruited for various reasons (age, severe anaemia, absence or refusal). Finally, placebo group had 427 participants, UltraRice old (URO) = 446, UltraRice new (URN) = 464 and Nutririce = 460, adding to a total of 2248, who were available for assessment at the end of follow up period. The mean age of children was 9.6 (SD 2.3) years and 49.9% of them were girls.
Interventions	4 groups received rice through a school meal. At randomisation: group 1 (n = 476) received cold‐extruded FFR (UltraRice® Old (URO)) providing per 100 g of uncooked rice 10.67 mg elemental iron, 3.04 mg zinc, 1.06 mg vitamin B1 (thiamine), 270 µg (0.27 mg) folic acid; group 2 (n = 496) received hot‐extruded FFR (UltraRice® new (URN)) providing per 100 g of uncooked rice 7.55 mg of elemental iron, 2.02 mg zinc, 1.43 mg vitamin B1 (thiamine), 2140 IU vitamin A, 12.57 mg vitamin B3 (niacin) and 3.8 µg vitamin B12; group 3 (n = 499) received hot extruded FFR (Nutririce®) providing per 100 g uncooked rice 7.46 mg elemental iron, 3.68 mg zinc, 0.69 mg vitamin B1 (thiamine), 140 µg (0.14 mg) folic acid, 960 IU vitamin A, 7.98 mg vitamin B3 (niacin), 1.26 µg vitamin B12, and 0.92 mg vitamin B6 (pyridoxine); and group 4 (n = 479) received non‐FFR (placebo). A fifth group consisted of those participating in a take‐home ration with no school meals. Blending of the FFR was done at the plant with a ratio of 1:100. Packages were coded A‐H with 2 letters per intervention group to improve blinding.
Outcomes	The primary outcomes of the study were the prevalence of anaemia and other micronutrient deficiencies, anthropometry, general health and well‐being and cognitive function. The secondary outcomes were prevalence of helminth infection, gut flora and immune function. This paper is limited to the impact on Hb concentration, iron and vitamin A deficiencies.
Notes	Sample size estimates were calculated to detect a difference of 4 g/L. The study did not report on malaria smear positivity but reported on the presence of intestinal parasites (17.9% overall at baseline ranging from 9.4% to 23.9%) Micronutrient content: multiple micronutrients Rice fortification method: cold‐extruded UltraRice®; hot‐extruded new UltraRice® and Nutririce® Cooking method most commonly used in study setting (as reported): absorption (study author correspondence) Public health significance of anaemia at baseline in the target group: mild (16% at baseline) Iron compound: comparable bioavailability (as ferric pyrophosphate) The study site had no endemic malaria (study author correspondence) Source of funding: USDA WFP‐DSM Consortium, IRD. The study was approved by the National Ethics Committee for Health Research (NECHR) of the Ministry of Health, Phnom Penh, Cambodia, the Ministry of Education, Youth and Sports, Phnom Penh, Cambodia, and the Research Ethical Committee (REC) of PATH, Seattle, WA, USA. The study was registered at ClinicalTrials.gov (Identifier: NCT01706419). For presenting the outcomes in analyses we combined the 3 intervention groups (URO, URN and Nutririce) as intervention arm and placebo group as control arm. Only for the subgroup analysis related to cold and hot extrusion process involved in fortification, URO was considered along with half of placebo group as a separate study than the combination of URN and Nutririce compared with half of placebo group. While presenting the outcomes anaemia, Hb concentration and iron deficiency, we adjusted for the design effect by calculating the effective sample size. We estimated the design effect as 4.016 for the outcomes anaemia, Hb concentration, iron deficiency and vitamin A deficiency by considering ICC = 0.02723, ICC for postal code reported towards outcome Hb in references from other studies (Adams 2004; Gulliford 1999). This study had mean cluster size of 111.75 (1788 participants from 16 clusters (schools), providing data for the outcome Hb). The adjusted sample size for UltraRice Old was 111 from 445, UltraRice New 116 from 464, NutriRice 112 from 454 and placebo was 106 from 425. Overall, when URO, URN and Nutririce were merged as single intervention arm and adjusted for design effect, there were 60 events of anaemia (from n = 239) out of a total of 339 participants (from n = 1363) and in the control arm, there were 22 events (from n = 89) out of 106 participants (from n = 425). Similarly, when we presented the outcome anaemia under the subgroup of type of extrusion, for URO, which was the cold extrusion arm, there were 18 anaemia events out of 111 participants and hot extrusion arm including URN and Nutririce had 42 events of anaemia out of 228 participants. For Hb concentration, the adjusted number was taken for total number and original weighted average and SD were retained in the meta‐analysis. For presenting the results of iron deficiency, we adjusted the sample size for the design effect and using the design effect for anaemia (4.016). The adjusted sample size was 37 events of iron deficiency (from n = 149) in the intervention arm having 366 (from n = 1471) and 14 events of iron deficiency (from n = 56) out of 119 participants in control arm (from n = 479). To present the outcome of vitamin A deficiency, the total sample size was adjusted to 338 (from n = 1356) in the intervention arm (URO, URN and Nutririce added together) and 104 (from n = 421) in control arm. The numbers of vitamin A deficiency (VAD) were adjusted to 24 (from n = 97) in the intervention arm and 13 (from n = 52) in the control arm. While presenting the subgroup of type of extrusion, for URO the adjusted events were 9 out of 110 participants and for hot extrusion arm (URN and Nutririce together), 15 out of 228 participants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Reported as cluster‐randomised. Allocation of schools was done via a computer‐generated list.
Allocation concealment (selection bias)	Low risk	Random allocation was performed by a researcher not involved in the field work and the codes were kept from the field staff and other researchers.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	High risk	Baseline measures of outcome measures were reported. Authors report "There were no significant differences in age and gender between the study groups. " and "However, despite the randomisation, the prevalence of marginal vitamin A status, ferritin and soluble transferrin receptors levels, inflammation, parasite infection, and haemoglobinopathy significantly differed between groups. Furthermore, the control group was significantly different from the placebo and intervention groups for most indicators."
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	High risk	Baseline characteristics were reported and there were no differences in age or sex, but there were significant differences in inflammation and parasite infection and haemoglobinopathy.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Around 8% of participants were not followed up at end line due to dropping out from school, transferring schools, absence, refusal to participate and severe anaemia at midline. The final sample size was below the targeted sample size of 528 per group.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The study was reported as double‐blind and the blinding of allocation into groups was described. Blinding of the intervention was described as being blended centrally and coded with a letter A to H. Each intervention group would receive packages with 2 letters. There was no report on whether the participants could tell whether they received FFR.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Hb was measured on site, all other assays were performed in the laboratory in Germany. Therefore the concealment of the codes were not described.
Contamination (performance bias)	Low risk	The study was cluster‐randomised with each cluster receiving an intervention that was labelled centrally at the rice blending plant.
Selective reporting (reporting bias)	Low risk	Of the primary outcomes noted above, the paper is limited to micronutrient deficiencies and these were all reported in this paper. The prevalence of anaemia was a stated primary outcome. The absence of a change in prevalence was reported in the discussion but not shown in the results.
Other bias	Low risk	There were no other clear signs of bias. Study authors have declared the source of funding: "USDA/FAS, WFP‐DSM consortium, and IRD"
Recruitment Bias	Low risk	Quote "Prior to the study, all parents of children from the 20 schools were invited to attend a meeting at which the study procedures were explained". Randomisation took place after the recruitment of the participants into the study.
Baseline imbalance	Unclear risk	However there is no evidence of differences across the clusters.
Loss of clusters	Low risk	No clusters were lost to follow‐up.
Incorrect analysis	Low risk	Quote: "Generalized mixed models (linear or binary logistic regression) were used to evaluate the effects of time, group, and time*group interaction on Hb, ferritin, soluble transferrin receptors, and the prevalence of vitamin A deficiency, while taking into account the random effects of individuals and school clusters."
Compatibility with individual RCTs	Low risk	The cluster design did not seem to effect the findings of the study.

