research paper on food fortification

• Nutritional Medicine
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• Food Fortification

Food Fortification: The Advantages, Disadvantages and Lessons from Sight and Life Programs

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Rice fortification: an emerging opportunity to contribute to the elimination of vitamin and mineral deficiency worldwide

Affiliation.

• 1 Centre for Health Innovation and Partnership, NSW Health Bldg 52B, Cumberland Hospital, 5, Fleet Street, North Parramatta, NSW 2151, Australia. [email protected]
• PMID: 23424896
• DOI: 10.1177/156482651203300410

Vitamin and mineral deficiencies are ranked among the top causes of poor health and disability in the world. These deficiencies damage developing brains, impair learning ability, increase susceptibility to infections, and reduce the work productivity of nations. Food fortification is a sustainable, cost-effective approach to reducing vitamin and mineral deficiency. As the staple food for an estimated 3 billion people, rice has the potential to fill an obvious gap in current fortification programs. In recent years, new technologies have produced fortified rice kernels that are efficacious in reducing vitamin and mineral deficiency. There are opportunities to fortify a significant share of rice that comes from large mills supplying centralized markets and national welfare programs in major rice-growing countries. The rice export markets, which handle 30 million MT of rice annually, also present a key fortification opportunity. The cost of fortifying rice is only 1.5% to 3% of the current retail price of rice. Countries that mandate rice fortification have the strongest evidence for achieving wide coverage and impact. The Rice Fortification Resource Group (RiFoRG), a global network of public and private partners that offers technical and advocacy support for rice fortification, has a vision of promoting rice fortification worldwide. It has a targeted approach, engaging multisector partners in key countries where the opportunities are greatest and there is receptivity to early adoption of large-scale rice fortification. The challenges are real, the imperative to address them is powerful, and the opportunities to deliver the promise of rice fortification are clear.

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Food fortification with multiple micronutrients: impact on health outcomes in general population

Vitamins and minerals are essential for growth and maintenance of a healthy body, and have a role in the functioning of almost every organ. Multiple interventions have been designed to improve micronutrient deficiency, and food fortification is one of them.

To assess the impact of food fortification with multiple micronutrients on health outcomes in the general population, including men, women and children.

Search methods

We searched electronic databases up to 29 August 2018, including the Cochrane Central Register of Controlled Trial (CENTRAL), the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register and Cochrane Public Health Specialised Register; MEDLINE; Embase, and 20 other databases, including clinical trial registries. There were no date or language restrictions. We checked reference lists of included studies and relevant systematic reviews for additional papers to be considered for inclusion.

Selection criteria

We included randomised controlled trials (RCTs), cluster‐RCTs, quasi‐randomised trials, controlled before‐after (CBA) studies and interrupted time series (ITS) studies that assessed the impact of food fortification with multiple micronutrients (MMNs). Primary outcomes included anaemia, micronutrient deficiencies, anthropometric measures, morbidity, all‐cause mortality and cause‐specific mortality. Secondary outcomes included potential adverse outcomes, serum concentration of specific micronutrients, serum haemoglobin levels and neurodevelopmental and cognitive outcomes. We included food fortification studies from both high‐income and low‐ and middle‐income countries (LMICs).

Data collection and analysis

Two review authors independently screened, extracted and quality‐appraised the data from eligible studies. We carried out statistical analysis using Review Manager 5 software. We used random‐effects meta‐analysis for combining data, as the characteristics of study participants and interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables, using the GRADE approach.

Main results

We identified 127 studies as relevant through title/abstract screening, and included 43 studies (48 papers) with 19,585 participants (17,878 children) in the review. All the included studies except three compared MMN fortification with placebo/no intervention. Two studies compared MMN fortification versus iodised salt and one study compared MMN fortification versus calcium fortification alone. Thirty‐six studies targeted children; 20 studies were conducted in LMICs. Food vehicles used included staple foods, such as rice and flour; dairy products, including milk and yogurt; non‐dairy beverages; biscuits; spreads; and salt. Fourteen of the studies were fully commercially funded, 13 had partial‐commercial funding, 14 had non‐commercial funding and two studies did not specify the source of funding. We rated all the evidence as of low to very low quality due to study limitations, imprecision, high heterogeneity and small sample size.

When compared with placebo/no intervention, MMN fortification may reduce anaemia by 32% (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.56 to 0.84; 11 studies, 3746 participants; low‐quality evidence), iron deficiency anaemia by 72% (RR 0.28, 95% CI 0.19 to 0.39; 6 studies, 2189 participants; low‐quality evidence), iron deficiency by 56% (RR 0.44, 95% CI 0.32 to 0.60; 11 studies, 3289 participants; low‐quality evidence); vitamin A deficiency by 58% (RR 0.42, 95% CI 0.28 to 0.62; 6 studies, 1482 participants; low‐quality evidence), vitamin B2 deficiency by 64% (RR 0.36, 95% CI 0.19 to 0.68; 1 study, 296 participants; low‐quality evidence), vitamin B6 deficiency by 91% (RR 0.09, 95% CI 0.02 to 0.38; 2 studies, 301 participants; low‐quality evidence), vitamin B12 deficiency by 58% (RR 0.42, 95% CI 0.25 to 0.71; 3 studies, 728 participants; low‐quality evidence), weight‐for‐age z‐scores (WAZ) (mean difference (MD) 0.1, 95% CI 0.02 to 0.17; 8 studies, 2889 participants; low‐quality evidence) and weight‐for‐height/length z‐score (WHZ/WLZ) (MD 0.1, 95% CI 0.02 to 0.18; 6 studies, 1758 participants; low‐quality evidence). We are uncertain about the effect of MMN fortification on zinc deficiency (RR 0.84, 95% CI 0.65 to 1.08; 5 studies, 1490 participants; low‐quality evidence) and height/length‐for‐age z‐score (HAZ/LAZ) (MD 0.09, 95% CI 0.01 to 0.18; 8 studies, 2889 participants; low‐quality evidence). Most of the studies in this comparison were conducted in children.

Subgroup analyses of funding sources (commercial versus non‐commercial) and duration of intervention did not demonstrate any difference in effects, although this was a relatively small number of studies and the possible association between commercial funding and increased effect estimates has been demonstrated in the wider health literature. We could not conduct subgroup analysis by food vehicle and funding; since there were too few studies in each subgroup to draw any meaningful conclusions.

When we compared MMNs versus iodised salt, we are uncertain about the effect of MMN fortification on anaemia (R 0.86, 95% CI 0.37 to 2.01; 1 study, 88 participants; very low‐quality evidence), iron deficiency anaemia (RR 0.40, 95% CI 0.09 to 1.83; 2 studies, 245 participants; very low‐quality evidence), iron deficiency (RR 0.98, 95% CI 0.82 to 1.17; 1 study, 88 participants; very low‐quality evidence) and vitamin A deficiency (RR 0.19, 95% CI 0.07 to 0.55; 2 studies, 363 participants; very low‐quality evidence). Both of the studies were conducted in children.

Only one study conducted in children compared MMN fortification versus calcium fortification. None of the primary outcomes were reported in the study.

None of the included studies reported on morbidity, adverse events, all‐cause or cause‐specific mortality.

Authors' conclusions

The evidence from this review suggests that MMN fortification when compared to placebo/no intervention may reduce anaemia, iron deficiency anaemia and micronutrient deficiencies (iron, vitamin A, vitamin B2 and vitamin B6). We are uncertain of the effect of MMN fortification on anthropometric measures (HAZ/LAZ, WAZ and WHZ/WLZ). There are no data to suggest possible adverse effects of MMN fortification, and we could not draw reliable conclusions from various subgroup analyses due to a limited number of studies in each subgroup. We remain cautious about the level of commercial funding in this field, and the possibility that this may be associated with higher effect estimates, although subgroup analysis in this review did not demonstrate any impact of commercial funding. These findings are subject to study limitations, imprecision, high heterogeneity and small sample sizes, and we rated most of the evidence low to very low quality. and hence no concrete conclusions could be drawn from the findings of this review.

Plain language summary

Impact of food fortification with multiple micronutrients on health

Review question Does multiple micronutrient fortification improve health?

Background Vitamins and minerals are important for growth and body functioning. Micronutrient deficiencies are common in many populations, and food fortification is one of the interventions to reduce the burden of micronutrient deficiencies and improve health in the general population. Food fortification involves adding micronutrients to processed foods. There have been studies with various single micronutrient fortification, dual micronutrient fortification and multiple micronutrient fortification, including zinc, iron, selenium, vitamin A, vitamin B complexes, vitamin C and vitamin E. We reviewed the evidence about the impact of food fortification with multiple micronutrients (MMNs) on health in the general population.

Study characteristics We included 43 studies (48 papers) in 19,585 participants (17,878 children) in this review. The evidence is current to August 2018. Most of the included studies assessed the impact of food fortification with MMN compared to placebo or to no intervention; two studies compared food fortification with MMN to iodised salt and one study compared food fortification with MMN to food fortification with calcium alone. Most of the studies (36 out of 43) targeted children. Twenty studies were conducted in developing countries. Food used for fortification included staple foods, such as rice and flour; dairy products, including milk and yogurt; non‐dairy beverages; biscuits; spreads; and salt. A high proportion of studies were funded by commercial sources (e.g. manufacturers of micronutrients), which can be associated with finding more beneficial effects than independently‐funded studies.

Key results Food fortification with MMN may reduce anaemia by 32%, iron deficiency anaemia by 72%, micronutrient deficiencies (including iron deficiency by 56%, vitamin A deficiency by 58%, vitamin B2 deficiency by 64%, vitamin B6 deficiency by 91% and vitamin B12 deficiency by 58%). MMN fortification may also improve child growth measured as weight for age and weight for height/length. We are uncertain of the effect of MMN fortification on zinc deficiency and child growth measured as height/length for age. The included studies did not report on any side effects associated with MMN fortification, including deaths and diseases. We are uncertain of the effect of food fortification with MMN compared to iodised salt for iron deficiency anaemia and vitamin A deficiency.

Quality of the evidence The quality of the evidence was low to very low, due to limitations in the study methods that could introduce a risk of bias, high heterogeneity (variation in the results from study to study), and small sample sizes.

Although the review suggests some positive effects of MMN fortification compared to no intervention, a number of other factors should also be considered. Firstly, there is no information on possible side effects of the MMN fortification. Secondly, we could not perform various subgroup analyses to identify whether MMN fortification is more effective in different population groups, food vehicles, dosage, duration of intervention and geographical region, due to limited number of studies in each subgroup. We performed a subgroup analysis to compare commercial and non‐commercially‐funded studies and did not find a significant difference between their results, although we remain cautious about these findings. Our results are uncertain, due to the low quality of the evidence.

Summary of findings

Description of the condition.

Vitamins and minerals are essential for growth and maintenance of a healthy body, and their deficiencies can lead to various diseases. Micronutrient deficiencies account for a substantial global burden of disease, with iron and vitamin A deficiency being among the 15 leading causes of global morbidity and mortality ( WHO 2002 ). Globally about 1.62 billion people are anaemic, with the highest prevalence among preschool children followed by pregnant women ( Benoist 2008 ). Iron, iodine, folate, vitamin A, and zinc deficiencies are the most widespread micronutrient deficiencies, and all of these are common contributors to poor growth, intellectual impairments, perinatal complications, and increased risk of morbidity and mortality ( Bailey 2015 ). In 2014, iron deficiency anaemia was one of the three most common causes of disability‐adjusted life years (DALYs) lost among adolescents along with other micronutrient deficiencies accounting for over 2500 DALYs per 100,000 adolescents ( Akseer 2017 ; WHO 2014 ). About 190 million preschool children and 19.1 million pregnant women are vitamin A‐deficient ( WHO 2009 ). Iodine and zinc deficiencies are estimated to affect 29% and 17% respectively of the world’s population ( Black 2013 ), with approximately 82% of pregnant women worldwide having inadequate zinc intake. Prevalence of suboptimal body stores of vitamins B6 and B12 have also been reported ( McLean 2008 ). Populations from developing countries are believed to be most affected, with multiple micronutrient (MMN) deficiencies frequently co‐existing among more than two billion people affected ( Bailey 2015 ; Best 2011 ; Dijkhuizen 2001 ; Ramakrishnan 2002 ; Stanger 2009 ).

Micronutrient deficiencies can result in impairments in mental and physical growth and development, and immune competence. They may also adversely affect reproductive outcomes ( Gibson 2002 ; Haimi 2014 ; Viteri 2002 ). MMN deficiencies are associated with increased incidence and severity of infectious illness and mortality from diarrhoea, measles, malaria and pneumonia ( Ibrahim 2017 ). In preschool children, zinc deficiency has been associated with an increased risk of diarrhoea, malaria and pneumonia, while vitamin A deficiency is associated with increased risk of mortality due to diarrhoea ( Black 2008 ; Black 2013 ). The prevalence of iron deficiency anaemia during pregnancy is a risk factor for maternal mortality ( Allen 2008 ).

Several strategies have been implemented to combat micronutrient deficiencies, including exclusive breastfeeding during the first six months of life, nutrition education, food rationing, control of parasitic infections and nutritional supplementation ( Bhutta 2008 ; Bhutta 2013 ). Food fortification is one of these strategies, in which a variety of micronutrient combinations can be added to foods, including zinc, iron, selenium, vitamin A, vitamin B complexes, vitamin C, vitamin D and vitamin E ( Allen 2006 ).

Description of the intervention

Food fortification adopts an integrated approach and provides support to reduce micronutrients malnutrition when other existing food supplies fail to do so ( Allen 2006 ). Food fortification is the process by which micronutrients are added to processed foods and has been applied at various levels and directed to different age groups ( De Lourdes Samaniego‐Vaesken 2012 ; Allen 2006 ). A range of micronutrient combinations has been used to fortify foods. There have been studies with various single micronutrient fortifications, dual micronutrient fortification and up to 20 micronutrient fortifications, including zinc, iron, selenium, vitamin A, vitamin B complexes, vitamin C and vitamin E. The advantage of fortification of food items consumed by the general population is that no or minimal behaviour change is required on the part of the population ( Serdula 2010a ; Serdula 2010b ). This provides an advantage in terms of coverage and efficiency. Food fortification could potentially also be cost‐effective, as it can be targeted at different age groups at a time ( Hurrell 1997 ; Lotfi 1996 ; Allen 2006 ). In contrast, supplementation depends upon a viable delivery mechanism and the availability and access to the intended individuals ( Harrison 2010 ). For fortification, however, issues related to safe and effective levels of micronutrients being used, the relevance of the micronutrients and appropriate food vehicle need to be considered ( Allen 2006 ; Allen 2008 ).

One of the issues concerning food fortification is that many of the these studies are funded by the manufacturers of fortified food products. The source of funding could be one of the biases in studies evaluating nutrition interventions if the researchers have a vested interest in the outcomes of the research. Industry‐funded research might skew the evidence towards solutions that favour industry interests by focusing on food components that can be manipulated and marketed by food companies ( Fabbri 2018 ). These concerns should therefore be explicitly evaluated when considering the evidence on food fortification.

How the intervention might work

Fortification could be mass fortification (that is, adding micronutrients to foods that are commonly consumed, such as flour, salt, sugar and cooking oil), or point‐of‐use fortification, which involves adding single‐dose packets of vitamins and minerals in powder form that can be sprinkled onto any ready‐to‐eat food consumed at home, school, nurseries, refugee camps or any other place where possible ( WHO 2014 ; Zlotkin 2005 ). For this review, we focus only on mass food fortification. Food fortification can combat micronutrient deficiencies at the population level at reasonable cost, making it a very efficient public health intervention.

Many trials have shown the positive impact of food fortification. Sazawal 2007 showed that milk fortified with multiple micronutrients reduced the odds for days with severe illnesses by 15% (95% confidence interval (CI) 5% to 24%), the incidence of diarrhoea by 18% (95% CI 7% to 27%) and the incidence of acute lower respiratory illness by 26% (95% CI 3% to 43%) in children. Another study by Osei 2010 reported improvement in vitamin A, vitamin B12, folate and total body iron status after fortification of school meals in a village in India. A review by Aaron 2015 reported a reduction in risk of anaemia (relative risk (RR) 0.58, 95% CI 0.29 to 0.88), iron deficiency (RR 0.34, 95%CI 0.21 to 0.55), and iron deficiency anaemia (RR 0.17, 95% CI 0.06 to 0.53) after use of fortified beverages in school‐aged children.

Concerns exist that food fortification may result in unacceptably high micronutrient levels among those consuming higher amounts of fortified foods. However, exceeding the upper intake level has not been shown to increase the risk of adverse effects, according to a review of data from national surveys conducted in European countries ( Hennessy 2013 ).

Why it is important to do this review

Several questions remain about the use of fortified foods. Many reviews to evaluate the use of fortified foods have suggested benefit, but usually focus on a particular food vehicle or a subset of the general population. A review by Eichler 2012 focused on MMN‐fortified dairy and cereal products delivered to pre‐school children in developing countries, and showed it to be effective in reducing anaemia. Das 2013 focused on the use of MMN‐fortified foods for women and children only. There is no evidence to suggest which combinations work best and whether certain combinations may work better with particular food vehicles. It is also unclear which population subgroups may derive the most benefit from these interventions and under what conditions.

This review serves as a comprehensive assessment of the effect of MMN fortification on the population as a whole, without being limited to certain age groups, regions or a particular food vehicle. Reviews of home or point‐of‐use fortification of food through micronutrient powders ( De‐Regil 2011 ; Salam 2013 ), and ready‐to‐use therapeutic food (RUTF) ( Schoonees 2019 ) already exist, and we have not focused on these areas.

To assess the impact of food fortification with MMNs on health outcomes in the general population, including men, women and children.

Criteria for considering studies for this review

Types of studies.

We have included:

• Randomised controlled trials (RCTs);
• Quasi‐randomised trials;
• Cluster‐RCTs (c‐RCTs);
• Controlled before‐after (CBA) studies;
• Interrupted time series (ITS) studies.

We intended to include quasi‐experimental study designs, CBA and ITS, along with RCTs, since we planned to assess the effectiveness of large‐scale programme evaluations that might not have been conducted in a randomised fashion. We applied no language or publication status restrictions.

Types of participants

We included studies that assess the effects of food fortification in the general population, including men, women and children. We also included studies that targeted fortification in specific populations (e.g. older people, pregnant women, women of reproductive age, and children at school through institutions such as schools or care facilities). We included studies from all countries, regardless of their level of income and development.

We excluded studies conducted among some special population groups, including critically‐ill people, anaemic people or people diagnosed with any specific diseases.

Types of interventions

Intervention: MMN fortification (three or more micronutrients) by any food vehicle, compared with a single micronutrient or no fortification.

We have not included studies evaluating point‐of‐use or home fortification of foods, therapeutic blended food or food supplementation.

Types of outcome measures

Primary outcomes.

• Anaemia (defined as haemoglobin (Hb) concentration < 11 g/dL)
• Iron‐deficiency anaemia (defined as Hb concentration < 11 g/dLwith serum ferritin < 15 µg/l)
• Deficiency of specific micronutrients (iron, zinc, vitamin A, B vitamins) (as defined by the World Health Organization (WHO) micronutrient deficiency cut‐offs)
• Anthropometric outcomes (e.g. incidence of stunting (defined as below minus two standard deviations from median height for age of reference population), wasting (defined as below minus two standard deviations from median weight for height of reference population) and underweight (defined as below minus two standard deviations from median weight for age of reference population)
• Morbidity (e.g. infectious diseases such as pneumonia, sepsis and diarrhoea)
• All‐cause mortality (defined as death due to any cause)
• Cause‐specific mortality (as defined by study authors) due to pneumonia, diarrhoea or malaria

Secondary outcomes

• Potential adverse outcomes (as defined by study authors)
• Serum haemoglobin levels (measured as g/dL)
• Serum concentration of specific micronutrients (folate, ferritin, vitamin A, B vitamins, zinc)
• Neuro‐developmental and cognitive outcomes

Search methods for identification of studies

Electronic searches.

We searched the following electronic databases for primary studies, without date or language restrictions. We conducted the final search on 29 August 2018.

• Cochrane Central Register of Controlled Trials (CENTRAL; 2018), in the Cochrane Library, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register and Cochrane Public Health Specialised Register (searched 29 August 2018);
• MEDLINE and MEDLINE(R) In‐Process; and Other Non‐Indexed Citations Ovid (searched 29 August 2018);
• PubMed for the most recent six months to identify records that are 'Epub ahead of print'; (searched 29 August 2018);
• Embase Ovid (1974 to August 2018) (searched 29 August 2018);
• Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus EBSCOhost; 1937 to August 2018 (searched 29 August 2018);
• PsycINFO (www.apa.org/pubs/databases/index; searched 30 August 2018);
• Education Resources Information Center (ERIC) (eric.ed.gov/ searched 22 August 2018);
• Latin American and Caribbean Health Sciences Literature (LILACS); (lilacs.bvsalud.org/en; searched 29 August 2018);
• AGRIS (aims.fao.org/search/node searched 30 August 2018);
• Science Citation Index and Social Sciences Citation Index Web of Science (SCI and SSCI; 1970 to August 2018);
• Food Science and Technology Abstracts (www.ebsco.com/products/research‐databases/fsta‐food‐science‐and‐technology‐abstracts searched 31 August 2018);
• AgriCOLA (agricola.nal.usda.gov/; searched 28 August 2018);
• Global Index Medicus ‐ AFRO (indexmedicus.afro.who.int/ searched 31 August 2018);
• EMRO (www.emro.who.int/index.html searched 31 August 2018);
• Pan American Health library (PAHO)/WHO Institutional Repository for Information Sharing (iris.paho.org/xmlui; searched 30 August 2018);
• WHOLIS Global Index Medicus (WHO Library Database; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 29 August 2018);
• WPRO (https://www.who.int/library/databases/wpro/en/ searched 29 August 2018);
• Global Index Medicus (Index Medicus for the South‐East Asian Region; IMSEAR) (search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 31 August 2018);
• 3ie Database of Impact studies (www.3ieimpact.org/evidence‐hub/impact‐evaluation‐repository; searched 29 August 2018);
• EPPI centre databases ‐ DoPHER (eppi.ioe.ac.uk/webdatabases4/Intro.aspx?ID=9 ) and TROPHI (eppi.ioe.ac.uk/webdatabases4/Intro.aspx?ID=12) searched 29 August 2018;
• OpenGrey (www.opengrey.eu/ searched 30 August 2018);
• Index to Conference Proceedings (mjl.clarivate.com/scope/scope_cpci‐s/ searched 30 August 2018);
• ClinicalTrials.gov (clinicaltrials.gov/), and WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/en/) (searched 30 August 2018).

We adapted the MEDLINE search strategy ( Appendix 1 ) for use in the other databases using the appropriate controlled vocabulary as applicable ( Appendix 2 ; Appendix 3 ; Appendix 4 ; Appendix 5 ; Appendix 6 ). We handsearched the journals and the proceedings of major relevant conferences relating to food and nutrition, including Micronutrient Forum, Nutrition and Food Sciences and Hidden Hunger. We also handsearched the journals in which the included studies appeared most frequently. We searched the top five journals (according to the number of included studies provided) for the previous 12 months.

Searching other resources

We checked the reference lists of included studies and relevant systematic reviews for additional papers to consider for inclusion.

Selection of studies

Two review authors (SBM and KM) independently assessed all the studies identified potentially for inclusion. We resolved any disagreement through discussion or, if required, consulted a third review author (RAS or JKD).

Data extraction and management

We designed a form for the extraction of data. Two of the review authors (from SBM, AM, ZL, KM and RK) extracted the data from each eligible study using the agreed form. We resolved discrepancies through discussion or, when required, consulted a third review author (JKD or RAS). We entered data into Review Manager 5 ( RevMan 2014 ), and checked them for accuracy by double data entry (SBM, ZL and RAS), having one review author entering data into a separate file and comparing the results. For the studies that reported outcomes at multiple time points, we extracted data for each time point and reported the outcomes at the last reported time period.

We used the PROGRESS checklist (place, race, occupation, gender, religion, education, socioeconomic status, social status) ( O’Neill 2014 ; Welch 2016 ) to record whether outcome data were reported by socio‐demographic characteristics known to be important from an equity perspective. We also recorded whether studies included specific strategies to address diversity or disadvantage. Where available, we extracted data on costs and process/implementation and source of funding of the primary studies. These details are presented in the Characteristics of included studies tables.

Assessment of risk of bias in included studies

Two review authors (from SBM, RAS, JKD and RK) independently assessed risks of bias (RoB) for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2017 ), with the exception that we conducted 'Risk of bias' assessments at the level of each study, and not for individual outcomes. We used the Cochrane Effective Practice and Organisation of Care ( EPOC 2017 ) nine‐point criteria for non‐RCTs and CBA studies to determine the quality of all eligible studies. We did not find any eligible studies using an ITS study design. We resolved any disagreement by discussion or by involving a third assessor. We report the risks of bias for each study in the Characteristics of included studies table. We did not exclude studies on the grounds of their quality, but clearly report methodological quality when presenting the results of the studies.

Random sequence generation (checking for possible selection bias)

We have described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We have assessed the methods as: • low risk of bias (any truly random process, e.g. random‐number table, computer random‐number generator); • high risk of bias (any non‐random process, e.g. odd or even date of birth, hospital or clinic record number); • unclear risk of bias.

Allocation concealment (checking for possible selection bias)

We have described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment. We have assessed the methods as: • low risk of bias (e.g. telephone or central randomisation, consecutively‐numbered sealed opaque envelopes); • high risk of bias (open random allocation, unsealed or non‐opaque envelopes, alternation, date of birth); • unclear risk of bias.

Blinding of participants and personnel (checking for possible performance bias)

We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We have considered that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We have assessed blinding separately for different outcomes or classes of outcomes. We have assessed the methods as: • low, high or unclear risk of bias for participants; • low, high or unclear risk of bias for personnel.

Blinding of outcome assessment (checking for possible detection bias)

We have described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We have assessed blinding separately for different outcomes or classes of outcomes. We have assessed methods used to blind outcome assessment as: • low, high or unclear risk of bias.

Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We have stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We considered studies with more than 20% loss to follow‐up, or with an imbalanced loss to follow‐up in different groups, to have insufficient completeness of outcome data. We also looked at the amount and distribution across intervention groups and the reasons for outcomes being missing. Where sufficient information was reported, or was supplied by the trial authors, we have re‐included missing data in the analyses which we undertook. We assessed methods as: • low risk of bias (e.g. no or minimal missing outcome data, missing outcome data balanced across groups); • high risk of bias (e.g. numbers or reasons for missing data imbalance across groups, ’as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation); • unclear risk of bias.

Selective reporting (checking for reporting bias)

We have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We have assessed the methods as: • low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported); • high risk of bias (where not all the study’s prespecified outcomes have been reported, one or more reported primary outcomes were not prespecified, outcomes of interest are reported incompletely and so cannot be used, study fails to include results of a key outcome that would have been expected to have been reported); • unclear risk of bias.

We have described for each included study any important concerns we have about other possible sources of bias. We have assessed whether each study was free of other problems that could put it at risk of bias: • low risk of other bias; • high risk of other bias; • unclear whether there is a risk of other bias.

Additional criteria for cluster‐RCTs

We assessed and report five additional criteria for all the included c‐RCTs in the section of 'Other bias' in the RoB table. These are recruitment bias; baseline imbalance; loss of clusters; incorrect analysis; and comparability with individually randomised trials.

Recruitment bias

We have assessed whether the individuals were recruited to the trial after the clusters have been randomised. We have assessed the methods as:

• low, high or unclear risk of bias.

Baseline imbalance

We have assessed the reporting of the baseline comparability of clusters, or statistical adjustment for baseline characteristics. We have assessed the methods as:

Loss of clusters

we have assessed whether there was any loss of complete clusters or omission of complete clusters from the analysis. We have assessed the methods as:

Incorrect analysis

We have assessed whether appropriate analysis has been conducted for adjusting the clustering. We have assessed the methods as:

Comparability with individually randomised trial

We assessed the possible differences between the intervention effects in individually‐randomised and cluster‐randomised trails. We have assessed the methods as:

Overall risk of bias

We have made explicit judgments about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2017 ). We assessed the likely magnitude and direction of the bias and whether we considered it likely to have had an impact on the findings. We judged the studies to be at overall high risk of bias if they were at high or unclear risk for any of the four criteria of allocation concealment, blinding of participants and personnel, blinding of outcome assessment or incomplete outcome data. We explored the impact of the level of bias by conducting sensitivity analyses for those studies with high or unclear risk of bias in any of the above four domains i.e. according to the method and adequacy of allocation concealment; blinding status of the participants/personnel and outcome assessor; or percentage lost to follow‐up or attrition of 20% or more, or with an imbalanced loss to follow‐up in different groups.

Measures of treatment effect

Dichotomous data.

For dichotomous data, we present results as a summary risk ratio (RR) with a 95% confidence interval (CI).

Continuous data

For continuous data, we have used the mean difference (MD) if outcomes were measured in the same way between trials. We would have used the standardised mean difference (SMD) to combine trials that measured the same outcome but with different methods. Where the studies reported change in continuous outcomes and did not report endline values, we combined these data using the MD.

Unit of analysis issues

Cluster‐randomised trials.

We have included cluster‐randomised trials in the analyses along with individually‐randomised trials. We used cluster‐adjusted estimates from c‐RCTs where available. If the studies had not adjusted for clustering, we attempted to adjust their standard errors using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2019 ), using an estimate of the intra‐cluster correlation coefficient (ICC) derived from the trial. If the trial did not report the cluster‐adjusted estimated or the ICC, we imputed an ICC from a similar study included in the review, adjusting if the nature or size of the clusters was different (e.g. households compared to classrooms). We assessed any imputed ICCs using sensitivity analysis. We considered it reasonable to combine the results from both if there was little heterogeneity between the study designs and if we considered the interaction between the effect of intervention and the choice of randomisation unit to be unlikely. We have also acknowledged heterogeneity in the randomisation unit and performed a subgroup analysis to investigate the effects of the randomisation unit.

Studies with more than two treatment groups

When we identified studies with more than two intervention groups (multi‐arm studies), 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 ( Higgins 2019 ) to avoid double‐counting study participants. For the subgroup analyses, when the control group was shared by two or more study arms, we divided the control group (events and total population) over the number of relevant subgroups to avoid double‐counting the participants.

Dealing with missing data

We have described missing data, including dropouts. Differential dropout rates can lead to biased estimates of the effect size, and bias may arise if the reasons for dropping out differ across groups. We have reported the reasons for dropout. If data were missing for some cases, or if the reasons for dropping out were not reported, we have contacted the authors. For included studies, we have noted levels of attrition. We have explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. For all outcomes, we have carried out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed the included studies for clinical, methodological, and statistical heterogeneity. We assessed clinical heterogeneity by comparing the distribution of important factors, such as the study participants, study setting, dose and duration of the intervention and co‐interventions. We evaluated methodological heterogeneity on the basis of factors such as the method of sequence generation, allocation concealment, blinding of outcome assessment, and losses to follow‐up. We have assessed statistical heterogeneity in each meta‐analysis using the T 2 , I 2 and Chi 2 statistics. We regard heterogeneity as substantial if I 2 was greater than 30% and either T 2 was greater than zero, or there was a low P value (< 0.10) in the Chi 2 test for heterogeneity.

Assessment of reporting biases

If there were 10 or more studies in the meta‐analysis we investigated reporting biases (such as publication bias) using funnel plots. We have assessed funnel plot asymmetry visually, and if asymmetry was visually apparent in any of the plots, we attempted to investigate it through sensitivity analysis (where possible) and compared the random‐effects with the fixed‐effect model. We considered non‐reporting bias as one of the possible explanations of the funnel plot asymmetry.

Data synthesis

We carried out the statistical analysis using the Review Manager 5 software. We categorised the studies into the following three comparisons:

• MMN fortification versus placebo or no intervention;
• MMN fortification versus iodised salt;
• MMN fortification versus calcium only fortification.

We used random‐effects meta‐analysis for combining data, as the characteristics of study participants and interventions differed significantly. We present the results as the average treatment effect with a 95% confidence interval, and the estimates of T 2 and I 2 . We used the Mantel‐Haenszel method for dichotomous data, the inverse variance for continuous data and generic Inverse variance for synthesis including data originating from c‐RCTs. We synthesised the findings from the RCTs and c‐RCTs together but did not pool non‐randomised studies, as we judged them to be too few in number. We have reported the findings from the non‐randomised studies separately.

GRADE and 'Summary of findings' tables

We have set out the findings of the primary outcomes in 'Summary of findings' tables, prepared using the GRADE approach ( Guyatt 2008 ) and using GRADE profiler software ( GRADEpro ). We have listed the outcomes for each comparison with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, we assessed the quality of the evidence using the GRADE approach, which involves consideration of within‐study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. We have rated the quality of the body of evidence for each key outcome as high, moderate, low or very low. We present these findings according to the standardised language adapted from Glenton 2010 .

Subgroup analysis and investigation of heterogeneity

We have conducted subgroup analyses on the basis of the following, where data permitted (where there were at least three studies in each subgroup):

• population (children, women of reproductive age, adults)
• baseline micronutrient status (malnourished, normal)
• various combination of MMNs (e.g. different numbers and types of micronutrients used)
• low‐to‐middle income countries versus high‐income countries
• duration of intervention (zero to six months, six to 12 months, more than 12 months)
• food vehicle used for fortification
• studies with and without commercial funding

We assessed differences between subgroups by interaction tests, and by inspection of the subgroups' CIs; non‐overlapping CIs indicate a statistically significant difference in treatment effect between the subgroups. Inferences for clinical relevance were based on these subgroup analyses, where possible. This ensured that the review's conclusions considered specific contextual factors in relation to food vehicle, target population and dose, among others.

Sensitivity analysis

We performed sensitivity analyses to examine the effect of removing studies at high overall risk of bias (those with high or unclear risk of bias according to the method and adequacy of allocation concealment, blinding status of the participants, or percentage lost to follow‐up, or attrition of 20% or more, or with an imbalanced loss to follow‐up in different groups).

Description of studies

See Characteristics of included studies ; Characteristics of excluded studies ; Additional tables.

Results of the search

We identified 5789 records, of which we screened 126 full texts and included 43 studies (from 48 papers) with 19,585 participants (17,878 children) in the review ( Figure 1 ).

Study flow diagram showing results of the literature search.

Included studies

Types of studies We include 43 studies which meet the eligibility criteria. Most of the included studies (39) were RCTs, of which six studies were c‐RCTs ( DeGier 2016 ; Liu 1993 ; Perignon 2016 ; Rahman 2015 ; Vinodkumar 2009 ; Wang 2017 ). There were four CBA studies ( Abrams 2003 ; Adams 2017 ; Azlaf 2017 ; Mardones 2007 ).