Pinkaew 2013.

Methods	RCT with 2 arms
Participants	203 school‐going children with low serum zinc concentration aged between 7‐12 years from low‐income Muslim families attending 8 primary schools in peri‐urban area of the Muang district, Satun province, southern Thailand. There were children aged between 4‐12 years in the schools (kindergarten to grade 6), who were provided with a school lunch programme for 5 days/week, with partial government subsidy
Interventions	Participants were randomised to 1 of 2 groups: group 1 (n = 101) received triple FFR providing 10 mg iron, 9 mg zinc and 1.05 mg of vitamin A/g of extruded rice; group 2 (n = 102) were given natural control rice. The rice was provided as a component of school lunch meals for 5 months. Lunch menus were changed frequently with rotation manner so that rice was given with chicken or fish and occasionally with vegetables. The schools also provided 200 mL of free milk daily to all children to improve the chance of showing an improvement in iron status even though it was not the primary outcome measure.
Outcomes	Hb level, serum ferritin, transferrin, anaemia, iron‐deficiency anaemia, vitamin A deficiency, zinc deficiency
Notes	Micronutrient content: ≥ 2 nutrients Rice fortification method: hot extrusion Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: moderate (5% to 39.9%) Iron compound: comparable bioavailability (as micronized ferric pyrophosphate) Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: Medicor Foundation (Triesen, Liechtenstein) and The Royal Thai Government Scholarship. Dr. Paul Lohmann GmbH (Emmerthal, Germany) provided iron and zinc compounds and DSM Nutritional Products Ltd. (Basel, Switzerland) provided the vitamin A compound.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not reported.
Allocation concealment (selection bias)	High risk	The individually packed rice portions were transported by research assistants from the central kitchen to the school each day.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	The dietary intake of macro‐ and micronutrients was comparable among the study groups except for vitamin A.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	There was no significant difference in any of the characteristics between the 2 groups except for BMI‐for‐age Z‐scores, which were found to be lower in the control group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The dropout rate was 3%, intervention group ‐ 2%, control group ‐ 4% and it was due to loss of interest. Authors also quote "fourteen children (5 in the triple‐fortified group, 9 in the control group) were excluded from data analysis because of low school attendance (<80% during the feeding period)".
Blinding of participants and personnel (performance bias) All outcomes	High risk	The individually packed rice portions were transported by research assistants from the central kitchen to the school each day. "The cooked rice was weighed into individual portions of 140 g into a colour‐coded container that was labelled with the child's name.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was reported a double‐blind study wherein individual rice packs in individual containers with child's name were transported from the central kitchen to the school.
Contamination (performance bias)	Unclear risk	Not clear.
Selective reporting (reporting bias)	Low risk	The study reported all the parameters concerned to the objectives.
Other bias	Unclear risk	Not clear.
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Pinkaew 2014.