Participants and Settings

Thirty‐six of the studies were conducted among children. Most of these (29) were conducted among pre‐school and school‐aged children ( Aaron 2011 ; Abrams 2003 ; Adams 2017 ; Ash 2003 ; Azlaf 2017 ; DeGier 2016 ; Economos 2014 ; Hieu 2012 ; Hyder 2007 ; Jinabhai 2001 ; Lopriore 2004 ; Nga 2009 ; Osendarp 2007 ; Perignon 2016 ; Petrova 2019 ; Pinkaew 2013 ; Pinkaew 2014 ; Powers 2016 ; Rahman 2015 ; Sazawal 2013 ; Solon 2003 ; Taljaard 2013 ; Thankachan 2012 ; Thankachan 2013 ; Van Stuijvenberg 1999 ; Vaz 2011 ; Vinodkumar 2009 ; Wang 2017 ; Zimmerman 2004 ). Four studies included infants aged from six months to 12 months ( Faber 2005 ; Gibson 2011 ; Liu 1993 ; Oelofse 2003 ), and three studies included children aged one to three years ( Nesamvuni 2005 ; Sazawal 2007 ; Villalpando 2006 ). Three studies targeted pregnant women ( Järvenpaa 2007 ; Mardones 2007 ; Tatala 2002 ), three studies targeted adults ( Tapola 2004 ; Tucker 2004 ; Van het Hof 1998 ), while one study targeted an elderly population aged over 70 years ( Chin A Paw 2000 ).

Twenty studies were conducted in lower‐middle income‐countries (LMICs) ( Aaron 2011 ; Adams 2017 ; Ash 2003 ; Azlaf 2017 ; DeGier 2016 ; Gibson 2011 ; Hieu 2012 ; Hyder 2007 ; Nga 2009 ; Perignon 2016 ; Rahman 2015 ; Sazawal 2007 ; Sazawal 2013 ; Solon 2003 ; Tatala 2002 ; Thankachan 2012 ; Thankachan 2013 ; Vaz 2011 ; Vinodkumar 2009 ; Zimmerman 2004 ), 13 in upper‐middle‐income countries (UMICs) ( Abrams 2003 ; Faber 2005 ; Jinabhai 2001 ; Liu 1993 ; Lopriore 2004 ; Nesamvuni 2005 ; Oelofse 2003 ; Pinkaew 2013 ; Pinkaew 2014 ; Taljaard 2013 ; Van Stuijvenberg 1999 ; Villalpando 2006 ; Wang 2017 ) and nine in high‐income countries (HICs) ( Chin A Paw 2000 ; Economos 2014 ; Järvenpaa 2007 ; Mardones 2007 ; Petrova 2019 ; Powers 2016 ; Tapola 2004 ; Tucker 2004 ; Van het Hof 1998 ). One trial was conducted in both LMICs and HICs ( Osendarp 2007 ).

We conducted a descriptive analysis of the PROGRESS‐Plus factors reported by included trials. We present an account of this analysis in Table 3 . Most trials did not directly report on these factors. The analysis suggests that equity‐related variables and analysis are commonly overlooked by trials, thus affecting the generation of evidence on how inequities are identified and how interventions can contribute to mitigate or reduce them. We present all PROGRESS‐Plus factors reported by the included trials in Table 4 .

HIC: high‐income countries; LMIC: low middle income countries

BMI: body mass index; BP: blood pressure; HIC: high‐income country; LIC: low‐income country; LMIC: low middle income country; MUAC: mid‐upper arm circumference; SES: socio‐economic status; UMIC: upper middle‐income country

Duration of Intervention

The duration of intervention varied from a minimum of eight weeks to a maximum of one year. The duration of intervention in 29 studies was six months or less ( Aaron 2011 ; Abrams 2003 ; Ash 2003 ; Chin A Paw 2000 ; DeGier 2016 ; Economos 2014 ; Faber 2005 ; Hieu 2012 ; Järvenpaa 2007 ; Jinabhai 2001 ; Liu 1993 ; Lopriore 2004 ; Nga 2009 ; Oelofse 2003 ; Perignon 2016 ; Petrova 2019 ; Pinkaew 2013 ; Pinkaew 2014 ; Powers 2016 ; Rahman 2015 ; Solon 2003 ; Tapola 2004 ; Tatala 2002 ; Thankachan 2012 ; Thankachan 2013 ; Tucker 2004 ; Vaz 2011 ; Villalpando 2006 ; Wang 2017 ), while in 14 studies the duration of intervention was between six months and one year ( Adams 2017 ; Azlaf 2017 ; Gibson 2011 ; Hyder 2007 ; Mardones 2007 ; Nesamvuni 2005 ; Osendarp 2007 ; Sazawal 2007 ; Sazawal 2013 ; Taljaard 2013 ; Van het Hof 1998 ; Van Stuijvenberg 1999 ; Vinodkumar 2009 ; Zimmerman 2004 ).

Food vehicles

Food vehicles used included staple food, such as rice and flour ( DeGier 2016 ; Faber 2005 ; Gibson 2011 ; Nesamvuni 2005 ; Oelofse 2003 ; Perignon 2016 ; Pinkaew 2013 ; Pinkaew 2014 ; Powers 2016 ; Rahman 2015 ; Thankachan 2012 ; Tucker 2004 ), dairy products, including milk and yogurt ( Azlaf 2017 ; Chin A Paw 2000 ; Mardones 2007 ; Petrova 2019 ; Sazawal 2007 ; Sazawal 2013 ; Van het Hof 1998 ; Villalpando 2006 ; Wang 2017 ), non‐dairy beverages ( Aaron 2011 ; Abrams 2003 ; Ash 2003 ; Economos 2014 ; Hyder 2007 ; Järvenpaa 2007 ; Osendarp 2007 ; Solon 2003 ; Taljaard 2013 ; Tapola 2004 ; Tatala 2002 ; Thankachan 2013 ; Vaz 2011 ), biscuits ( Adams 2017 ; Hieu 2012 ; Jinabhai 2001 ; Liu 1993 ; Nga 2009 ; Van Stuijvenberg 1999 ), spreads ( Lopriore 2004 ), and salt ( Vinodkumar 2009 ; Zimmerman 2004 ). Outcomes

Anaemia, micronutrient deficiencies, anthropometric measures and serum micronutrient levels were the most commonly reported outcomes. Eight studies reported neuro‐cognitive outcomes in children ( Faber 2005 ; Nga 2009 ; Osendarp 2007 ; Taljaard 2013 ; Thankachan 2012 ; Van Stuijvenberg 1999 ; DeGier 2016 ; Petrova 2019 ). None of the included studies reported on morbidity, adverse events, or all‐cause or cause‐specific mortality.

Fourteen of the included studies were fully commercially funded ( Ash 2003 ; Economos 2014 ; Järvenpaa 2007 ; Mardones 2007 ; Osendarp 2007 ; Petrova 2019 ; Powers 2016 ; Sazawal 2007 ; Taljaard 2013 ; Tapola 2004 ; Thankachan 2012 ; Thankachan 2013 ; Van Stuijvenberg 1999 ; Vaz 2011 ); 13 of the included studies had partial commercial funding ( Aaron 2011 ; Abrams 2003 ; Chin A Paw 2000 ; Faber 2005 ; Gibson 2011 ; Hyder 2007 ; Jinabhai 2001 ; Nesamvuni 2005 ; Pinkaew 2013 ; Pinkaew 2014 ; Solon 2003 ; Tatala 2002 ; Tucker 2004 ); 14 studies were non‐commercially funded ( Adams 2017 ; Azlaf 2017 ; Hieu 2012 ; Liu 1993 ; Rahman 2015 ; Villalpando 2006 ; DeGier 2016 ; Lopriore 2004 ; Nga 2009 ; Perignon 2016 ; Vinodkumar 2009 ; Zimmerman 2004 ; Sazawal 2013 ; Wang 2017 ), while two studies ( Van het Hof 1998 ; Oelofse 2003 ) did not specify the source of funding.

Excluded studies

We excluded 78 studies at full‐text screening. Common reasons for exclusion included point‐of‐use fortification, a pre‐post design without a control group, no outcomes of interest, and supplementation rather than fortification. See Characteristics of excluded studies for a full list of reasons for exclusion.

Risk of bias in included studies

See Figure 2 ; Figure 3 for the 'Risk of bias' summary and graph.

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

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

Of the 39 included RCTs, we considered five to be at overall low risk of bias ( Perignon 2016 ; Petrova 2019 ; Rahman 2015 ; Sazawal 2007 ; Vaz 2011 ) , and the remaining 34 to be at overall high risk of bias, due to concerns around allocation concealment, blinding of participants, or incomplete outcome data.

We judged 18 studies to be at a low risk for random sequence generation ( DeGier 2016 ; Economos 2014 ; Faber 2005 ; Gibson 2011 ; Hieu 2012 ; Lopriore 2004 ; Nga 2009 ; Osendarp 2007 ; Perignon 2016 ; Petrova 2019 ; Rahman 2015 ; Sazawal 2007 ; Sazawal 2013 ; Tatala 2002 ; Thankachan 2012 ; Thankachan 2013 ; Vaz 2011 ; Wang 2017 ); we judged one study to be at high risk of bias for sequence generation ( Zimmerman 2004 ), while the rest were at unclear risk of bias.

We rated nine studies at a low risk for allocation concealment ( Chin A Paw 2000 ; DeGier 2016 ; Hieu 2012 ; Perignon 2016 ; Petrova 2019 ; Rahman 2015 ; Sazawal 2007 Sazawal 2013 ; Vaz 2011 ), one study at high risk of bias for allocation concealment ( Wang 2017 ), while the rest were at unclear risk of bias.

We judged 24 studies to be at low risk of bias for blinding of participants and personnel ( Aaron 2011 ; Ash 2003 ; DeGier 2016 ; Economos 2014 ; Gibson 2011 ; Hieu 2012 ; Hyder 2007 ; Lopriore 2004 ; Nga 2009 ; Osendarp 2007 ; Perignon 2016 ; Petrova 2019 ; Powers 2016 ; Rahman 2015 ; Sazawal 2007 ; Sazawal 2013 ; Solon 2003 ; Taljaard 2013 ; Thankachan 2012 ; Thankachan 2013 ; Van Stuijvenberg 1999 ; Vaz 2011 ; Villalpando 2006 ; Zimmerman 2004 ), four studies at high risk of bias for blinding of participants and personnel ( Chin A Paw 2000 ; Oelofse 2003 ; Van het Hof 1998 ; Wang 2017 ), while rest were at unclear risk of bias.

We rated 23 studies were at low risk of bias for blinding of outcome assessment ( Aaron 2011 ; Ash 2003 ; DeGier 2016 ; Economos 2014 ; Gibson 2011 ; Hieu 2012 ; Hyder 2007 ; Lopriore 2004 ; Nga 2009 ; Osendarp 2007 ; Perignon 2016 ; Petrova 2019 ; Powers 2016 ; Rahman 2015 ; Sazawal 2007 ; Sazawal 2013 ; Solon 2003 ; Thankachan 2012 ; Thankachan 2013 ; Van het Hof 1998 ; Vaz 2011 ; Villalpando 2006 ; Zimmerman 2004 ), four studies at high risk of bias for blinding of outcome assessment ( Chin A Paw 2000 ; Nesamvuni 2005 ; Oelofse 2003 ; Wang 2017 ), while the rest were at unclear risk of bias.

Incomplete outcome data

As the studies involved significant lifestyle changes and were carried out over a period of many weeks and months, dropouts were present, but these were either comparable in the different trial arms, or few and addressed and accounted for. We rated 26 studies at low risk of attrition bias ( Aaron 2011 ; Ash 2003 ; Faber 2005 ; Hyder 2007 ; Järvenpaa 2007 ; Nga 2009 ; Perignon 2016 ; Petrova 2019 ; Pinkaew 2013 ; Pinkaew 2014 ; Powers 2016 ; Rahman 2015 ; Sazawal 2007 ; Solon 2003 ; Taljaard 2013 ; Tapola 2004 ; Thankachan 2012 ; Thankachan 2013 ; Tucker 2004 ; Van het Hof 1998 ; Van Stuijvenberg 1999 ; Vaz 2011 ; Villalpando 2006 ; Vinodkumar 2009 ; Wang 2017 ; Zimmerman 2004 ), 12 studies at high risk of attrition bias ( Chin A Paw 2000 ; DeGier 2016 ; Economos 2014 ; Gibson 2011 ; Hieu 2012 ; Liu 1993 ; Lopriore 2004 ; Nesamvuni 2005 ; Oelofse 2003 ; Osendarp 2007 ; Sazawal 2013 ; Tatala 2002 ), while one study ( Jinabhai 2001 ) was rated at unclear risk of bias.

Selective reporting

Most of the studies did not report trial registration details, but in most cases the outcomes discussed in the paper were reported. We judged only one study ( DeGier 2016 ) to be at high risk for selective reporting, since it was powered to assess the micronutrient status but this outcome was not reported in the paper. There was a very minimal risk of reporting bias in the studies and generally we did not detect selective reporting. None of the included studies mentioned or reported on adverse effects.

Other potential sources of bias

We rated all studies at low risk for other potential bias.

For the six c‐RCTs ( DeGier 2016 ; Liu 1993 ; Perignon 2016 ; Rahman 2015 ; Vinodkumar 2009 ; Wang 2017 ), we have assessed and reported additional criteria. We found all six c‐RCTs to be at low risk for recruitment bias, baseline imbalance, loss of clusters, incorrect analysis, and for comparability with individually‐randomised trials.

Risk of bias for CBA

Four studies ( Abrams 2003 ; Adams 2017 ; Azlaf 2017 ; Mardones 2007 ) were assessed on additional criteria based on EPOC 2017 , since these were CBA studies.

We judged all four studies to be at high risk for random sequence generation, allocation concealment and knowledge of the allocated interventions adequately prevented during the study; we rated Mardones 2007 at high risk for incomplete outcome data, while all studies were at low risk for all other criteria, including baseline outcome measurements, baseline characteristics, incomplete outcome data, protection against contamination and selective outcome reporting. We found no other sources of bias.

Risk of bias for CBA studies are reported under the 'Other Bias' section of their respective 'Risk of bias' table.

Effects of interventions

See: Table 1 ; Table 2

for the main comparison

a Assumed risk is the mean of the post‐intervention values in the control groups in the included studies. b Downgraded by one level due to study limitations including lack of randomisation, blinding and attrition. c Downgraded by one level due to high heterogeneity (I 2 > 30%). d Downgraded by one level due to imprecision.

a Assumed risk taken from post‐intervention value in the iodised salt group of a single included study. b Downgraded by one level due to study limitations including lack of randomisation, blinding and attrition. c Downgraded by two levels due to serious imprecision, including small sample size. d Assumed risk is the mean of the post‐intervention values in the iodised salt groups in the included studies.

Comparison 1: Multiple micronutrient fortification versus placebo/no intervention

Forty studies compared MMN fortification with placebo or no intervention ( Aaron 2011 ; Abrams 2003 ; Adams 2017 ; Ash 2003 ; Azlaf 2017 ; Chin A Paw 2000 ; DeGier 2016 ; Faber 2005 ; Gibson 2011 ; Hieu 2012 ; Hyder 2007 ; Järvenpaa 2007 ; Jinabhai 2001 ; Liu 1993 ; Lopriore 2004 ; Mardones 2007 ; Nesamvuni 2005 ; Nga 2009 ; Oelofse 2003 ; Osendarp 2007 ; Perignon 2016 ; Petrova 2019 ; Pinkaew 2013 ; Pinkaew 2014 ; Powers 2016 ; Rahman 2015 ; Sazawal 2007 ; Sazawal 2013 ; Solon 2003 ; Taljaard 2013 ; Tapola 2004 ; Tatala 2002 ; Thankachan 2012 ; Thankachan 2013 ; Tucker 2004 ; Van het Hof 1998 ; Van Stuijvenberg 1999 ; Vaz 2011 ; Villalpando 2006 ; Wang 2017 ). Of these, Mardones 2007 did not measure any of the outcomes included in this review.

Primary Outcomes

Among the primary outcomes, included studies reported anaemia, micronutrient deficiencies (iron, zinc, vitamin A, B vitamins) and anthropometric outcomes (weight‐for‐age z‐score (WAZ), height/length‐for‐age z‐score (HAZ/LAZ) and weight‐for‐height/length z‐score (WHZ/WLZ)). None of the included studies reported morbidity, all‐cause mortality or cause‐specific mortality.

Anaemia: Pooled study results

MMN fortification may reduce anaemia by 32% when compared to placebo/no intervention (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.56 to 0.84; I 2 = 61%; 11 studies, 3746 participants; low‐quality evidence; Analysis 1.1 ; Figure 4 ).

Forest plot of comparison: 1 MMN vs Placebo/No intervention, outcome: 1.1 Anaemia.

Comparison 1 MMN vs placebo/no intervention, Outcome 1 Anaemia.

Findings from Abrams 2003 and Adams 2017 were not pooled with the meta‐analysis since these were non‐randomised studies. Both Adams 2017 and Abrams 2003 reported reduced anaemia in the intervention group compared to the control group (RR 0.67, 95% CI 0.41 to 0.93 and OR 0.48, 95% CI 0.27 to 0.87, respectively).

Iron deficiency anaemia: Pooled study results

MMN fortification may reduce the prevalence of iron deficiency anaemia by 72% (RR 0.28, 95% CI 0.19 to 0.39; I 2 = 19%; 6 studies, 2189 participants; low‐quality evidence; Analysis 1.2 ; Figure 5 ).

Forest plot of comparison: 1 MMN vs Placebo, outcome: 1.2 Iron deficiency anaemia.