Methods	RCT with 2 arms
Participants	203 school‐going children aged between 7‐12 years from 8 primary schools in periurban area of the Muang district, Satun province, southern Thailand. The schools included children mainly from low‐income Muslim families. There were children aged between 4‐12 years in the schools (kindergarten to grade 6). They were provided with a school lunch programme for 5 days/week, with a partial government subsidy. Children who had consumed the triple‐FFR in a previous study (Pinkaew 2013), or showed clinical symptoms of vitamin A deficiency were excluded.
Interventions	Participants with low serum zinc (n = 203) were randomised to 1 of 2 groups: group 1 (n = 101) received rice fortified with 10 mg iron, 9 mg zinc and 1.05 mg of vitamin A/g of extruded rice; group 2 (n = 102) were given natural control rice. The rice was provided as a component of school lunch meals for 5 months. They used paired stable isotope dilution technique with labelled 13C2‐retinyl acetate (13C‐RID) to quantify vitamin A pool size. Lunch menus were changed frequently with rotation manner so that rice was given with chicken or fish and occasionally with vegetables. The schools also provided 200 mL of free milk daily to all children to improve the chance of showing an improvement in iron status even though it was not the primary outcome measure. Triple FFR once a day for 5 times a week.
Outcomes	Hb level, serum ferritin, transferrin, anaemia, iron‐deficiency anaemia, vitamin A deficiency, zinc deficiency
Notes	Micronutrient content: ≥ 2 nutrients. Rice fortification method: hot extrusion Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: moderate (5% to 39.9%) Iron compound: comparable bioavailability (as micronized ferric pyrophosphate) Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: Medicor Foundation (Triesen, Liechtenstein), the International Atomic Energy Agency (Vienna, Austria), and the Royal Thai Government Scholarship. Dr. Paul Lohmann (GmbH, Emmerthal, Germany) provided the iron and zinc compounds, and DSM Nutritional Products Ltd. (Basel, Switzerland) provided the vitamin A compound.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation not reported.
Allocation concealment (selection bias)	High risk	The individually packed rice portions were transported by research assistants from the central kitchen to the school each day.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	The dietary intake of macro‐ and micronutrients was comparable among the study groups except for vitamin A.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	There was no significant difference in any of the characteristics between the 2 groups except for BMI‐for‐age Z‐scores, which were found to be lower in the control group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Among the total of 50 children who were enrolled, 45 children completed it. 2 children dropped out because they shifted out of the study area (1 child in each group), and 3 children (1 in the intervention group and 2 in the control group) were excluded due to low compliance.
Blinding of participants and personnel (performance bias) All outcomes	High risk	The individually packed rice portions were transported by research assistants from the central kitchen to the school each day. "The cooked rice was weighed into individual portions of 140 g into a colour coded container that was labelled with the child's name.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was reported a double‐blind study wherein individual rice packs in individual containers with child's name were transported from the central kitchen to the school.
Contamination (performance bias)	Unclear risk	Not clear.
Selective reporting (reporting bias)	Low risk	The study reported all the parameters concerned to the objectives including the findings of the pilot study.
Other bias	Unclear risk	Not clear.
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Radhika 2011.

Methods	Double‐blind RCT with 2 arms
Participants	140 school children aged 5–11 years (54 boys and 86 girls) with Hb ≥ 70 g/L attending school through the public distribution system of the government of Andhra Pradesh, India
Interventions	Participants were randomly allocated to 1 of 2 groups: group 1 (n = 70, 27 boys and 43 girls) received a meal consisting of 125 g rice (dry weight) containing 19 mg elemental iron (as micronized ferric pyrophosphate (FFR; normal rice mixed with Ultra Rice® (3.14‐lm mean particle size)); group 2 (n = 70, 27 boys and 43 girls) received a meal 125 g non‐FFR. The extruded kernels were produced by a cold‐extrusion process. Rice served in combination with a typical liquid preparation of pulse, locally called sambar (prepared by combining dehusked split pigeon peas, tamarind pulp, and vegetables, e.g. bottle gourd, cucumber, brinjal), or a semi‐liquid preparation of the same pulse with green leafy vegetables (e.g. spinach, amaranth, sorrel), locally called aakukoora pappu. Another variation in the menu included rice seasoned with tamarind pulp, locally called pulihora. The main ingredients used on a daily basis were tomatoes, onions, peanuts, red chilies, salt, and peanut oil. The intervention lasted 8 months. The process of blending the rice with the premix was done through manual mixing in 50‐kg batches outside rice mills or normal packaging facilities, for the sole purpose of use in the school study. All of the participating children were dewormed with 100 mg mebendazole (Mebex®, Cipla Limited) twice daily for 3 days, 1 week before initiating the feeding study.
Outcomes	Average consumption amounts of the midday meal, height, weight, Hb, ferritin, and C‐reactive protein at baseline and at 8 months
Notes	Micronutrient content: single nutrient Rice fortification method: cold extrusion Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: severe (≥ 40% ), 40% in intervention group and 38.1% in control group Iron compound: comparable bioavailability (as micronized ferric pyrophosphate) Malaria endemicity at the time that the study was conducted: unknown/unreported malaria setting Source of funding: Department of Biotechnology, Government of India. PATH USA provided UltraRice premix for the use in the study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported.
Allocation concealment (selection bias)	Low risk	The codes were kept secure, and the decoding was completed after the analysis of data.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	The prevalence of anaemia, iron deficiency, and iron‐deficiency anaemia was similar between the 2 groups at baseline.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	The prevalence of anaemia, iron deficiency, and iron‐deficiency anaemia was similar between the 2 groups at baseline.
Incomplete outcome data (attrition bias) All outcomes	Low risk	12 participants were lost to follow‐up.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind. The study group randomisation and the process of fortification and coding of rice were completed by a scientist not involved in the study, to ensure the double‐blinding of the study. The codes were kept secure, and the decoding was completed after the analysis of data.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The codes were kept secure, and the decoding was completed after the analysis of data.
Contamination (performance bias)	Unclear risk	It is possible that contamination occurred but the risk of this happening is not clear.
Selective reporting (reporting bias)	Low risk	The protocol was approved by the Institutional Ethical Committee of the National Institute of Nutrition and the Human Subject’s Protection Committee of PATH.
Other bias	Unclear risk	Unclear.
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Salcedo 1950.