Comparison 1 MMN vs placebo/no intervention, Outcome 2 Iron deficiency anaemia.

Micronutrient deficiencies: Pooled study results

MMN fortification may reduce micronutrient deficiencies including iron deficiency by 56% (RR 0.44; 95% CI 0.32 to 0.60; I 2 = 54%; 11 studies, 3289 participants; low‐quality evidence; Analysis 1.3 ; Figure 6 ); vitamin A deficiency by 58% (RR 0.42, 95% CI 0.28 to 0.62; I 2 = 31%; 6 studies, 1482 participants; low‐quality evidence; Analysis 1.4 ; Figure 7 ); vitamin B2 deficiency by 64% (RR 0.36, 95% CI 0.19 to 0.68; 1 study, 296 participants; low‐quality evidence; Analysis 1.5 ); vitamin B6 deficiency by 91% (RR 0.09, 95% CI 0.02 to 0.38; I 2 = 0%; 2 studies, 301 participants; low‐quality evidence; Analysis 1.5 ) and vitamin B12 deficiency by 58% (RR 0.42, 95% CI 0.25 to 0.71; I 2 = 0%; 3 studies; n = 728; moderate‐quality evidence; Analysis 1.5 ). We are uncertain of the effect of MMN fortification on zinc deficiency (RR 0.84, 95% CI 0.65 to 1.08; I 2 = 74%: 5 studies, 1490 participants; very low‐quality evidence; Analysis 1.6 ; Figure 8 ).

Forest plot of comparison: 1 MMN vs placebo/no intervention, outcome: 1.3 Micronutrient deficiencies: Iron.

Forest plot of comparison: 1 MMN vs placebo/no intervention, outcome: 1.4 Micronutrient deficiencies: Vitamin A.

Forest plot of comparison: 1 MMN vs placebo/no intervention, outcome: 1.6 Micronutrient deficiencies: Zinc.

Comparison 1 MMN vs placebo/no intervention, Outcome 3 Micronutrient deficiencies: Iron.

Comparison 1 MMN vs placebo/no intervention, Outcome 4 Micronutrient deficiencies: Vitamin A.

Comparison 1 MMN vs placebo/no intervention, Outcome 5 Micronutrient deficiencies: B Vitamin.

Comparison 1 MMN vs placebo/no intervention, Outcome 6 Micronutrient deficiencies: Zinc.

Findings from Adams 2017 and Azlaf 2017 were not pooled with the meta‐analysis since these were not RCTs. Adams 2017 reported no effect of MMN fortification on zinc deficiency (RR 0.76, 95% CI 0.5 to 1.02), while Azlaf 2017 reported a significant effect of MMN fortification on vitamin A deficiency (prevalence of vitamin A deficiency of 4.3% in the fortified group compared to 25.2% in the control group (P < 0.001)) which are consistent with the findings of the meta‐analysis.

Anthropometric outcomes: Pooled study results weight for age

MMN fortification may improve WAZ (mean difference (MD) 0.10 z‐scores, 95% CI 0.02 to 0.17; I 2 = 26%; 8 studies, 2889 participants; low‐quality evidence; Analysis 1.7 ) and WHZ/WLZ (MD 0.10 z‐scores, 95% CI 0.02 to 0.18; I 2 = 5%; 6 studies, 1758 participants; low‐quality evidence; Analysis 1.8 ). We are uncertain about the effect of MMN fortification on HAZ/LAZ (MD 0.09, 95% CI 0.01 to 0.18; I 2 = 39%; 8 studies, 2889 participants; very low‐quality evidence; Analysis 1.9 ).

Comparison 1 MMN vs placebo/no intervention, Outcome 7 Anthropometric: WAZ.

Comparison 1 MMN vs placebo/no intervention, Outcome 8 Anthropometric: WHZ/WLZ.

Comparison 1 MMN vs placebo/no intervention, Outcome 9 Anthropometric: HAZ/LAZ.

Almost all the studies included in analyses of the primary outcomes were at high risk of bias. Sensitivity analysis removing all studies at overall high risk of bias left all primary analyses with only one or no included studies, indicating that risks of bias may have an important impact on the reported results.

Among the secondary outcomes, included trials reported on serum haemoglobin, serum micronutrient concentrations (folate, ferritin, vitamin A, B vitamins and zinc) and neuro‐cognitive outcomes. None of the included trials reported any potential adverse effects.

Serum haemoglobin: Pooled study results

MMN fortification may improve serum haemoglobin (MD 3.01 g/L, 95% CI 2.14 to 3.87; I 2 = 99%; 20 studies, 6985 participants; low‐quality evidence; Analysis 1.10 ).

Comparison 1 MMN vs placebo/no intervention, Outcome 10 Biochemical: Serum haemoglobin (g/L).

Serum micronutrient levels: Pooled study results

MMN fortification may improve serum ferritin (MD 8.27 μg/mL, 95% CI 3.26 to 13.27; I 2 = 88%; 7 studies, 2407 participants; low‐quality evidence; Analysis 1.11 ), vitamin B6 (MD 35.02 nmol/L, 95% CI 22.95 to 47.09; I 2 = 82%; 2 studies, 301 participants; low‐quality evidence; Analysis 1.12 ), vitamin B9 (folate) (MD 12.41 nmol/L, 95% CI 6.55 to 18.28; I 2 = 100%; 5 studies, 568 participants; low‐quality evidence; Analysis 1.12 ) and vitamin B12 (MD 61.90 pmol/L, 95% CI 53.56 to 70.23; I 2 = 100%; 6 studies, 893 participants; low‐quality evidence; Analysis 1.12 ). We are uncertain of the effect of MMN fortification on serum vitamin A (MD 0.04 μmol/L, 95% CI −0.01 to 0.09; I 2 = 68%; 13 studies, 2457 participants; low‐quality evidence; Analysis 1.13 ), on serum zinc (MD 0.25 ug/dL, 95% CI −0.05 to 0.55; I 2 = 76%; 15 studies, 4428 participants; low‐quality evidence; Analysis 1.14 ) or on vitamin B1 (MD 4.80 nmol/L, 95% CI −2.77 to 12.37; 1 study, 118 participants; low‐quality evidence; Analysis 1.12 ).

Comparison 1 MMN vs placebo/no intervention, Outcome 11 Biochemical: Serum ferritin (μg/mL).

Comparison 1 MMN vs placebo/no intervention, Outcome 12 Biochemical: B Vitamin.

Comparison 1 MMN vs placebo/no intervention, Outcome 13 Biochemical: Serum vitamin A (μmol/L).

Comparison 1 MMN vs placebo/no intervention, Outcome 14 Biochemical: Serum zinc (μg/dL).

Neuro‐cognitive outcome: single‐study results

Eight studies reported various neuro‐cognitive outcomes in children ( Faber 2005 ; Nga 2009 ; Osendarp 2007 ; Taljaard 2013 ; Thankachan 2012 ; Van Stuijvenberg 1999 ; DeGier 2016 ; Petrova 2019 ). We are uncertain of the effect of MMN fortification on motor development score (MD 1.10, 95% CI 0.17 to 2.03; 1 study, 266 participants; very low‐quality evidence; Analysis 1.15 ), Raven’s Colored Progressive Matrices test (RCPM) (MD 0.13, 95% CI −0.86 to 1.11; I 2 = 59%; 2 studies, 1124 participants; very low‐quality evidence; Analysis 1.15 ), general intelligence (MD −0.07, 95% CI −0.34 to 0.20; 1 study, 251 participants; very low‐quality evidence; Analysis 1.15 ), verbal learning and memory (MD 0.13, 95% CI −0.10 to 0.37; 1 study, 251 participants; very low‐quality evidence; Analysis 1.15 ), visual attention (MD 0.09, 95% CI −0.11 to 0.29; 1 study, 251 participants; very low‐quality evidence; Analysis 1.15 ) and coding (MD −0.53, 95% CI −1.26 to 0.21; 3 studies, 509 participants; I 2 = 0%; low‐quality evidence; Analysis 1.15 ).

Comparison 1 MMN vs placebo/no intervention, Outcome 15 Neuro‐cognitive outcomes.

Taljaard 2013 assessed cognition using the Kaufman Assessment Battery for Children version II (KABC) sub‐tests and the Hopkins Verbal Learning Test (HVLT), suggesting that fortification increased KABC Atlantis (intervention group mean score 5.9 compared to control group mean score 5) and HVLT Discrimination Index scores (intervention group mean score 14.7 compared to control group mean score 13.8); there was no effect on story completion, number recall, rover, triangles, word order, hand movements, recall and recognition. Van Stuijvenberg 1999 used cognitive tests designed to record speed of processing and capacity of working memory in tasks closely related to the intellectual skills required for schoolwork, suggesting improvement in the digit span forward task (short‐term memory) (P < 0.05) only, with no effect on any of the other cognitive functions (verbal fluency, digit copying, writing crosses, counting letters, cancelling letters, reading numbers, digit span backward task and counting backward).

Assessment of reporting bias

We were able to generate funnel plots for five outcomes, as they included 10 or more studies; these include anaemia, iron deficiency, serum haemoglobin, serum vitamin A and serum zinc ( Figure 9 ; Figure 10 ; Figure 11 ; Figure 12 ; Figure 13 ). The funnel plots for the outcomes of anaemia and serum haemoglobin were visually asymmetrical, suggesting that publication bias could be one of the possible sources of asymmetry. We compared the fixed‐effect model with the random‐effects model for these two anaemia outcomes. We found the estimates to be in a similar direction of effect with overlapping CIs, indicating that smaller studies were not systematically finding more positive results, and that there is no specific indication that reporting bias might be having an important impact on this outcome. For serum haemoglobin, the sensitivity analysis showed a notably smaller result using a fixed‐effect analysis, indicating that smaller studies on average reported more positive results than larger ones. Reporting bias may be one cause of this heterogeneity, although there may be other causes that we were not able to identify (see section on subgroup analysis below).

Funnel plot of comparison: 1 MMN vs Placebo/No intervention, outcome: 1.1 Anaemia.

Funnel plot of comparison: 1 MMN vs placebo/no intervention, outcome: 1.3 Micronutrient deficiencies: Iron.

Funnel plot of comparison: 1 MMN vs placebo/no intervention, outcome: 1.10 Biochemical: Serum haemoglobin (g/L).

Funnel plot of comparison: 1 MMN vs Placebo/No intervention, outcome: 1.13 Biochemical: Serum Vitamin A (umol/L).

Funnel plot of comparison: 1 MMN vs Placebo/No intervention, outcome: 1.14 Biochemical: Serum Zinc (ug/dL).

Subgroup analysis

We could only conduct subgroup analysis by duration of intervention (for the outcomes of WAZ and HAZ/LAZ) and by source of funding (for the outcomes of anaemia and iron deficiency). There were fewer than three studies in each subgroup for all other outcomes.

Subgroup analysis by the duration of intervention suggested no difference between the 'six months or less' intervention duration and 'more than six months to one year' intervention duration for WAZ ( Analysis 2.1 ) and HAZ/LAZ ( Analysis 2.2 ).

Comparison 2 MMN vs placebo/no intervention (Subgroup analysis by duration of intervention), Outcome 1 Anthropometric: WAZ.

Comparison 2 MMN vs placebo/no intervention (Subgroup analysis by duration of intervention), Outcome 2 Anthropometric: HAZ/LAZ.

Subgroup analysis by funding suggested no difference between non‐commercial, partial and full commercial funding for anaemia ( Analysis 3.1 ) and iron deficiency ( Analysis 3.2 ).

Comparison 3 MMN vs placebo/no intervention (Subgroup analysis by funding), Outcome 1 Anaemia.

Comparison 3 MMN vs placebo/no intervention (Subgroup analysis by funding), Outcome 2 Micronutrient Deficiencies: Iron.

Comparison 2: Multiple micronutrient fortification versus iodised salt

Two studies compared MMN fortification with iodised salt in children ( Vinodkumar 2009 ; Zimmerman 2004 ). We could not conduct any subgroup analysis for this comparison due to the limited number of studies.

Among the primary outcomes, included studies reported anaemia, iron deficiency anaemia and micronutrient deficiencies (iron and vitamin A). None of the included trials in this comparison reported anthropometric outcomes, morbidity, all‐cause mortality or cause‐specific mortality.

Anaemia: SIngle‐study result

We are uncertain of the effect of MMN fortification when compared to iodised salt for anaemia (RR 0.86, 95% CI 0.37 to 2.01; 1 study, 88 participants; very low‐quality evidence; Analysis 4.1 ).

Comparison 4 MMN vs iodised salt, Outcome 1 Anaemia.

We are uncertain of the effect of MMN fortification when compared to iodised salt for iron deficiency anaemia (RR 0.40, 95% CI 0.09 to 1.83; I 2 = 77%; 2 studies, 245 participants; very low‐quality evidence; Analysis 4.2 ).

Comparison 4 MMN vs iodised salt, Outcome 2 Iron deficiency anaemia.

Micronutrient deficiency: Single‐study result

We are uncertain of the effect of MMN fortification compared to iodised salt for iron deficiency (RR 0.98, 95% CI 0.82 to 1.17; 1 study, 88 participants; very low‐quality evidence; Analysis 4.3 ).

Comparison 4 MMN vs iodised salt, Outcome 3 Micronutrient deficiencies: Iron.

We are uncertain of the effect of MMN fortification compared to iodised salt on vitamin A deficiency when compared to iodised salt (RR 0.19, 95% CI 0.07 to 0.55; I 2 = 96%; 2 studies, 363 participants; very low‐quality evidence; Analysis 4.4 ).

Comparison 4 MMN vs iodised salt, Outcome 4 Micronutrient deficiencies: Vitamin A.

Among the secondary outcomes, included studies reported serum haemoglobin, serum micronutrient concentrations (ferritin, B vitamins, vitamin A and zinc). None of the included studies reported any potential adverse events or neuro‐cognitive outcomes.

Serum haemoglobin: pooled study results

MMN fortification when compared to iodised salt may improve serum haemoglobin (MD 10.20 g/L, 95% CI 3.06 to 17.35; I 2 = 96%; 2 trials, 559 participants; low‐quality evidence; Analysis 4.5 ).

Comparison 4 MMN vs iodised salt, Outcome 5 Biochemical: Serum haemoglobin (g/L).

Serum micronutrient levels: single‐study results

We are uncertain of the effect of MMN fortification compared to iodised salt on serum ferritin (MD 0.18, 95% CI −36.14 to 36.50; 1 study, 88 participants; very low‐quality evidence; Analysis 4.6 ), serum vitamin B9 (MD 5.04, 95% CI −0.92 to 11.00; 1 study, 95 participants; very low‐quality evidence; Analysis 4.7 ), serum vitamin B12 (MD 15,184, 95% CI 6336.35 to 24,031.65; 1 study, 95 participants; very low‐quality evidence; Analysis 4.7 ), serum vitamin A (MD 2.82, 95% CI −2.88 to 8.51; I 2 = 87%; 2 studies, 363 participants; very low‐quality evidence; Analysis 4.8 ) and serum zinc (MD 39.77, 95% CI −86.29 to 165.83; 1 study, 95 participants; very low‐quality evidence; Analysis 4.9 ).

Comparison 4 MMN vs iodised salt, Outcome 6 Biochemical: Serum ferritin (ug/L).

Comparison 4 MMN vs iodised salt, Outcome 7 Biochemical: B Vitamin.

Comparison 4 MMN vs iodised salt, Outcome 8 Biochemical: Serum vitamin A (umol/L).

Comparison 4 MMN vs iodised salt, Outcome 9 Biochemical: Serum zinc.

Comparison 3: Multiple micronutrient fortification versus calcium fortification alone

Only one trial ( Economos 2014 ) compared MMN fortification with calcium fortification in children.

None of the primary outcomes were reported in the trial.

Among the secondary outcomes, only serum micronutrient levels were reported.

Serum micronutrient levels: SIngle study results

We are uncertain of the effect of MMN fortification on serum vitamin E (MD 5.10, 95% CI 3.49 to 6.71; 1 study, 93 participants; very low‐quality evidence; Analysis 5.1 ) and serum vitamin D (MD 15.10, 95% CI 3.06 to 27.14; 1 study, 93 participants; very low‐quality evidence; Analysis 5.2 ), serum calcium (MD 0.00, 95% CI −0.17 to 0.17; 1 study, 88 participants; very low‐quality evidence; Analysis 5.3 ) and serum vitamin A (MD 0.10, 95% CI −0.03 to 0.23; 1 study, 88 participants; very low‐quality evidence; Analysis 5.4 ) compared to calcium fortification alone.

Comparison 5 MMN vs calcium fortification alone, Outcome 1 Biochemical: Serum vitamin E.

Comparison 5 MMN vs calcium fortification alone, Outcome 2 Biochemical: Serum vitamin D.

Comparison 5 MMN vs calcium fortification alone, Outcome 3 Biochemical: Serum calcium.

Comparison 5 MMN vs calcium fortification alone, Outcome 4 Biochemical: Serum vitamin A (umol/L).

Summary of main results

This review summarises findings from 43 studies (48 papers) with 19,585 participants (17,878 children). Most of the included studies compared MMN fortification with placebo/no intervention; two studies compared MMN fortification with iodised salt and one study compared it with calcium fortification alone. Most of the included studies targeted children, so the overall evidence generated from this review applies to children. We rated most of the evidence as of low to very low quality, due to study limitations, imprecision, high heterogeneity and small sample size. When compared to placebo/no intervention, MMN fortification may reduce anaemia, iron deficiency anaemia and micronutrient deficiencies (including iron, vitamin A, vitamin B2 and vitamin B6 deficiency). We are uncertain of the effect of MMN fortification on WAZ, WHZ/WLZ, HAZ/LAZ and other micronutrient deficiencies (including zinc and vitamin B12). Among the secondary outcomes, MMN fortification may improve serum haemoglobin, serum folate, serum ferritin, serum vitamin A and serum vitamin B12; but we are uncertain of the effect on serum zinc, serum vitamin B1 and serum vitamin B6 and any of the neuro‐cognitive outcomes. None of the included trials reported morbidity, all‐cause mortality, cause‐specific mortality or adverse events.