Methods	Non randomised‐controlled study: cross‐sectional study with 2 arms
Participants	Children from welfare institutions of selected municipalities of Bataan Province, Philippines (aged 3‐18 years).
Interventions	The 7 municipalities of the east coast, with a population of 63,508 as of 1 October 1948, made up the experimental area (FFR); the remainder of the province, comprising a larger, more sparsely settled area in 5 municipalities, with a population of 29,393, became the control zone (non‐FFR). In the control zone, only the 2 municipalities of Bagac and Moron were considered. A sample was selected in each area. 3 sets of observations were made: group 1, among government employees; group 2, among children housed and fed in the welfare Institutions of the Social Welfare Commission; and group 3, among personnel of the Armed Forces of the Philippines. There were 3 studies reported: Study 1: this study only assessed acceptability of the FFR among the population. All residents (n = 2188) from the selected towns received FFR with thiamine, niacin and iron (n = 7 towns) and non‐FFR (n = 2 towns) serving as control. Study 2: 1 group of children aged 3‐18 years (n = 287) were given FFR and another group of 287 were given non‐FFR. Both groups consumed between 200‐250 g of rice. Biochemical outcomes were confined to 30 participants in each arm. Comparisons were contemplated of the prevalence of beriberi in Bataan before and after introduction of the new rice, as well as with the prevalence in other provinces and used an isolated population as a control. Study 3: a total of military personnel (n = 1416) were given FFR, but clinical assessment was limited to 350 participants serving as the experimental group and an additional 116 participants serving as the control. Rice grains impregnated with premix and mixed at 1:200 to have a final FFR (per kg) with 4.4 mg thiamine, 33 mg niacin, 28.6 mg elemental (as iron pyrophosphate). FFR was given for 7 months. Only studies 2 and 3 (n = 1703) are pertinent for this review. However, the records available of these studies do not allow for data extraction and thus do not contribute data for this review.
Outcomes	For children: average increase in height (cm) and weight (kg), % gaining height and weight, red cell count (counts), increase in Hb (%)
Notes	Micronutrient content: multiple micronutrients Rice fortification method: coated (impregnated grains) Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: unknown/unreported Iron compound: comparable bioavailability (as iron pyrophosphate) Malaria endemicity: not reported Source of funding: Williams‐Wateran Fund for the Combat of Dietary Diseases, New York, USA; Government of Bataan Province; Hoffmann‐La Roche Inc, Nutley, USA and the National Rice and Corn Corporation of Philippines
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Not used.
Allocation concealment (selection bias)	High risk	Quote: "Accordingly, it was early decided to set up within Bataan a control area as well as an experimental one, which might then be compared with one another with respect to morbidity, mortality and other features before and after a reasonable trial period."
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Unclear risk	Not reported.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	Quote: "Both groups were in fairly good health and showed no symptoms of thiamine deficiency at the start of or during the experiment."
Incomplete outcome data (attrition bias) All outcomes	High risk	Only small samples were analysed from each of the universe of the population receiving the FFR or non‐FFR. Quote: "Twenty‐seven children from each group had to be dropped due to transfers and discharges from the institutions."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not reported.
Blinding of outcome assessment (detection bias) All outcomes	High risk	It was an open assessment.
Contamination (performance bias)	Unclear risk	Not reported.
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	Unclear risk	Unclear.
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

Thankachan 2012.

Methods	Randomized, double masked, placebo controlled design. A block randomisation with a computer‐generated list in blocks of 20 was used to assign children to 1 of the 3 intervention groups.
Participants	258 children aged 6–12 years attending 4 primary schools in the Bangalore Urban District of Karnataka State in South India. This region is not endemic for malaria and the incidence of intestinal parasitic infestation is estimated to be low.
Interventions	Participants were randomly assigned to 1 of 3 groups: group 1 (n= 86) received multiple‐micronutrient–FFR containing 12.5 mg elemental iron (as micronized ground ferric pyrophosphate); group 2 (n= 86) received multiple‐micronutrient–FFR with 6. 25 mg elemental iron (as micronized ground ferric pyrophosphate); group 3 (n= 86) received an identical unfortified control meal. All the FFR also contained per 100 g 0.5 mg vitamin A (as vitamin A palmitate), 0.38 mg thiamine (as thiamin mononitrate), 5 mg niacin (as niacinamide), 0.38 mg vitamin B6 (as pyridoxine hydrochloride), 0.00075 mg vitamin B‐12 (as vitamin B12 0.1%), 0.075 mg (75 µg) folic acid, and 3 mg zinc (as zinc oxide). A rotating menu of 5 traditional recipes was used: lemon rice, tamarind rice, vegetable rice, curd rice, and tomato rice. Dedicated technicians were responsible for preparing the daily meals according to the standard recipes, supervising the cooking, weighing and packing the individual rice meals in colour‐coded plastic containers, and transporting it to the schools. All study children were dewormed under the supervision of the research staff with 400 mg albendazole (Low‐Cost Pharmaceuticals) before the study and near the study midpoint. The schools were instructed not to provide iron and folic acid supplements, vitamin A supplements, and deworming medication to the children who were included in the study.
Outcomes	Hb, C‐reactive protein, zinc protoporphyrin, serum ferritin, serum transferrin receptor, serum retinol, serum zinc, plasma homocysteine, serum vitamin B12
Notes	Micronutrient content: ≥ 2 nutrients Rice fortification method: hot extrusion Cooking method most commonly used in study setting (as reported): unknown/unreported Public health significance of anaemia at baseline in the target group: severe (40% and more) Iron compound: comparable bioavailability (as ferric pyrophosphate (milled) Malaria endemicity at the time that the study was conducted: malaria‐free area Source of funding: DSM, Mumbai, India
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A block randomisation with a computer‐generated list in blocks of 20 was used to assign children to 1 of the 3 intervention groups.
Allocation concealment (selection bias)	Unclear risk	Unclear.
Similarity of baseline outcome measurements (checking for confounding, a potential consequence of selection bias)	Low risk	There were no differences in baseline characteristics among the study groups except for the prevalence of low serum retinol, which was greater in the low‐iron group compared with the high‐iron group.
Similarity of baseline characteristics (checking for confounding,a potential consequence of selection bias)	Low risk	Children who did not complete the study were comparable to those who remained in the study by baseline characteristics (data not shown) except for the prevalence of low serum retinol, which was greater in the low‐iron group compared with the high‐iron group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was balanced among the groups.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Each group was randomly assigned a distinct colour code, which remained unknown to both the study staff and the children until the completion of the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Each group was randomly assigned a distinct colour code, which remained unknown to both the study staff and the children until the completion of the study.
Contamination (performance bias)	Unclear risk	It is possible that contamination occurred but the risk of this happening is not clear.
Selective reporting (reporting bias)	Low risk	The study protocol was approved by the Institutional Ethical Review Board of St. John’s Medical College, Bangalore. This study was registered at the Clinical Trials Registry of India as CTRI/20/09/091/000941.
Other bias	Unclear risk	Unclear.
Recruitment Bias	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Baseline imbalance	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Loss of clusters	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Incorrect analysis	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.
Compatibility with individual RCTs	Unclear risk	Not applicable. We only evaluated this domain in cluster‐randomised studies.

BMI: body‐mass index; CBA: controlled before‐and‐after study; FFR: fortified rice; Hb: haemoglobin; ICC: intra‐cluster correlation; RCT: randomised controlled trial; SD: standard deviation; UN: United Nations; USAID: United States Agency for International Development; USDA: United States Department of Agriculture; VGD: Vulnerable Group Development; WFP: World Food Programme

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Ando 2012	The type of study design is outside the scope of this review. In this study, 144 residents (100 women and 44 men) of a long‐term care health facility, Soka Royal Care Center (Soka city, Saitama prefecture of Japan) aged ≥ 65 years received folic acid‐FFR from March 2010 and were examined for blood cell parameters (n = 144) and vitamin B12 and/or serum folate concentrations (n = 68) after 1 year. 3 meals a day were prepared to contain 240 μg of folate derived from food stuff on average. Additional folic acid was made by adding calculated amounts of synthetic mono glutamyl folic acid‐FFR (House Wellness Foods Co) to washed rice before cooking. There was no control group. Participants who stayed more than 2 years (n = 49) were classified as high or low basal folate status.
Angeles‐Agdeppa 2011	It did not involve a control group and hence was excluded.The study was carried out among 766 mothers and their children aged 6‐9 years in Orion, Bataan. This involved seeking political support, networking with local organisations, market surveys, and social marketing activities. In addition to these social marketing, the haemoglobin concentrations and levels of anaemia among mothers and children were measured before and after the introduction of the iron FFR into the market commercially.
Arsenault 2010	The study design and the type of intervention (micronutrient biofortification) are not within the scope of this review. A total of 480 children, aged 24‐48 months and their female caregivers residing in 2 rural districts of northern Bangladesh participated in a study that quantified their usual rice and zinc intakes and serum zinc concentrations in order to simulate the potential impact of zinc‐biofortified rice on their zinc intakes.
Bagni 2009	The type of intervention is point‐of‐use fortification with iron drops and is therefore out of the scope of this review. Here, 360 children aged between 12‐60 months attending 4 public day‐care centres in Rio de Janeiro, Brasil, were randomly assigned to 1 of 2 groups: group 1 (n = 180) received a daily meal prepared with iron‐fortified rice (with iron bisglycinate); group 2 (n = 174) received non‐fortified placebo rice. The rice was fortified once a week for 16 weeks at a dose of 4.2 mg of iron for every 100g of food ready in the supplemented group. In the days of fortification, the solution was added as drops to the rice by the researcher during assembly of the dishes from lunch. If the child repeats the meal, the solution was administered proportional to the quantity of rice offered repetition. The number of drops of solution offered to every child, every day of intervention, was recorded in order to know, the end of the study, the total amount of iron offered the intervention.
Barboza 2011	This was a retrospective study. Food that was supplemented was not limited to rice and since the study design was not in the scope of this review, the study was excluded. National Data Center Congenital Diseases Registry record national population base and Central American Population Center, were used and prevalence of neural tube defects before the implementation of food supplementation of folic acid and after the same were compared.
Beinner 2010	The study was excluded because the participants were outside the age range and fortification is compared with another form of micronutrient intervention (supplementation). Randomised trial including 175 mildly anaemic infants and young children, 6‐24 months of age from the metropolitan region of Belo Horizonte in southeastern Brazil, who were randomly assigned to 1 of 2 groups for 5 months: group 1 received 100 g of cooked rice fortified with micronized ferric pyrophosphate and a placebo solution; group 2 received an identical, unfortified rice and iron drops.
Castro 2017	This study did not include rice as a medium of intervention and the included intervention was not fortification. Hence this study was excluded. Children aged between 2‐5 years were provided with the supplement daily as part of the afternoon snack, diluted in water. The dietary, biochemical, haematological and anthropometric parameters were measured before and after the interventions.
Finkelstein 2013	Study was excluded since the iron fortification intervention employed was bio fortification. This study discusses the collective results of iron fortification interventions on iron status, from 3 RCTs from India and Philippines. A total of 686 participants were enrolled in the study. The primary outcome was measured in terms of serum haemoglobin and ferritin levels, Incidence of anaemia and iron‐deficiency anaemia and its resolution. There was no significant impact on the haematological outcomes during the follow‐up period, but likelihood of resolution of existing iron deficiency increased by 50%.
Florentino 1998	This is a review paper on the history, technological aspects and challenges from rice fortification efforts in Phillipines. This is not the type of study considered for this review.
Graham 2007	The study combined fortification and supplementation and therefore did not meet the inclusion criteria. RCT of 116 night‐blind, pregnant women in Nepal who were assigned either a supplement providing 30 mg iron and 6 mg riboflavin or a placebo while receiving vitamin A–FFR providing 850 g retinal activity equivalents for 6 days/week under supervision for 6 weeks. Iron and riboflavin supplements significantly reduced the prevalences of riboflavin deficiency, iron‐deficiency anaemia, and abnormal papillary threshold from baseline. The study concluded that iron deficiency may limit the efficacy of vitamin A to normalise dark adaptation in pregnant Nepali women.
Haskell 2005	The type of interventions and comparisons are outside the scope of this review. The study was conducted in seven 6‐week cycles between July 2000 and May 2002 in a total of 60 clusters, with each cluster forming the Nepali structure called a Village Development Committee, in the Saptari district in the eastern Terai region of Nepal; 405 pregnant women aged 18–45 years were identified and were randomly assigned to 1 of 6 treatment groups to receive a midday meal and capsule supplements 6 days/week for a period of 6 weeks: group 1 (n = 57) received 200 g cooked rice, ≈150 g vegetables with low vitamin A content (curried cauliflower or white squash or white potatoes), and a high‐dose capsule containing 2.0 mg vitamin A as retinyl palmitate in ≈200 μL corn oil); group 2 (n = 55) received 200 g cooked rice, ≈150 g curried vegetables with low vitamin A content, and a low‐dose capsule containing 850 μg vitamin A as retinyl palmitate in ≈200 μL corn oil; group 3 (n = 69) received 200 g cooked vitamin A–fortified rice containing 850 μg vitamin A, ≈150 g curried vegetables with low vitamin A content, and a capsule containing ≈200 μL corn oil; group 4 (n = 56) received 200 g cooked rice, ≈150 g curried vegetables with low vitamin A content, 8 g goat liver containing 850 μg vitamin A, and a capsule containing ≈200 μL corn oil; group 5 (n = 54) received 200 g cooked rice, ≈150 g amaranth greens containing 850 μg RE (425 μg retinol activity equivalents (RAE)) as β‐carotene, and a capsule containing 200 μL corn oil; and group 6 (n = 57) 200 g cooked rice, ≈128 g carrots containing 850 μg RE (425 μg RAE) as β‐carotene, and a capsule containing 200 μL corn oil.