Two studies in children compared MMN fortification with iodised salt. We are uncertain of the effect of MMN fortification on anaemia, iron deficiency anaemia, vitamin A deficiency, serum ferritin, vitamin B9, vitamin B12, vitamin A and zinc; MMN fortification compared to iodised salt may improve haemoglobin. One trial compared MMN fortification with calcium fortification alone in children, showing inconclusive results on serum vitamin E and serum vitamin D, serum calcium and serum vitamin A in the MMN fortification group compared to calcium fortification alone.

Most of the included studies did not directly report on PROGRESS‐Plus factors or the equity‐related variables, and none of the studies reported on adverse events.

Overall completeness and applicability of evidence

This review summarises findings from 43 studies conducted between 1998 and 2018. Most of the studies were conducted in low‐ and middle‐income countries, apart from nine studies from high‐income countries, including Australia, Finland, Spain, Netherlands and the USA. Most of the studies compared MMN fortification with placebo, reporting all the primary outcomes except for morbidities, all‐cause mortality and cause‐specific mortality. None of the included trials reported on any adverse events of food fortification with MMN.

Most of the included studies targeted children, and hence the conclusions apply predominantly to children. Twenty‐nine studies were conducted among pre‐school and school‐aged children; four studies included infants aged between six and 12 months; four studies included children aged one to three years; three studies targeted pregnant women; three studies targeted adults, while one study targeted an elderly population aged over 70 years. Trials had interventions of variable duration, ranging from eight weeks to a maximum of one year. Trials used different food vehicles and numbers and concentrations of micronutrients, and the frequency of intake was also not uniform. There is limited information on the baseline nutritional status of the trial participants.

We were unable to conduct planned subgroup analysis by the various study designs, population groups, baseline micronutrient status, various combination of MMNs, low‐to‐middle income countries versus high‐income countries and the food vehicle used for fortification, due to the limited number of trials with various outcomes. Subgroup analyses comparing different durations of intervention did not identify any significant differences in outcomes. Future updates of this review could add data to various subgroups, if available at that time, which could lead to more meaningful conclusions.

Most of the included studies were fully or partially commercially funded, with a few trials being non‐commercially funded. Subgroup analyses comparing commercial versus non‐commercial funding did not find a significant difference in outcomes, although this was not a large number of studies, and the level of commercial funding remains a concern, because of the possibility of conflict of interest, and the possible association between commercial funding and more positive findings ( Fabbri 2018 ). Independent trials and evaluations are needed to truly assess the impact of food fortification with MMN.

None of the included trials reported adverse events, which limits the completeness and applicability of the existing evidence. A descriptive analysis of the PROGRESS‐Plus factors reported by included studies suggests that most studies lack direct reporting on these factors. Equity‐related variables and analyses were commonly missing from the included studies, thus affecting the availability of evidence on how inequities are identified and how food fortification with MMN can contribute to mitigate or reduce them.

Quality of the evidence

We judged most of the outcomes to be of low to very low quality. Outcomes were mainly downgraded due to study limitations, high heterogeneity and imprecision. Study limitations included a lack of blinding of outcome assessment, incomplete outcome data and inconsistency among studies reporting the outcome. There was high heterogeneity for most of the reported outcomes. None of the included studies reported morbidity, all‐cause or cause‐specific mortality. Information on random sequence generation and allocation concealment was unclear in half of the included studies. In more than half of the included studies the methods used to conceal allocation were not described. Blinding of participants and personnel was also not clearly reported in many studies, while some of the studies were judged to be at a high risk of bias for blinding of outcome assessors. We also rated studies at high risk of bias for incomplete outcome data. This represented a major limitation, as most of the studies were fully or partially commercially funded. Lack of information on dietary intake and baseline nutritional status was another limitation of the review.

Potential biases in the review process

We were aware of the possibility of introducing bias at every stage of the reviewing process. We developed a comprehensive search strategy for a list of pre‐identified databases to capture the eligible studies. We tried to minimise bias in a number of ways; two review authors assessed eligibility for inclusion, carried out data extraction and assessed risks of bias. Nevertheless, the process of assessing risk of bias, for example, is not an exact science and includes many personal judgements. While we tried to be as inclusive as possible in our search strategies, the literature identified was predominantly written in English and published in North American and European journals. Although we tried to assess reporting bias, we largely relied on information available in the published trial reports, meaning that reporting bias was not usually apparent.

Agreements and disagreements with other studies or reviews

Our findings agree with another systematic review ( Das 2013 ), which concluded that food fortification with MMN reduced anaemia and improved serum haemoglobin, ferritin and retinol. Another review ( Best 2011 ) evaluating the impact of MMN fortification on micronutrient status, growth, health, and cognitive development of school children also suggested that MMN fortification improved micronutrient status and reduced anaemia prevalence, with some studies reporting positive effects on morbidity, growth, and cognitive outcomes, but the overall effects on these outcomes were equivocal. This review did not conduct any meta‐analyses. A more recent review evaluating the impact of MMN‐fortified non‐dairy beverage interventions in school‐aged children in LMICs, suggested improved serum haemoglobin and ferritin and reduced anaemia and iron deficiency anaemia ( Aaron 2015 ).

Reviews on home fortification with MMN suggests that it is effective in reducing anaemia and iron deficiency in children aged six months to 23 months ( De‐Regil 2011 ). There was very limited evidence on home fortification for pregnant women, suggesting that micronutrient powders for point‐of‐use fortification of foods did not have any clear effect on maternal anaemia and haemoglobin at or near term, compared with multiple micronutrient supplements ( Suchdev 2014 ). Another review of micronutrient powders in women and children also suggests that they are effective in improving anaemia and haemoglobin among children reporting lack of impact on growth; evidence of increased diarrhoea requires careful consideration before recommending the intervention for large‐scale implementation ( Salam 2013 ).

Implications for practice

The evidence from this review suggests that MMN fortification when compared to placebo may improve anaemia, iron deficiency anaemia, micronutrient deficiencies (including iron, vitamin A, vitamin B2 and vitamin B6 deficiency), serum haemoglobin, serum folate, serum ferritin, serum vitamin A, serum vitamin B12 and some motor and cognitive outcomes. However, there are a number of other factors that should also be considered. Firstly, the quality of the evidence was low to very low. Secondly, there are no reported data to assess possible side effects of the MMN fortification. Thirdly, we could not draw reliable conclusions from various subgroup analyses on population groups, food vehicles, dosage and region, due to a limited number of studies in each subgroup and measuring varying outcomes. Lastly, we remain cautious about the level of commercial funding among the included studies, although a direct effect of commercial funding was not demonstrated in this review.

Implications for research

The findings of our review provide a number of implications for future research. Future research should focus on generating high‐quality evidence with longer follow‐ups, and assessing the impact in various population groups. The evidence can be consolidated with the use of larger sample sizes and better study designs. It would also be important for study authors to report allocation, randomisation and blinding procedures in detail. There is a need for non‐commercially funded studies and independent evaluations. There are limited data on how fortification affects population groups with variable baseline health status and underlying micronutrient deficiencies and levels of malnutrition. Research should also focus on evaluating the direct health outcomes, including morbidities, mortality and adverse events, especially in LMIC settings. It is also important to report on equity variables for future studies, to assess whether food fortification has any impact on equity.

Acknowledgements

We thank members of Cochrane Public Health for their extensive editorial support during the preparation and finalisation of this review.

We would also like to acknowledge Ms. Sultana Jabeen for assisting us with the PROGRESS‐PLUS criteria.

Appendix 1. MEDLINE search strategy

(food or crops or crop or flour or salt or salts or fish or soy foods or sauce* or cereals or carbohydrates or sugar* or Oryza sativa or rice* or milk or bread or oil or oils or beverages or yogurt or margarine or cheese or maize* or condiments or triticum or wheat* or spice or spices or curry powder* or fats or fat or dairy).mp. OR exp Zea mays/

2. Micronutrients

(iron or ferr* or iodine or vitamin a or beta carotene or folic or folate* or micronutrients).mp.

3. Fortification

(enrich* or forti* or enhance* or refine*).mp.

1 AND 2 AND 3

Appendix 2. Embase search strategy

1. (food or 'food supply' or crop or bread or flour or salt or 'fish products' or 'soy food*' or sauce or sugar or wheat or triticum or rice or cereal* or grain* or cheese or dairy or cake* or biscuit* or juice* or yogurt or chocolate or margarine or milk or oil or butter or cream or yogurt or beverages or spice or 'curry powder*' or 'dietary fats' or fat or fats or condiment*)

2. Iron or ferr* or Iodine or Vitamin A or beta Carotene or Folic Acid or folate* or Micronutrients

3. enrich* or forti* or enhance* or refine*

Appendix 3. CINAHL

1. (food or “food supply” or crop or bread or flour or salt or “fish products” or “soy foods” or sauce or sugaror wheat or triticum or rice or cereal* or grain* or cheese or dairy or cake* or biscuit* or juice* or yogurt or chocolate or margarine or milk or maize or oil or butter or cream or yogurt or beverages or Spices or "curry powder*" or fat or fats or condiment*)

3. (enrich* or forti* or enhance* or refine*)

Appendix 4. Cochrane

(Food or "Food Supply" or "Agricultural Crops" or crop or Flour or Salts or "Fish Products" or "Soy Foods" or sauce* or Cereals or "Dietary Carbohydrates" or sugar* or "Oryza sativa" or rice or Milk or Bread or Oils or Beverages or Yogurt or Margarine or Cheese or "Zea mays" or maize* or Condiments or Triticum or wheat* or Spices or "curry powder" or "Dietary Fats" or fat or fats or "Dairy Products") AND (Iron or ferr* or Iodine or "Vitamin A" or "beta Carotene" or "Folic Acid" or folate or Micronutrients) AND (enrich or fortified or enhance or refine)

Appendix 5. WHOLIS

words or phrase “food or food supply or crop or bread or flour or salt or fish product or soy food or sauce or sugar or wheat or triticum or rice or cereal or grain or cheese or dairy or cake or biscuit or juice or yogurt or chocolate or margarine or milk or oil or butter or cream or yogurt or beverages or spices or curry powder or dietary fat or fats or fat” AND words or phrase "fortified or fortification or enriched or enhanced or refined” AND Iron or ferr* or Iodine or Vitamin A or beta Carotene or Folic Acid or folate* or Micronutrients

Appendix 6. Others

Fortification or fortified or enriched (Subject)

Fortified (All fields) OR Enrich (All fields) OR fortification (All fields)

African Index Medicus:

fortification or fortified or enriched (titles and keywords)

fortification or fortified or enriched (with atleast one word)

fortified or fortification or enriched

allintitle: fortified OR fortification OR enriched

fortified OR fortification OR enriched

3ie Database of Impact studies

fortification OR enriched OR fortified (Health and Nutrition and Population subcategory

fortification OR enriched OR fortified (Free text terms)

fortification OR fortified AND food discipline:(05T ‐ Health services, health administration, community care services) discipline:(06H ‐ Food technology, food microbiology)

Clinical trials.gov:

"food fortification" OR fortified (restricted to interventional studies only)

http://apps.who.int/trialsearch/AdvSearch.aspx

"food fortification" OR fortified or enriched (titles)

Food Science and Technology Abstracts

fortification OR enriched OR fortified

AgriCOLA: https://agricola.nal.usda.gov/

Edited (no change to conclusions)

Data and analyses

Comparison 1.

Comparison 2

Comparison 3

Comparison 4

Comparison 5

Characteristics of studies

Characteristics of included studies [ordered by study id].

BMI: body mass index; CRP: C‐reactive protein; DHA: docosahexaenoic acid; HAZ: height‐for‐age Z‐score; HDL: high‐density lipoprotein; LAZ: length‐for‐age Z‐score; LD: low‐density lipoprotein; MUAC: middle upper arm circumference; RBP: retinol binding protein; RDA: recommended daily allowance; RNI: recommended nutritional intake; TG: triglycrides; WAZ: wight‐for‐age Z‐score; WHZ: weight‐for‐height Z‐score; WLZ: weight‐for‐length Z‐score

Characteristics of excluded studies [ordered by study ID]

Differences between protocol and review

• Background has been updated to reflect current information.
• We have modified the search strategy from the protocol, in consultation with the Information Scientist.
• We have now specified that we excluded studies conducted among special population groups including critically‐ill people, anaemic people or people diagnosed with any specific diseases. We also excluded studies on therapeutic blended food and food supplementation.
• We have removed the text pertaining to contacting the trial authors for more data, since this was not needed and hence not done.
• We have removed subgroup analysis by study design (RCTs/non‐RCTs, CBA/ITS).
• We have specified that we have only conducted subgroup analysis where there were at least three studies in each subgroup.
• We have modified the methods used to assess reporting bias to indicate that we used visual assessment rather than statistical tests, and that we explored any asymmetric funnel plots using sensitivity analysis to compare the fixed‐effect and random‐effects meta‐analyses.
• One of our prespecified primary outcomes was anthropometric measures and we had intended to include stunting, wasting and underweight. However, since none of the included studies reported these outcomes, we could not report them. We reported WAZ, HAZ/LAZ and WHZ as anthropometric outcomes, since they were reported in the included studies.
• We could not conduct all of the planned subgroup analyses under every comparison due to a limited number of included studies reporting on the relevant comparisons.

Contributions of authors

All authors contributed to the development of the review. Rohail Kumar (RK), Anoosh Moin (AM), Kashif Mukhtar (KM) and Salman Bin Mahmood (SBM) developed and ran the search strategy and obtained copies of the studies; Jai K Das (JKD), SBM and Rehana A Salam (RAS) selected which studies to include; RK, AM, KM, SBM and Zohra Lassi (ZL) extracted data from studies and entered data into Review Manager 5; SBM, JKD, ZL and RAS carried out and interpreted the analysis. RAS and JKD evaluated the studies according to the PROGRESS‐PLUS criteria. JKD, RAS, SBM, ZL and Zulfiqar A Bhutta (ZAB) drafted the final review, with input from all the authors.

Sources of support

Internal sources.

• Aga Khan University, Pakistan.

External sources

• No sources of support supplied

Declarations of interest

JKD: no competing interests.

RAS: no competing interests.

SBM: no competing interests.

AM: no competing interests.

RK: no competing interests.

KM: no competing interests.

ZL: Participated in a Nestlé Nutrition Institute workshop on Health and Nutrition in Adolescents and Young Women: preparing for the next generation for the related publication Nestlé Nutrition Institute Series Volume 80 (2015)

ZAB: Participated in a Nestlé Nutrition Institute workshop on Health and Nutrition in Adolescents and Young Women: preparing for the next generation and co‐edited the related publication Nestlé Nutrition Institute Series Volume 80 (2015). ZAB declares previous travel support from the Nestlé Nutrition Institute for attendance at a meeting on fortification strategies at the University of Winterthur, Winterthur, Switzerland, in October 2011. ZAB received an institutional grant from GAIN on fortification program evidence review in 2014. The paper is currently in press.

References to studies included in this review

Aaron 2011 {published data only}.