Huo 2014	The study design is outside the scope of this review. In this descriptive cross‐sectional study from China, effectiveness of iron‐fortified food items among school‐age children aged between 11‐16 years of age was assessed. Iron‐fortified soy sauce, multinutrient fortified rice and vitamin A‐fortified cooking oil provided to a school cafeteria for a period of 10 months. Baseline Hb, zinc, vitamin A, serum ferritin and transferrin levels were measured at baseline and at the end of 10 months. There was a significant increase in the serum zinc, vitamin A and Hb levels and a decrease in anaemia prevalence.
Hyun 2015	This is an abstract with no data available to further evaluate this study. In this study in Korea, 78 women between 19 and 35 years at risk of folate deficiency were randomly assigned to groups: fortified‐food group, non‐fortified food group, and fortified‐food group and nutrition education group and non‐fortified with nutrition education group. Instant rice fortified with 400 μg of folic acid per serving (1 bowl) was developed and used in this study. Fortified or non‐fortified food was consumed once a day for 4 weeks and nutrition education was given once a week.
Kagawa 2017	The study design is outside the scope of this review. Here, 1101 participants (male: n = 345, female: n = 756) aged 61 ± 10 years completed a dietary intake through a food frequency questionnaire of 56 foods and beverages commonly consumed by the Japanese population. Blood chemistry analysis included serum folate and total homocysteine concentration as well as genotype assessment. Participants then received “folate fortified rice” containing 26.7 mg folic acid, 187 mg thiamin, 66.7 mg vitamin B6 and 320 μg vitamin B12 per 100 g rice (House‐wellness Foods Company) and a folic acid‐fortified bread called Sakado Folate Bread, containing215 ± 14.7 μg folic acid per slice of 64.0 g bread. Commercially available Sakado Folate Bread contains 160 μg folic acid/slice. All participants received lecture, genotyping, blood analysis, nutrition surveys, and guidance according to the collected data. All participants were exposed to the folic acid from the fortified foods: rice and bread, as well as other foods. The study authors report that in the population of Sakado City (approximately 101,000 inhabitants in 2015) there were 693 births in 2015; consequently, a decrease in neural tube defects could not be confirmed. There is no control group and the interventions include availability of the fortified foods, the blood testing and the education component.
Ma 2016	Since the study population was < 2 years of age, it was excluded. The study included infants in the age group of 6 months being randomised to receive meat with equi‐caloric fortified cereal supplement or local cereal supplement.
Nogueira Arcanjo 2012	The participants were outside the age for inclusion in this review. Cluster‐RCT with infants, 10‐23 months of age from 2 public day‐care centres in northeast of Brazil who received either 50 g of iron fortified rice or a control rice weekly for 18 weeks. Though the effect was small, iron‐FFR was effective in increasing Hb levels and reducing anaemia in infants.
Pham 2012	The study was excluded since it was conducted among infants. In this intervention study from Vietnam, effect of micronutrient fortified complementary foods among normal infants was assessed. 29 villages were randomly divided into 3 groups and received 3 different interventions instant flour fortified with micronutrients, Traditional flour gruel fortified with micronutrients and no fortification. After 6 months of intervention, anthropometric indices were greater in the 2 intervention groups compared to the non‐intervention group.
Pham Van 2013	This is a poster presentation in an international congress reporting a randomised, double‐masked study of 244 reproductive‐age women, in 2 groups. No data available to further evaluate this study. A meal based on iron‐fortified rice (SunActive® FeP80) was served 6 days/week with 15 mg premix per 150g rice‐iron fortified group or 0.75mg iron/day and no added iron‐control group. Concentrations of haemoglobin, serum ferritin, transferrin receptor were measured at baseline 3 and 6 months. After intervention, in iron‐FFR group, concentrations of Hb, serum ferritin were significant higher, but no further data are available.
Skau 2015	The study was excluded since the study participants were infants. This was a randomised, single‐blind study conducted among infants to assess the impact of animal source food and micronutrient fortification on body fat composition and iron status. The infants were randomised to receive 2 different types of rice‐based complementary foods. WinFood (WF) with small fish and edible spiders and WinFood‐Lite (WF‐L) fortified with small fish, against 2 existing fortified corn‐soy blend products, CSB+ (purely plant based) and CSB++ (8% dried skimmed milk). Outcomes were assessed in terms of increments in fat‐free mass, serum transferrin and ferritin levels and anthropometric indices.
Sridevi 2013	The study was excluded as the vehicle of fortification was not rice. This observational study was conducted among women working in ginning industries (i.e. industry using machines separating the fibres of cotton from the seeds). 20 moderately anaemic women from a sample of 150 ginning workers were selected and given intervention in the form of micronutrient fortified soy biscuit. The haematological parameters and anthropometric indices were assessed after a period of 4 months. There was drastic improvement in the Hb levels and serum iron levels in the intervention group.
Vitolol 1998	The type of intervention is outside the scope of this review. This observational study was carried out to assess the impact of iron‐fortified cereal on anthropometric parameters and Hb levels among children aged 1‐4 years. 54 children, 24 in 1 room and 30 in another room in a nursery were provided with iron‐fortified cereal given in the form of cereal that provided 2‐3 g of iron for a period of 2 months. 1 group children were assisted by teachers during feeding and the other group fed on themselves. The commercial product used was a cereal porridge which was composed of 43.0% corn starch, 40.0% corn flour, 10.0% oatmeal, 4.0% rice flour, and 2.0% rye, sweetened at 7.5%.
Walter 1993	The participants were outside the age range for inclusion and type of interventions are outside the scope of this review. This study included 515 infants who weighed > 3000 g at birth and who were started on a cereal diet at 4 months of age, from a low‐ and low‐middle‐income group living in urban Santiago in Chile. The study compared iron‐FFR cereal to non‐FFR cereal in infants who were exclusively breast‐fed for > 4 months and to iron‐fortified formula in infants who were weaned to formula before 4 months of age. The design was double‐blind in respect to the presence or absence of fortification iron in the cereal or formula. Among infants weaned to formula before 4 months, the cumulative percentages of infants excluded for anaemia by 15 months were 8%, 24%, and 4%, respectively, in the fortified cereal, unfortified cereal and formula, and fortified formula groups. In infants breast‐fed for more than 4 months, the corresponding values were 13% and 27%, respectively, in the fortified and unfortified cereal groups.

FFR: fortified rice; Hb: haemoglobin; RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

NCT02714075.

Trial name or title	Comparison of iron absorption from extruded FePP‐fortified rice containing zinc, citric acid/trisodium citrate and EDTA (MM_Rice)
Methods	Bioavailability study intervention model
Participants	Children 5‐9 years of age (both male and female) with these criteria for inclusion: iron deficient or anaemic as per definition; read and signed informed consent form by the caregiver (or has been read out to the caregiver in case of illiteracy) and absence of any metabolic, gastrointestinal or chronic diseases
Interventions	Administration of iron‐FFR to all participants; participants will act as their own controls and each participant will receive all foreseen treatments/interventions
Outcomes	Fractional iron absorption, Hb, plasma ferritin, C‐reactive protein concentrations, zinc protoporphyrin measurement as zinc to heme ratio, soluble Transferrin receptor
Starting date	April 2016
Contact information	Prof. Dr. Michael B Zimmermann Zurich, Switzerland, Tel +41 44 632 86 57
Notes	Sponsors: Swiss Federal Institute of Technology, Switzerland and University for Development Studies, Tamale, Ghana.

NCT03056625.

Trial name or title	Efficacy of vitamin A fortified rice in lactating Thai women (EVAL)
Methods	2‐arm interventions, vitamin A‐FFR and non‐FFR with 35 participants (lactating women) per group
Participants	70 healthy lactating Thai women 18‐38 years of age, with gestational age between 37 to 42 weeks, willing to breast feed for a period of 4‐6 months. Women with Hb concentrations < 70 gt/L, postpartum haemorrhage, twin birth, or low birth weight infant, or receiving vitamin A supplements during the study period will be excluded.
Interventions	Participants will receive 1 meal/day on weekdays for a period of 14 weeks and will be randomly assigned to receive "normal" rice 1 meal/day on weekdays for a period of 14 weeks or vitamin A‐FFR 1 meal/day. The fortified dose will be measured in the final cooked product, but we will aim to administer approximately 500 µg retinol in the rice meal. Vitamin A‐FFR rice is produced by extrusion technology by adding retinol into an artificial rice to be mixed with the normal rice.
Outcomes	Vitamin A liver stores, breast milk retinol, serum retinol, Hb concentration, gut microbiota
Starting date	15 March 2017
Contact information	Dr Siwaporn Pinkaew, Prince of Songkla University Tel +66 89 9772266 Email: siwaporn.p@psu.ac.th
Notes	Sponsor: Prince of Songkla University

FFR: fortified rice; Hb: haemoglobin

Differences between protocol and review

We aimed at searching two databases in the protocol that were not available to us at the review stage: BIOSIS and Food Science and Technology Abstracts (FSTA). We also made the following changes from the published protocol (Ashong 2012).