• Aaron GJ, Kariger P, Aliyu R, Flach M, Iya D, Obadiah M, et al. A multi‐micronutrient beverage enhances the vitamin A and zinc status of Nigerian primary schoolchildren . Journal of Nutrition 2011; 141 ( 8 ):1565‐72. [ PubMed ] [ Google Scholar ]

Abrams 2003 {published data only}

• Abrams SA, Mushi A, Hilmers DC, Griffin IJ, Davila P, Allen L. A multinutrient‐fortified beverage enhances the nutritional status of children in Botswana . Journal of Nutrition 2003; 133 ( 6 ):1834‐40. [ PubMed ] [ Google Scholar ]

Adams 2017 {published data only}

• Adams AM, Ahmed R, Latif AM, Rasheed S, Das SK, Hasib E, et al. Impact of fortified biscuits on micronutrient deficiencies among primary school children in Bangladesh . PloS One 2017; 12 ( 4 ):e0174673. [ PMC free article ] [ PubMed ] [ Google Scholar ]

Ash 2003 {published data only}

• Ash DM, Tatala SR, Frongillo EA Jr, Ndossi GD, Latham MC. Randomized efficacy trial of a micronutrient‐fortified beverage in primary school children in Tanzania . American Journal of Clinical Nutrition 2003; 77 ( 4 ):891‐8. [ PubMed ] [ Google Scholar ]

Azlaf 2017 {published data only}

• Azlaf M, Hamdouchi A, Benjeddou K, Zahrou FZ, Menchawy I, Kari K, et al. School fortified milk improves vitamin A status of rural children in Morocco: A longitudinal interventional and controlled study 1 . Mediterranean Journal of Nutrition and Metabolism 2017; 10 ( 1 ):13‐27. [ Google Scholar ]

Chin A Paw 2000 {published data only}

• Chin A Paw MJ, Jong N, Pallast EG, Kloek GC, Schouten EG, Kok FJ. Immunity in frail elderly: a randomized controlled trial of exercise and enriched foods . Medicine and Science in Sports and Exercise 2000; 32 ( 12 ):2005‐11. [ PubMed ] [ Google Scholar ]

DeGier 2016 {published data only}

• Gier B, Campos Ponce M, Perignon M, Fiorentino M, Khov K, Chamnan C, et al. Micronutrient‐fortified rice can increase hookworm infection risk: a cluster randomized trial . PLoS One 2016; 11 ( 1 ):e0145351. [ PMC free article ] [ PubMed ] [ Google Scholar ]
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Economos 2014 {published data only}

• Economos CD, Moore CE, Hyatt RR, Kuder J, Chen T, Meydani SN, et al. Multinutrient‐fortified juices improve vitamin D and vitamin E status in children: a randomized controlled trial . Journal of the Academy of Nutrition and Dietetics 2014; 114 ( 5 ):709‐17. [ PubMed ] [ Google Scholar ]

Faber 2005 {published data only}

• Faber M, Kvalsvig JD, Lombard CJ, Benadé AJ. Effect of a fortified maize‐meal porridge on anemia, micronutrient status, and motor development of infants . American Journal of Clinical Nutrition 2005; 82 ( 5 ):1032‐9. [ PubMed ] [ Google Scholar ]

Gibson 2011 {published data only}

• Gibson RS, Kafwembe E, Mwanza S, Gosset L, Bailey KB, Mullen A, et al. A micronutrient‐fortified food enhances iron and selenium status of Zambian infants but has limited efficacy on zinc . Journal of Nutrition 2011; 141 ( 5 ):935‐43. [ PubMed ] [ Google Scholar ]

Hieu 2012 {published data only}

• Hieu NT, Sandalinas F, Sesmaisons A, Laillou A, Tam NP, Khan NC, et al. Multi‐micronutrient‐fortified biscuits decreased the prevalence of anaemia and improved iron status, whereas weekly iron supplementation only improved iron status in Vietnamese school children . British Journal of Nutrition 2012; 108 ( 8 ):1419‐27. [ PubMed ] [ Google Scholar ]

Hyder 2007 {published data only}

• Hyder SM, Haseen F, Khan M, Schaetzel T, Jalal CS, Rahman M, et al. A multiple‐micronutrient‐fortified beverage affects hemoglobin, iron, and vitamin A status and growth in adolescent girls in rural Bangladesh . Journal of Nutrition 2007; 137 ( 9 ):2147‐53. [ PubMed ] [ Google Scholar ]

Järvenpaa 2007 {published data only}

• Järvenpää J, Schwab U, Lappalainen T, Päkkilä M, Niskanen L, Punnonen K, et al. Fortified mineral water improves folate status and decreases plasma homocysteine concentration in pregnant women . Journal of Perinatal Medicine 2007; 35 ( 2 ):108‐14. [ PubMed ] [ Google Scholar ]

Jinabhai 2001 {published data only}

• Jinabhai CC, Taylor M, Coutsoudis A, Coovadia HM, Tomkins AM, Sullivan KR. A randomized controlled trial of the effect of antihelminthic treatment and micronutrient fortification on health status and school performance of rural primary school children . Annals of Tropical Paediatrics 2001; 21 ( 4 ):319‐33. [ PubMed ] [ Google Scholar ]

Liu 1993 {published data only}

• Liu DS, Bates CJ, Yin TA, Wang XB, Lu CQ. Nutritional efficacy of a fortified weaning rusk in a rural area near Beijing . American Journal of Clinical Nutrition 1993; 57 ( 4 ):506‐11. [ PubMed ] [ Google Scholar ]

Lopriore 2004 {published data only}

• Lopriore C, Guidoum Y, Briend A, Branca F. Spread fortified with vitamins and minerals induces catch‐up growth and eradicates severe anemia in stunted refugee children aged 3‐6 y . American Journal of Clinical Nutrition 2004; 80 ( 4 ):973‐81. [ PubMed ] [ Google Scholar ]

Mardones 2007 {published data only}

• Mardones F, Urrutia MT, Villarroel L, Rioseco A, Castillo O, Rozowski J, et al. Effects of a dairy product fortified with multiple micronutrients and omega‐3 fatty acids on birth weight and gestation duration in pregnant Chilean women . Public Health Nutrition 2008; 11 ( 1 ):30‐40. [ PubMed ] [ Google Scholar ]

Nesamvuni 2005 {published data only}

• Nesamvuni AE, Vorster HH, Margetts BM, Kruger A. Fortification of maize meal improved the nutritional status of 1‐3‐year‐old African children . Public Health Nutrition 2005; 8 ( 5 ):461‐7. [ PubMed ] [ Google Scholar ]

Nga 2009 {published data only}

• Nga TT, Winichagoon P, Dijkhuizen MA, Khan NC, Wasantwisut E, Furr H, et al. Multi‐micronutrient‐fortified biscuits decreased prevalence of anemia and improved micronutrient status and effectiveness of deworming in rural Vietnamese school children . Journal of Nutrition 2009; 139 ( 5 ):1013‐21. [ PubMed ] [ Google Scholar ]
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Oelofse 2003 {published data only}

• Oelofse A, Raaij JM, Benade AJ, Dhansay MA, Tolboom JJ, Hautvast JG. The effect of a micronutrient‐fortified complementary food on micronutrient status, growth and development of 6‐to 12‐month‐old disadvantaged urban South African infants . International Journal of Food Sciences and Nutrition 2003; 54 ( 5 ):399‐407. [ PubMed ] [ Google Scholar ]

Osendarp 2007 {published data only}

• Osendarp SJ, Baghurst KI, Bryan J, Calvaresi E, Hughes D, Hussaini M, et al. NEMO Study Group. Effect of a 12‐mo micronutrient intervention on learning and memory in well‐nourished and marginally nourished school‐aged children: 2 parallel, randomized, placebo‐controlled studies in Australia and Indonesia . American Journal of Clinical Nutrition 2007; 86 ( 4 ):1082‐93. [ PubMed ] [ Google Scholar ]

Perignon 2016 {published data only}

• Perignon M, Fiorentino M, Kuong K, Dijkhuizen MA, Burja K, Parker M, et al. Impact of multi‐icronutrient fortified rice on hemoglobin, iron and vitamin A status of Cambodian schoolchildren: a double‐blind cluster‐randomized controlled trial . Nutrients 2016; 8 ( 1 ):29. [DOI: 10.3390/nu8010029] [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Petrova 2019 {published data only}

• Petrova D, Litrán MA, García‐Mármol E, Rodríguez‐Rodríguez M, Cueto‐Martín B, López‐Huertas E, et al. Еffects of fortified milk on cognitive abilities in school‐aged children: results from a randomised‐controlled trial . European Journal of Nutrition 2019; 58 ( 5 ):1863‐72. [ PubMed ] [ Google Scholar ]

Pinkaew 2013 {published data only}

• Pinkaew S, Winichagoon P, Hurrell RF, Wegmuller R. Extruded rice grains fortified with zinc, iron, and vitamin A increase zinc status of Thai school children when incorporated into a school lunch program . Journal of Nutrition 2013; 143 ( 3 ):362‐8. [DOI: 10.3945/jn.112.166058] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Pinkaew 2014 {published data only}

• Pinkaew S, Wegmuller R, Wasantwisut E, Winichagoon P, Hurrell RF, Tanumihardjo SA. Triple‐fortified rice containing vitamin A reduced marginal vitamin A deficiency and increased vitamin A liver stores in school‐aged Thai children . Journal of Nutrition 2014; 144 ( 4 ):519‐24. [ PubMed ] [ Google Scholar ]

Powers 2016 {published data only}

• Powers HJ, Stephens M, Russell J, Hill MH. Fortified breakfast cereal consumed daily for 12 wk leads to a significant improvement in micronutrient intake and micronutrient status in adolescent girls: a randomised controlled trial . Nutrition Journal 2015; 15 ( 1 ):69. [ PMC free article ] [ PubMed ] [ Google Scholar ]

Rahman 2015 {published data only}

• Rahman AS, Ahmed T, Ahmed F, Alam MS, Wahed MA, Sack DA. Double‐blind cluster randomised controlled trial of wheat flour chapatti fortified with micronutrients on the status of vitamin A and iron in school‐aged children in rural Bangladesh . Maternal & Child Nutrition 2015; 11 Suppl 4 :120‐31. [ PMC free article ] [ PubMed ] [ Google Scholar ]

Sazawal 2007 {published data only}

• Sazawal S, Dhingra U, Dhingra P, Hiremath G, Kumar J, Sarkar A, et al. Effects of fortified milk on morbidity in young children in north India: community based, randomised, double masked placebo controlled trial . BMJ 2007; 334 ( 7585 ):140. [ PMC free article ] [ PubMed ] [ Google Scholar ]
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Sazawal 2013 {published data only}

• Sazawal S, Habib A, Dhingra U, Dutta A, Dhingra P, Sarkar A, et al. Impact of micronutrient fortification of yoghurt on micronutrient status markers and growth ‐ a randomized double blind controlled trial among school children in Bangladesh . BMC Public Health 2013; 13 :514. [ PMC free article ] [ PubMed ] [ Google Scholar ]

Solon 2003 {published data only}

• Solon FS, Sarol JN Jr, Bernardo AB, Solon JA, Mehansho H, Sanchez‐Fermin LE, et al. Effect of a multiple‐micronutrient‐fortified fruit powder beverage on the nutrition status, physical fitness, and cognitive performance of schoolchildren in the Philippines . Food and Nutrition Bulletin 2003; 4 ( 2 ):129‐40. [ PubMed ] [ Google Scholar ]

Taljaard 2013 {published data only}

• Taljaard C, Covic NM, Graan AE, Kruger HS, Smuts CM, Baumgartner J, et al. Effects of a multi‐micronutrient‐fortified beverage, with and without sugar, on growth and cognition in South African schoolchildren: a randomised, double‐blind, controlled intervention . British Journal of Nutrition 2013; 110 ( 12 ):2271‐84. [ PubMed ] [ Google Scholar ]

Tapola 2004 {published data only}

• Tapola NS, Karvonen HM, Niskanen LK, Sarkkinen ES. Mineral water fortified with folic acid, vitamins B6, B12, D and calcium improves folate status and decreases plasma homocysteine concentration in men and women . European Journal of Clinical Nutrition 2004; 58 ( 2 ):376‐85. [ PubMed ] [ Google Scholar ]

Tatala 2002 {published data only}

• Makola D, Ash DM, Tatala SR, Latham MC, Ndossi G, Mehansho H. A micronutrient‐fortified beverage prevents iron deficiency, reduces anemia and improves the hemoglobin concentration of pregnant Tanzanian women . Journal of Nutrition 2003; 133 ( 5 ):1339‐46. [ PubMed ] [ Google Scholar ]
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Thankachan 2012 {published data only}

• Thankachan P, Rah JH, Thomas T, Selvam S, Amalrajan V, Srinivasan K, et al. Multiple micronutrient‐fortified rice affects physical performance and plasma vitamin B‐12 and homocysteine concentrations of Indian school children . Journal of Nutrition 2012; 142 ( 5 ):846‐52. [ PubMed ] [ Google Scholar ]

Thankachan 2013 {published data only}

• Thankachan P, Selvam S, Surendran D, Chellan S, Pauline M, Abrams SA, et al. Efficacy of a multi micronutrient‐fortified drink in improving iron and micronutrient status among schoolchildren with low iron stores in India: a randomised, double‐masked placebo‐controlled trial . European Journal of Clinical Nutrition 2013; 67 ( 1 ):36‐41. [ PubMed ] [ Google Scholar ]

Tucker 2004 {published data only}

• Tucker KL, Olson B, Bakun P, Dallal GE, Selhub J, Rosenberg IH. Breakfast cereal fortified with folic acid, vitamin B‐6, and vitamin B‐12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial . American Journal of Clinical Nutrition 2004; 79 ( 5 ):805‐11. [ PubMed ] [ Google Scholar ]

Van het Hof 1998 {published data only}

• het Hof KH, Tijburg LB, Boer HS, Wiseman SA, Weststrate JA. Antioxidant fortified margarine increases the antioxidant status . European Journal of Clinical Nutrition 1998; 52 ( 4 ):292‐9. [ PubMed ] [ Google Scholar ]

Van Stuijvenberg 1999 {published data only}

• Stuijvenberg ME, Kvalsvig JD, Faber M, Kruger M, Kenoyer DG, Benadé AJ. Effect of iron‐, iodine‐, and beta‐carotene‐fortified biscuits on the micronutrient status of primary school children: a randomized controlled trial . American Journal of Clinical Nutrition 1999; 69 ( 3 ):497‐503. [ PubMed ] [ Google Scholar ]

Vaz 2011 {published data only}

• Vaz M, Pauline M, Unni US, Parikh P, Thomas T, Bharathi AV, et al. Micronutrient supplementation improves physical performance measures in Asian Indian school‐age children . Journal of Nutrition 2011; 141 ( 11 ):2017‐23. [ PubMed ] [ Google Scholar ]

Villalpando 2006 {published data only}

• Villalpando S, Shamah T, Rivera JA, Lara Y, Monterrubio E. Fortifying milk with ferrous gluconate and zinc oxide in a public nutrition program reduced the prevalence of anemia in toddlers . Journal of Nutrition 2006; 136 ( 10 ):2633‐37. [ PubMed ] [ Google Scholar ]

Vinodkumar 2009 {published data only}

• Vinodkumar M, Erhardt JG, Rajagopalan S. Impact of a multiple‐micronutrient fortified salt on the nutritional status and memory of schoolchildren . International Journal for Vitamin and Nutrition Research 2009; 79 ( 5‐6 ):348‐61. [ PubMed ] [ Google Scholar ]

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• Wang X, Hui Z, Dai X, Terry PD, Zhang Y, Ma M, et al. Micronutrient‐fortified milk and academic performance among Chinese middle school students: a cluster‐randomized controlled trial . Nutrients 2017; 9 ( 3 ):226. [ Google Scholar ]

Zimmerman 2004 {published data only}

• Zimmermann MB, Wegmueller R, Zeder C, Chaouki N, Biebinger R, Hurrell RF, et al. Triple fortification of salt with microcapsules of iodine, iron, and vitamin A . American Journal of Clinical Nutrition 2004; 80 ( 5 ):1283‐90. [ PubMed ] [ Google Scholar ]

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Janmohamed 2016 {published data only}

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Kumar 2008 {published data only}

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Lucas 1996 {published data only}

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Lutter 2007 {published data only}

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SYSTEMATIC REVIEW article

Impact of food-based fortification on nutritional outcomes and acceptability in older adults: systematic literature review.

• 1 Centre des Sciences du Goût et de l'Alimentation, CNRS, INRAE, Institut Agro, Université de Bourgogne, Dijon, France
• 2 CHU Dijon Bourgogne, Unité de recherche Pôle Personnes Âgées, Dijon, France

Background: “Do it yourself” (DIY) food-based fortification involves adding fortificants into everyday foods. It is a flexible solution that allows older people with reduced appetite to meet their nutritional needs.

Objectives: The aims of the systematic review are (a) to describe DIY fortified recipes, (b) to evaluate their acceptability, and (c) to evaluate whether they are effective levers to improve nutritional outcomes in older people.

Methods: A systematic search of 3 databases (Web of Science, PubMed, Scopus, last searched on January 2022) was undertaken. Main eligibility criteria include older adults aged ≥60 years living at home, in an institution or in hospital. Studies carried out for a specific medical condition or targeting only micronutrient fortification were excluded. After reviewing all titles/abstracts then full-text papers, key data were extracted and synthesized narratively. The quality of included studies was assessed using Kmet et al.

Results: Of 21,493 papers extracted, 44 original studies were included (3,384 participants), with 31 reporting nutritional outcomes, 3 reporting acceptability outcomes and 10 reporting both nutritional and acceptability outcomes. The review highlighted a wide variety of DIY fortified recipes, with additional energy ranging from 23 to 850 kcal/d ( M  = 403; SE = 62) and/or protein ranging from 4 to 40 g/d ( M  = 19; SE = 2). Compared to a standard diet, DIY fortification seems to be a valuable strategy for increasing energy and protein intake in older people. However, no strong evidence was observed on the nutritional status.

Implication for future: Further acceptability studies are crucial to ensure that DIY fortified foods are palatable and thus have a significant impact on the nutritional status. In addition, it would be useful for studies to better describe DIY recipes. This information would result in a better understanding of the factors that maximize the impact of DIY fortification on nutritional outcomes. Study registration: PROSPERO no. CRD42021244689.

Systematic review registration : PROSPERO: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021244689 .

1. Introduction

Contrary to common beliefs, our nutritional needs decrease little with age and are sometimes higher in late adulthood than in early adulthood. With regard to caloric intake, the European Food Safety Authority ( 1 ) recommends a daily allowance from 2000 to 2,500 Kcal for people aged 50 to 59 and from 1800 to 2,300 Kcal for people aged 70 to 79. More recently Volkert et al. ( 2 ) established that recommended energy intake should reach 30 Kcal per kg of body weight per day. With regard to protein intake, recent works carried out by the PROT-AGE consortium ( 3 ) and by the European Society for Clinical Nutrition and Metabolism (EPSEN) ( 4 ) show that older people need to ingest more protein than younger people to stay healthy, to maintain their abilities and to fight infections. As a result, the daily protein intake should be 1 to 1.2 g protein per kg of body weight per day for a healthy person over 60 versus 0.8 to 1 g per kg of body weight in younger adults. The literature review by Shad et al. ( 5 ) highlighted the importance of a constant distribution of protein intake over the main meals of the day at amounts of 25–30 g/meal to avoid catabolic protein status [see also ( 3 , 6 )].

At the same time, a decline in appetite can appear with aging ( 7 ). Various studies have reported that 31 to 56% of the aged population are “small eaters” ( 8 – 10 ). Small eaters are characterized by a low consumption of every food category compared to the overall population – they eat foods in small or even very small amounts ( 8 – 11 ). A recent French survey carried out by CREDOC (“Centre de Recherche pour l’Observation et les Conditions de Vie”) showed that 87% of adults aged 18–54 met the recommendations for protein intake compared with only 56% of those over 65 ( 12 ). This situation is even worse when older adults are frail and dependent. In an aged population receiving a Home-Delivery Meal (HDM) service or living in nursing homes, Sulmont-Rossé and Van Wymelbeke ( 13 ) observed that 7–8 out of 10 people did not meet their energy and/or protein needs. This study also showed that 55% of home-delivery meal recipients and 46% of people living in nursing homes had energy and/or protein intake lower than 2/3 of the recommendations. In addition to age, many factors can be at the origin of this decline in appetite, such as physiological changes, sensory decline and eating/swallowing difficulties, which appear during aging. It also can be related to “life-breaking moments” (e.g., widowhood, illness, dependence) that can amplify iatrogenic factors correlated with medications and affect sociological/psychological aspects ( 13 ). Thus, poor appetite in older adults leads to a decrease in food and nutrient intake, which increases the risk of undernutrition ( 14 , 15 ). Undernutrition, a recognized pathology in the older population, corresponds to an imbalance between nutritional intake and the body’s needs. This imbalance leads to weight loss, a decrease in muscle reserves and an alteration of the body’s defences. In older people, undernutrition increases the risk of falls and therefore fractures. It contributes to the increase in infectious morbidity ( 16 ), nosocomial infections ( 17 ) and the appearance of pressure ulcers ( 18 ). If left untreated, undernutrition can induce or aggravate a state of fragility and dependence, which affects the quality of life and life expectancy of our elders ( 16 , 19 ).

Understanding the factors responsible for appetite decline is certainly important, but a major challenge is to get older people with reduced appetite to fulfill their nutritional needs in order to prevent undernutrition and the associated consequences. Food-based fortification, which consists in incorporating ingredients of nutritional interest (namely “fortificants”) in commonly consumed foods ( 20 ) in order to deliberately increasing the content of an essential nutrient in a diet without increasing (too much) the volume to be ingested, is acknowledged to be a relevant approach for older adults with reduced appetite ( 21 ). Fortificants can be: (a) regular food products (e.g., semolina, oils, butter, cream, pureed nuts, egg), or (b) macronutrients extracts (e.g., whey protein isolate, milk protein concentrate, caseinate, maltodextrin) ( 22 , 23 ). Besides the numerous fortified foods developed and marketed by the food industry, “do it yourself” (DIY) fortification recipes empower older adults and their carers to take a personalized approach to their nutrition and current diet. DIY fortification is a flexible strategy that may fit better with older people’s food habits and preferences: older people (or their carers) add fortificants to the food they usually eat, during the preparation of daily meals. This constitutes a significant advantage in the older population, which is often reluctant to change their consumption habits. However, DIY fortification remains largely unknown and underused by older adults as well as by caregivers and healthcare professionals although it is now known to be a relevant approach to counterbalance appetite decline and to adjust to nutritional needs ( 24 ).

The goal of the present study was to conduct a systematic review of all studies related to the nutritional and acceptability aspects of DIY food-based fortification in older people. The aims of this review are (a) to describe the DIY food-based fortification solutions and recipes that have been developed, (b) to evaluate the acceptability of these solutions in older people, and (c) to evaluate whether these solutions can be relevant and effective levers to preserve or improve nutritional outcomes in older people.

2. Materials and methods

The present systematic review followed the approach proposed by Xiao and Watson ( 25 ), which summarizes the evidence available on a topic to convey the breadth and depth of that topic. The protocol was written using the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P, ( 26 ), see Supplementary material ). The protocol was deposited on the HAL website 1 and on PROSPERO with the registration number CRD42021244689. The PRISMA checklist is available on the Supplementary material .

2.1. Research question

The research question is: “What are the objectives, characteristics and results of existing research conducted on the nutritional issues and/or on acceptability among older people receiving DIY fortified foods?”

2.2. Inclusion and exclusion criteria

The PICOS (Population, Intervention, Comparator, Outcome, Study design) eligibility criteria was as follows ( 27 ):

Population: Any studies focusing on adults aged 60 years and older living either at home, in an institution or in hospital was eligible for inclusion. Older adults of all nutritional status, cognitive status and oral ability (e.g., chewing, swallowing) were eligible for inclusion. Studies carried out in the context of a specific medical condition (e.g., cardiac rehabilitation, renal failure, cancers, diabetes) were excluded.

Intervention: Any DIY food-based fortification intervention was eligible for inclusion (e.g., incorporating ingredients of nutritional interest in food products). Fortification in energy and/or macronutrients was eligible for inclusion. Studies without an intervention (e.g., observational studies) were relevant for inclusion. Were excluded from the review: (a) studies targeting only micronutrient fortification, non-food dietary supplement or bio-fortification (genetically modified crop), (b) studies using only fortified food developed and marketed by the Food Industry, and (c) interventions targeting artificial nutrition (e.g., tube feeding, parenteral feeding, enteral feeding).

Comparators: As the present review aimed at compiling DIY food-based fortification recipes and reporting their acceptability, any comparator was eligible for inclusion (e.g., studies comparing food-based fortification versus Oral Nutritional Supplements (ONS), or studies comparing two types of fortified food). In addition, studies without a comparator were eligible for inclusion.

Outcomes: Three categories of outcomes were considered: (a) characterization of the nutritional intake (e.g., dietary pattern, nutrient intake), (b) characterization of the nutritional status (e.g., body mass index (BMI), weight, undernutrition) and (c) characterization of the acceptability (e.g., liking, preference, pleasure).

Study design: All types of study design including interventional and observational design were eligible. All period of times and duration of follow-up were eligible.

Other: No restriction was set for the publication date. Only publications written in English were included because of the uncertainty surrounding the words used to refer to the concept of “DIY food-based fortification” in foreign languages. Narrative review, conference abstracts, editorials, and grey literature were excluded.

2.3. Information sources and search strategy

A search strategy with both thesaurus and free-text terms was developed – after repeated attempts and adjustments – to retrieve relevant articles in the following databases: Web of Science (WOS), PubMed and Scopus ( Supplementary material ). Separate title, abstract and keywords searches were conducted for older people, food-based fortification and outcomes in February 2021. An update was performed in January 2022. The results for the three separate search strings were combined to identify relevant articles. Afterwards, for further screening, references from selected articles and systematic reviews were checked manually in case they were not identified during the whole search process. After duplicates removal, titles and abstracts in the first step and full texts in a second step were screened by two independent reviewers (AG and MP) according to the agreed inclusion and exclusion criteria. For each screening level, a training exercise was conducted before the starting of the screening process on a random sample of 100 titles and abstracts and 10 full texts to ensure high inter-reviewer reliability. Disagreements between reviewers were resolved by consensus or by consulting a third reviewer (CSR or VVW). The reasons for exclusion were recorded at the full-text stage (the list of excluded studies at the full-text stage and the reasons of exclusion are presented on Supplementary material ).

2.4. Charting the data

A standardized data summarization form was developed a priori and revised, as needed, after the completion of a training exercise completed on a sample of 5 articles. All included studies were summarized by two reviewers (AG and MP), independently, with conflicts resolved by a third reviewer (CSR or VVW). The data summarization included the following items:

- Article identifiers (authors, year of publication)

- Study identifiers (objective, design, country)

- Population (age, gender, sample size, inclusion and exclusion criteria)

- Intervention (description of the DIY fortification recipes)

- Comparator (if applicable)

- Outcomes (endpoints, measurement method, main results)

2.5. Quality assessments

All included studies were independently assessed for quality by two reviewers (AG and MP); conflicts were resolved by consensus. The articles’ quality was assessed with the quality assessment criteria developed by Kmet et al. ( 28 ). The criteria are presented in Supplementary material . In addition, the description quality of the DIY fortification recipes (fortificants, food matrices, concentration) was assessed (but not included in the quality score).

2.6. Collating, summarizing and reporting the results

A descriptive numerical summary of the characteristics of the included studies was performed. Tables and graphs were created to reflect the number of studies included, study designs and settings, publication years, the characteristics of the study populations, the outcomes reported, and the countries where the studies were conducted. In line with systematic literature review guidelines, the quality of the included studies was assessed ( 25 , 29 ).

3.1. Characteristics of the included studies

On the 21,493 articles retrieved, 253 records were kept for full text screening and 49 studies were included in the systematic review: 44 original studies ( Figure 1 ; 3,384 participants) and 5 systematic literature reviews ( 21 – 24 , 30 ). The reasons for excluding papers were: no original research ( n  = 18), wrong population ( n  = 18), no DIY food-based fortification ( n  = 135), fortification with micronutrients only ( n  = 15), wrong outcomes ( n  = 18). Wrong outcomes included functional outcomes (muscle strength), gastric emptying, glycemia, gut hormones, bone mineral density, quality of life. Two articles ( 31 , 32 ) were excluded because they did not provide enough information about the nutritional strategy used.

Figure 1 . PRISMA flow diagram.

The included articles were published between 1996 and 2021, and most were published after 2011 ( n  = 34) ( Table 1 ). The studies mainly took place in Europe ( n  = 33). The rest took place in Australia ( n  = 4), North America ( n  = 4) or Asia ( n  = 3). The setting was most often the hospital ( n  = 20) followed by nursing homes ( n  = 13) and home setting ( n  = 13). Twenty-seven studies of the selection were longitudinal with follow-up times between 10 days to 12 months and 16 studies were cross-sectional ( Table 1 ). In addition, 30 studies used a between-subject design while 13 studies used a within-subject design; only 1 study was observational. Finally, sample sizes varied (ranging from 7 to 320 participants), but most studies recruited 20 to 49 subjects ( n  = 17).

Table 1 . Characteristics of the systematic literature review articles.

Among the 44 original research studies, 3 were fully focused on the acceptability outcome ( 33 – 35 ). Among the 41 remaining articles, the majority ( n  = 31) were entirely dedicated to nutritional outcomes. Finally, 10 articles were “mixed” and assessed both nutritional and acceptability outcomes.

A descriptive summary of the included studies yielded the four following topics:

- Description of DIY fortification recipes: which types of food are fortified? Which nutrients are added? In what form? At which concentration?

- Assessment of DIY fortified foods acceptability: to which extent do older people like fortified food? Do the sensory characteristics of fortified foods fulfil older people’ sensory expectations and preferences?

- Assessment of the nutritional impact of DIY food-based fortification: did older people who received fortified food improve their nutritional intake and nutritional status compared to a standard diet?

- Comparison of DIY food-based fortification with other alternatives (e.g., dietary counseling, Oral Nutritional Supplement – ONS): is fortified food more acceptable and/or does it provide a nutritional benefit compared to other alternatives?

3.2. Quality assessment

A quality assessment was performed for each outcome, i.e., nutritional outcome and acceptability outcome ( Supplementary material ). In fact, in mixed articles, different panels and designs were often used for nutritional and acceptability outcomes.

Regarding nutritional outcomes, the methodological quality of the studies was in general good with an average quality score of 0.92 (standard deviation: 0.09) ranging from 0.62 ( 36 ) to 1 ( 37 – 54 ) ( Supplementary material ). Overall, recruitment of participants was the variable that was the most poorly rated in the selected studies. This was because the majority of studies did not detail the recruitment procedure nor the precise localization where the study took place. Sample size and control for confounding factors were badly rated because a large number of studies did not reach an appropriate sample size or did not consider confounding variables (e.g., age, gender, Body Mass Index (BMI), weight, nutrition status) in data analysis. Study design and subject description factors were moderately rated due to insufficient/incoherent information preventing clear understanding of concerned articles.

The methodological quality of the 13 studies related to acceptability outcomes was on the whole lower than for the nutritional outcomes, with an average quality score of 0.75 (standard deviation: 0.23) ranging from 0.33 ( 37 ) to 1 ( 33 , 43 , 44 ) ( Supplementary material ). Usually, recruitment of participants, sample size, analytic methods and results were the lowest rated factors. As for the nutritional quality assessment, the majority of studies did not detail the recruitment procedure nor the precise localization where the study took place. Moreover, most studies did not clearly describe the analytic method used when it was mentioned. For 4 criteria (sample size, results, outcomes measures and study design) the poor quality is related to the fact that the acceptability measure was not the main outcome of the article.

Finally, the description of the DIY fortification recipes was also poorly rated: very few studies provided precise information about food matrices, fortificants and recipes.

3.3. Description of DIY fortified recipes

Table 2 shows the description of the DIY fortified recipes. On the whole, 7 articles implemented energy fortification, 18 implemented protein fortification and 19 implemented a combination of protein and energy fortification. It should be noted that 10 articles did not specify the nature of food matrices ( 38 , 44 , 55 , 58 , 61 , 64 , 65 , 67 , 72 , 74 ) and 5 articles did not specify the nature of the fortificants ( 50 , 53 , 56 , 57 , 74 ). Only 8 articles provided enough details about the recipes for them to be reproduced by a third party ( 33 – 35 , 39 , 46 , 49 , 54 , 73 ).

Table 2 . Description of DIY fortified recipes.

Overall, 137 DIY fortified recipes were listed: 75 savory and 62 sweet. Among these recipes, 64 were meant to be eaten cold and 67 were meant to be eaten hot (6 can be eaten cold or hot). The food matrices included desserts ( n  = 20 articles; mousse, pie, muffin, cake, biscuit, ice-cream…), meat and fish dishes ( n  = 18; meatball, chicken sticks, marinated duck, baked salmon…), side dishes ( n  = 17; purée, sautéed vegetables), dairy products ( n  = 17; milk, yoghurt, cream), soups ( n  = 14), carbohydrate-based dishes ( n  = 14; oatmeal, cereal, risotto, pancake), beverages ( n  = 9; fruit juice, tea), sauces ( n  = 9), breads ( n  = 8), fruits ( n  = 7; compote/purée, salad, smoothie), eggs dishes ( n  = 3; omelet) and pulse-based dishes ( n  = 1). It is interesting to note that food matrices included both liquids (milk, soup, fruit juice…), semi-liquid foods (purée, yoghurt…) and solid foods (cake, chicken sticks, bread). There was a large variability in the number of matrices used for fortification in the articles. Twelve articles used one only matrix category to be fortified ( 33 – 36 , 39 , 40 , 46 , 49 , 52 , 54 , 75 , 77 ). Munk et al. ( 66 ) developed 36 fortified dishes in collaboration with dietitians, chefs and patients from a hospital. These dishes covered a large range of different food types (soup, meat and fish dishes, vegetable dishes, bread, dessert, beverages).

Twenty different fortificants were identified across all the studies, including 10 regular food ingredients and 10 macronutrient isolates or concentrates. Four articles ( 38 , 45 , 59 , 66 ) did not provide enough details about fortificants (“high fat dairy food,” “dairy,” “non-dairy substitute,” “natural energy-dense ingredient,” “protein powder,” “soy origin”), thus they could not be classified. Seven fortificants targeted energy fortification, 8 targeted protein fortification and 5 targeted both. Most of the fortificants were powdered ( n  = 11). Other fortificants were solid ( n  = 4), semi-liquid ( n  = 3) or liquid ( n  = 2). Energy fortificants included cream ( n  = 20 articles), butter/margarine ( n  = 13), oils ( n  = 10), carbohydrates ( n  = 7), hydrolyzed starch ( n  = 1), mayonnaise ( n  = 1) and maize ( n  = 1). Protein fortificants included whey protein ( n  = 15 articles), protein concentrates/isolates ( n  = 5; Protifar, Hyperprotidine, L-Carnitine…), soy ( n  = 3), pea ( n  = 2), meat ( n  = 2), collagen ( n  = 1), casein ( n  = 1), and gelatine ( n  = 1). Energy and protein fortificants included milk powder ( n  = 10), cheese ( n  = 7), milk ( n  = 5), eggs ( n  = 3) and almonds ( n  = 3). Finally, Figures 2 , 3 illustrate the wide variability regarding the additional load of energy and protein provided by fortified food across the studies. This additional load varies from 23 to 850 kcal / day for energy (M = 403; SE = 62) and from 4 to 40 g / day for protein (M = 19; SE = 2).

Figure 2 . Additional protein load (g/d).

Figure 3 . Additional energy load (kcal/d).

3.4. Assessment of DIY fortified foods acceptability

Thirteen studies have assessed consumer acceptability for DIY fortified foods ( Table 3 ). All these studies conducted the acceptability evaluation with older people except for one ( 71 ), who asked nursing home staff to provide feedback on product acceptance based on residents’ observation. Six articles ( 33 , 34 , 43 , 44 , 52 , 59 ) used liking scales to assess product acceptance while the others only collected qualitative data through interviews, focus groups or an acceptability survey. However, most of the articles do not provide enough information about the methodology used to assess acceptability and/or about the results. In most of the articles ( n  = 10/13), acceptability was only a secondary outcome while nutrition was the first one. In these studies, acceptability tests were usually conducted with the same sample as the one recruited for nutritional assessment (the whole sample in 6 articles; a smaller sub-sample in 2 articles). Three articles ( 33 – 35 ) were dedicated to assessing acceptability of DIY fortified foods versus regular foods.

Table 3 . DIY fortified food acceptability assessment.