1. We removed the subgroup analysis by prevalence of stunting in children under five years in the study site: moderate (number of children whose height‐for‐age Z‐score is between −2.0 and 2.99 standard deviations (SD) below the mean) versus severe stunting (number of children whose height‐for‐age Z‐score is less than −3.0 SD below the mean) versus mixed/unknown/unreported. This information was not available in most studies and not all studies were conducted in children. The most commonly used form of reporting was by mean Z‐score in each group rather than the prevalence.

2. We removed the subgroup by iron compound as most studies used micronized pyrophosphate and ferrous sulphate, which have similar bioavailability with differences varying depending on encapsulation, particle size and other factors not captured in these studies.

3. Given the different ways that diarrhoea was reported, we changed our protocol definition of three liquid stools in a single day, to any as defined by study authors in order to be able to capture this adverse effect, if present.

4. We have included any adverse effects to primary outcomes. They are reported separately.

5. We did not consider before‐and‐after studies without a control group for inclusion in this review as planned in protocol.

6. We did not include data from non‐randomised studies in the quantitative synthesis and the review conclusions, since these studies provided little information on the comparative effectiveness of rice fortification in improving nutrition. However, we did include them in the qualitative synthesis because of their details on contextual aspects and concepts of fortification. We mentioned their findings under the subheading 'Summary of non‐randomised studies' at the end of the main synthesis.

7. We have made the change from the proposed type of participants in the protocol being general population of all age groups (including pregnant women) from any country to general population older than two years of age (including pregnant women) from any country.

8. We planned to examine the effects of two or more nutrients (in the same study arm) in multiple comparisons. However, owing to the duplication of findings because most of the studies had iron as one of the micronutrients in the fortification arm, we included multi nutrient studies in comparison 1 only and since one study had vitamin A only in one of the arms, we included it in comparison 2.

Contributions of authors

Protocol development: Joseph Ashong drafted an initial protocol with technical input from Sumithra Muthayya, Arnaud Laillou, Luz Maria De‐Regil and Juan Pablo Pena‐Rosas. Luz Maria De‐Regil, Belinda Burford and Juan Pablo Pena‐Rosas developed the methods of the protocol. All authors provided input and contributed to drafting the final version of the protocol.

Review development: all authors contributed to screening, extraction and assessment of data, as described in the Methods. MNGC, JPP and LMD prepared the GRADE 'Summary of findings' tables. All the review authors wrote and approved the final manuscript.

Juan Pablo Peña‐Rosas is the guarantor for the review.

Disclaimer: Juan Pablo Peña‐Rosas and Maria Nieves Garcia‐Casal are full‐time staff members of the World Health Organization. The review authors alone are responsible for the views expressed in this publication and they do not necessarily represent the official position, decisions, policy or views of the World Health Organization.

Sources of support

Internal sources

• Centre for Health Innovation and Partnership, NSW Health, North Parramatta, Australia.

• Department of Nutrition for Health and Development, World Health Organization, Switzerland.

External sources

• Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

  WHO provided partial financial support from the Department of Nutrition for Health and Development for this work for some of the authors of this review.

• Global Alliance for Improved Nutrition (GAIN), Switzerland.

  WHO thanks GAIN for their financial support for conducting systematic reviews on micronutrient interventions. SM received partial financial support from GAIN during the preparation of the protocol.

• Centers for Disease Control and Prevention (CDC), USA.

  The National Center for Birth Defects and Developmental Disabilities provided financial support for conducting this systematic review.

• Nutrition International, Canada.

  WHO thanks Nutrition International for their financial support for conducting systematic reviews on micronutrient interventions.

• The Bill & Melinda Gates Foundation, USA.

  WHO acknowledges the financial support from the Bill & Melinda Gates Foundation for the development of systematic reviews of the evidence on the effects of nutrition interventions.

Declarations of interest

Juan Pablo Peña‐Rosas (JPP) co‐ordinates the Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, which received financial resources from the Bill & Melinda Gates Foundation (2013‐2019); US Centers for Disease Control and Prevention (CDC) (2014‐2019); Nutrition International (2014‐2019) and USAID (2014‐2019). Donors do not fund specific guidelines and do not participate in any decision related to the guideline development process including the composition of policy questions, membership of the guideline groups, the conduct and interpretation of systematic reviews, or the formulation of recommendations.

Prasanna Mithra (PM) received partial financial support from the Department of Nutrition for Health and Development, World Health Organization for this work.

B Unnikrishnan (BUK) received partial financial support from the Department of Nutrition for Health and Development, World Health Organization for this work.

Nithin Kumar (NK) received partial financial support from the Department of Nutrition for Health and Development, World Health Organization for this work.

Luz Maria De‐Regil (LMD) was a full‐time staff member of Nutrition International (formerly Micronutrient Initiative), an international not‐for‐profit organisation that delivers nutrition interventions to children, women of reproductive age and pregnant women. Nutrition International supports the implementation of large‐scale research projects on food fortification. None of them met the inclusion criteria of this review. Nutrition International is a partner of the Food Fortification Initiative and receives funds from the Canadian Department of Foreign Affairs. LMD was an Editor for the Cochrane Developmental, Psychosocial and Learning Problems Group.

Sreekumar Nair (SN) received partial financial support from the Department of Nutrition for Health and Development, World Health Organization for this work.

Maria Nieves Garcia‐Casal (MNG) is a scientist in the Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, which received financial resources from the Bill & Melinda Gates Foundation (2013‐2019); US Centers for Disease Control and Prevention (CDC) (2014‐2019); Nutrition International (2014‐2019) and USAID (2014‐2019). Donors do not fund specific guidelines and do not participate in any decision related to the guideline development process including the composition of policy questions, membership of the guideline groups, the conduct and interpretation of systematic reviews, or the formulation of recommendations.

Juan Antonio Solon (JAS) is president of the Nutrition Center of the Philippines, a non‐profit organisation working towards nutrition security (www.ncp.org.ph). He received partial financial support for this work. His involvement with the review was at the final stage where he helped with the interpretation of the results.

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