Seven articles provided results on comparison between DIY fortified and regular foods. Among them, 4 articles ( 37 , 43 , 44 , 59 , 75 ) reported no significant difference in acceptability when comparing fortified and regular foods while 2 articles ( 33 , 35 ) reported that fortified foods were less appreciated than regular food. Only one article reported that some fortified foods were more appreciated than regular food, but it depended on the nature of the fortificant added to the food ( 34 ). In fact, tomato sauce fortified with cream or with a mix of whey protein and maltodextrin were more liked than regular tomato sauce, but tomato sauce fortified with butter was less liked than regular tomato sauce. Wendin et al. ( 35 ) also showed some difference between foods fortified with different fortificants: the regular muffin was more liked than the muffin fortified with almond flour, which was more liked than the whey muffin, itself more liked than the soy muffin.

3.5. Assessment of the nutritional impact of DIY food-based fortification

Forty studies assessed the impact of diet enrichment including DIY food-based fortification on nutritional outcomes (food and/or nutrient intakes, nutritional status or body weight) compared to a standard diet ( Table 4 ). Among these studies, 3 combined DIY food-based and diet-based fortification (i.e., modifying the diet by adding nutritionally rich foods), 6 combined food-based fortification and fortified foods marketed by the Food Industry, 1 combined food-based fortification and Oral Nutritional Supplements (ONS), and 2 combined food-based fortification, diet-based fortification and ONS, while 27 studies assessed the impact of DIY food-based fortification alone. Nutritional intake was mainly measured by using dietary record. Nutritional status was mainly assessed by measuring body weight or BMI (20 studies), by using the Mini-Nutritional Assessment Questionnaire [MNA, 8 studies – ( 39 , 48 , 49 , 52 , 57 , 72 , 73 , 77 )] or by measuring muscle mass [4 studies – ( 39 , 46 , 49 , 58 )]. A few studies used other indicators such as the Subjective Global Assessment ( 74 ) or albumin and pre-albmin ( 40 , 47 , 52 , 58 , 72 ).

Table 4 . Comparison between DIY fortified diet and standard diet on nutritional outcomes.

When all the studies are considered, results highlight that provided protein-fortified foods led to a significant increase in protein intake (26 studies over 29) and that provided energy-fortified led to a significant increase in energy intake (15 studies over 20). Only a few studies showed a significant impact of DIY fortification on nutritional status compared to regular food offer: 3 out 8 observed a significant impact on MNA score, 7 out 20 observed a significant impact on body weight or BMI and 2 out 4 observed a significant impact on muscle mass. None observed a negative impact.

When only the studies which assessed the impact of DIY fortification alone are considered (in bold in the Table 4 ), results still highlight that provided protein-fortified foods led to a significant increase in protein intake (16 studies over 18) and that provided energy-fortified led to a significant increase in energy intake (9 studies over 13). Only a few studies showed a significant impact of DIY fortification on nutritional status compared to regular food offer: 1 out 5 observed a significant impact on MNA score, 4 out 13 observed a significant impact on body weight or BMI and 1 out 3 observed a significant impact on muscle mass.

3.6. Comparison of DIY food-based fortification with other alternatives

Seven studies evaluated two DIY food-based fortification strategies with either different energy/protein loads ( 36 , 49 , 59 ), different fortificants ( 46 , 61 , 65 ) or different portion sizes ( 43 ). Four studies compared DIY food-based fortification with another alternative such as ONS ( 76 ), ( 74 ), adding high-energy and/or high-protein food items to the menu ( 55 ), or increased staff assistance to older people during mealtime ( 50 ) ( Table 5 ). However, very few studies have produced statistics to compare the different options. Not surprisingly, higher energy/protein loads are associated with higher energy/protein intake ( 36 , 49 ). However, there was no significant difference between the 1.2 and the 1.5 g of protein / kg of body weight / day in the evolution of nutritional status and muscle mass over the 12-week intervention ( 49 ). In Ziylan et al. ( 43 ), the reduced-size enriched chicken meal led to a significantly higher energy intake than the normal-size meal. However, the difference in intake was rather small and no impact of portion size was observed for the enriched beef meals. In Evans et al. ( 46 ), a combination of three amino acids significantly improved muscle mass over 2 months while no change was observed when a single amino acid was used to fortify the orange juice. Stow et al. ( 76 ) observed no difference between food-based fortification and ONS while Sossen et al. ( 74 ) observed a slight advantage for DIY food-based fortification compared to ONS. Energy and protein intakes were higher with DIY fortification than with ONS, and body weight was stable with DIY fortification whereas it decreased with ONS during the 6 months of follow-up. Finally, providing DIY fortified food led to higher energy and protein intake when compared with improving staff assistance to older people during mealtime ( 50 ).

Table 5 . Comparison between DIY fortification and other alternatives.

4. Discussion

4.1. originality/value of the present review.

A survey of the literature allowed the identification of five systematic literature reviews close to the topic of the present review ( 21 – 24 , 30 ). Firstly, the systematic review of Trabal and Farran-Codina ( 23 ) investigated whether, compared to a standard diet, DIY food-based fortification with regular ingredients and/or powdered modules could improve energy and protein intake in older adults in hospital settings, long-care facilities or home settings. This review included 9 articles. The authors concluded that DIY fortification is a valid intervention for improving energy intake in older adults yet there was insufficient evidence for protein intake, nutritional status and body weight. Secondly, Morilla-Herrera et al. ( 21 ) targeted all studies related to DIY food-based fortification with macronutrients to prevent the risk of malnutrition in older patients receiving hospital services for acute or chronic disease, in older people living in nursing homes and in older people with home-care. This review encompassed 7 articles, and the meta-analysis highlighted that DIY food-based fortification yields positive results in the total amount of ingested calories and protein. Thirdly, Douglas et al. ( 22 ) aimed to evaluate the effect of DIY fortification with regular food ingredients (excluding protein powders) on energy and protein intake compared to standard diet among adults aged 60 and more in acute-care hospitals, long-term care settings or living at home. Ten articles were included. This review suggested that DIY fortification was effective in increasing energy and protein intake among older individuals. Fourthly, the systematic review by Mills et al. ( 24 ) explored the evidence for the use of energy and/or protein dense meals (DIY food-based fortification) or additional snacks (diet-based fortification) to increase the dietary energy and protein intake of adults older than 60 in hospital or rehabilitation facilities. Ten articles were identified. Authors reported that when compared with usual nutritional care, DIY fortification could be an effective, well-tolerated and cost-effective intervention to improve dietary intake among hospitalized patients. Finally, Sossen et al. ( 30 ) investigated the effect of food-based and diet-based fortification on energy and protein intake compared to any/no nutritional strategy in residents living in nursing homes. Sixteen articles were included. The results of the meta-analysis showed that fortified menus may significantly increase energy and protein intakes compared with standard menus.

The present review retrieved 44 articles that tested DIY food-based fortification in people over the age of 65. This review differs from previous reviews in the following respects. Firstly, we focused the review on DIY food-based fortification, i.e., the addition of regular food ingredients or macronutrient extracts into conventional food matrices to increase energy and protein content in the final dishes. Douglas et al. ( 22 ) considered only culinary ingredients. Mills et al. and Sossen et al. ( 24 , 30 ) considered both food-based fortification and diet-based fortification via the addition of supplementary conventional foods like snacks to participants’ diets. Second, we considered all living settings, i.e., at home, with or without assistance, institutions and hospitals [Morilla-Herrera et al. ( 21 ) only considered dependent older people]. Thirdly, we considered not only nutritional outcomes but also acceptability outcomes. In addition, we used a wide range of keywords to account for the lack of consensual terminology regarding the concept of DIY food-based fortification ( Supplementary material ). This allowed us to identify a much larger number of articles than in previous reviews.

4.2. Description of DIY fortified recipes

A wide variety of DIY fortified recipes were extracted from this review, including liquid (35% of the recipes), semi-solid (17%) and solid food matrices (48%). However, the quality evaluation of the articles highlighted the lack of information provided by the authors on the description of fortified recipes. Only 8 articles provided sufficient information for a third party to reproduce the same fortified recipes as used in the articles. In order to identify efficient DIY fortified solutions, it is essential that in future articles provide a detailed description of the fortified recipes, including the nature of food matrices and fortificants, final energy and protein concentration, additional nutrient load provided by the fortified food compared to the standard food, consumption time, and portion size. From the information collected, energy fortification is mainly achieved through the use of fats and dairy products (cream, butter, oil) while protein fortification is mainly achieved through protein extracts. Such products are usually in powder form (‘protein powders’) and proved to have varied applications and uses within food processing as well as high nutritional and functional value ( 68 ). The present review showed that the protein products used in fortified recipes were mainly derived from animal sources (85% of the recipes), especially from milk (67% of the recipes), and to a lesser extent from plant sources (15% of the recipes). Animal-derived proteins are more readily digestible and effective in muscle protein synthesis than plant derived proteins ( 78 ).

4.3. Evaluation of DIY food-based fortification solutions

Results suggest that food-based fortification is an effective strategy to improve energy and/or protein intake. This trend is observed whether all the studies – including the ones that combined DIY fortification with other strategies (i.e., providing ONS, additional food items, fortified foods from Food Industry) or whether only the studies which assessed the impact of DIY fortification alone are considered. In other words, DIY fortification seems to be an effective strategy to improve nutritional intake, whether used alone or combined with other enrichment strategies. However, no strong evidence is observed regarding the impact of DIY fortification to improve the nutritional status (e.g., MNA score, body weight, muscle mass).

It should be noted that providing fortified food was not necessarily enough to get participants to meet the recommended nutritional allowance ( 50 , 55 , 60 , 75 ). For instance, in Stelten et al. ( 75 ), 64% of the fortified group did not reach the threshold of 1.2 g protein/kg of body weight/day. This raises the question of the need for new fortification solutions with higher levels of energy and protein content. In addition, consuming fortified foods throughout the various meals of the day may be more efficient than consuming fortified foods only once per day. For instance, Castellanos et al. ( 59 ) reported higher energy intake when both breakfast and lunch were fortified than when only lunch was fortified, but they did not carry out statistical analysis to compare these two conditions.

Besides the relatively large number of studies that have tested the impact of DIY food-based fortification on nutritional outcomes, very few studies have looked at the acceptability of DIY fortified food. Only 10 of the 41 nutrition-related articles reported an evaluation of the acceptability of DIY fortified foods and only 3 of the 44 articles included in this review were completely devoted to the assessment of acceptability of DIY fortified food. Unsurprisingly, the quality of the acceptability studies is much better in the articles focused only on this outcome than in the articles that conducted an acceptability study alongside a nutritional study. In the latter, the sample size is often insufficient, the methods are often qualitative and the results are often imprecise and incomplete. In addition, the people who assess the acceptability of fortified food are sometimes different from the end-users [e.g., the fortified foods are tasted by the staff ( 37 )]. Overall, the results tend to show that DIY fortified foods are equally or less appreciated than standard foods – never more. However, before drawing any final conclusions, there is a need to carry out further acceptability studies with a higher quality, taking into account the good practices and the norms of sensory evaluation ( 79 , 80 ). Indeed, fortified foods should not only be good from a nutritional point of view, but also “good to eat” to ensure that they are actually consumed by the target population. Furthermore, it would be worthwhile to optimize the sensory quality of fortified foods by recruiting older adults in tasting panels. Fortification improvement based on older people’s feedback led to increased food intake in nursing homes ( 81 , 84 ).

4.4. Limitations and strengths of the present SLR

The strength of this paper is its reliable literature search, with a complete overview of nutritional and acceptability issues for fortified food targeting older people. Given the lack of a consensual definition of the concept of food-based fortification, we have used a broad set of keywords to retrieve articles of interest. The limitations of the present literature review are the following: the literature search strategy did not include trial registries, nor grey literature, and it was restricted to English papers. There are two discrepancies between the present method and the one published before the review was carried out. In the published method, we considered including papers published in both English and French (the authors’ native language), but papers in French were ultimately excluded in order to avoid a language bias in the literature search. In addition, in the published method, we considered including papers related to micronutrients fortification, but ultimately focused the scope of the present review on macronutrient fortification, otherwise the scope of the review would have been too broad. Finally, a limitation lies in the fact that it was not always easy to determine whether the products used in the nutritional interventions were a DIY fortified food, a fortified food marketed by the Food Industry or an ONS. For instance, we excluded the studies where enrichment consisted of providing participants with a sachet of nutrient constituents to be dissolved in water [for instance ( 82 , 83 )]. Indeed, dissolving a sachet of powder in water is more like taking a drug than having a drink. Conversely, all the interventions consisting of adding a nutrient-dense ingredient to a food matrix were included, even when the fortificant was very specific [for example, branched chain amino acids powder ( 58 ), L-carnitine ( 46 )]. However, the question arises as to the accessibility of this type of fortificant to the end-user in real life.

5. Conclusion

The present systematic literature review highlighted that, compared to a standard diet, DIY food-based fortification – i.e., incorporating ingredients of nutritional interest into commonly consumed foods – is a valuable strategy for increasing energy and protein intake in older people. However, no strong evidence was observed regarding the impact of DIY fortification to improve the nutritional status (i.e., MNA score, body weight, muscle mass). In addition, further research is needed to better assess the acceptability of this strategy among end-users. Given the limitations of the studies included in this systematic review, we put forward four recommendations for future research. First, we emphasize the need to develop a consistent definition of DIY food-based fortification that clearly distinguishes this strategy from other enrichment strategies such as the consumption of ONS or fortified food from food industry. Second, it would be useful for studies to better describe the recipes used for DIY fortification. This information would result in a better understanding of the factors that maximize the impact of food-based fortification on nutritional outcomes. Third, it would be relevant to systematically assess the acceptability of DIY fortified foods in addition to the nutritional outcomes. This should be done by implementing consumer tests that respect the good practices and the recommendations defined in sensory evaluation for such tests (sample size, methods…). To achieve this, it is essential to encourage more pluri-disciplinary research projects involving experts in nutrition, sensory evaluation and food technology. Fourth, we encourage researchers to further compare the impact of food-based fortification with other enrichment strategies, and in particular ONS, in order to better decipher the impact of each of these strategies in tackling undernutrition in the older people. Finally, future research should also study how to promote DIY food fortification among the older people, their caregivers, as well as among catering and health professionals. Indeed, despite this strategy has proved effective in sustaining caloric and protein intake in older people, it remains largely unknown and underused. Several dissemination strategies could be considered. A first one could be the development and the diffusion of DIY fortified recipes booklets. Such booklets should indicate the amount of protein provided by each portion. These booklets would also need to be co-created with end-users, to ensure the feasibility and acceptability of the recipes in the field, considering various settings (home cooking, home-delivery meals, nursing home, hospital). A second dissemination strategy could be the organization of therapeutic workshops at hospital discharge or in day hospital, bringing together dieticians, chefs and older people to promote DIY food fortification. However, from a more global perspective, public policies are needed to raise awareness of the nutritional needs of the older people. These policies must combine information and tools to maintain adequate energy and protein intakes, in order to prevent undernutrition in the older population.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author/s.

Author contributions

AG: methodology, investigation, formal analysis, and writing – original draft. MP: methodology, investigation, formal analysis, and writing – review and editing. VW-D: conceptualization and writing – review and editing. CS-R: conceptualization, methodology, formal analysis, writing – original draft, and funding acquisition. All authors contributed to the article and approved the submitted version.

This work received funding by the French “Investissements d’Avenir” program, project ISITE-BFC (contract ANR-15-IDEX-0003) and from ANR (ANR-20-HDHL-0003 FORTIPHY), Research Council Norway (RCN 321819), BBSRC (BB/V018329/1) under the umbrella of the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL) and of the ERA-NET Cofund ERA-HDHL (GA N°696295 of the EU Horizon 2020 Research and Innovation Programme).

Conflict of interest

During the past 36 months, CSGA and CHU Dijon received research grants from OGUST, SAVEURS et VIE, and INSTITUT NUTRITION. CS-R received consulting fees from BEL FOOD and author fees from Correspondances en Métabolismes Hormones Diabètes et Nutrition.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2023.1232502/full#supplementary-material

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Keywords: elderly, enrichment, supplementation, food-first, malnutrition, intake, body weight, acceptability

Citation: Geny A, Petitjean M, Van Wymelbeke-Delannoy V and Sulmont-Rossé C (2023) Impact of food-based fortification on nutritional outcomes and acceptability in older adults: systematic literature review. Front. Nutr . 10:1232502. doi: 10.3389/fnut.2023.1232502

Received: 31 May 2023; Accepted: 02 October 2023; Published: 27 October 2023.

Reviewed by:

Copyright © 2023 Geny, Petitjean, Van Wymelbeke-Delannoy and Sulmont-Rossé. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Claire Sulmont-Rossé, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Microgreens production: exploiting environmental and cultural factors for enhanced agronomical benefits.

1. Introduction

2. optimising growing conditions of microgreens, 2.1. seed density and quality, 2.2. substrate, 2.2.1. physicochemical properties of growing media, physical properties, chemical properties, 2.4.1. light quantity, 2.4.2. light quality, 2.5. temperature, 2.6. relative humidity (rh), 2.7. genetic traits influencing growth and yield, 2.8. fertiliser, 3. nutritional profile and sensory attributes, 4. agronomical benefits of microgreens, 4.1. short-growing time, 4.2. carbon footprint, 4.3. energy conservation, 4.4. higher productivity, 4.5. food security, 4.6. minimising waste, 5. future of microgreens, 5.1. comprehensive nutritional assessment, 5.2. increased demand and market growth, 5.3. advancements in cultivation techniques, 5.4. environmental impact and sustainability, 5.5. policy and regulatory frameworks, 6. conclusions, author contributions, data availability statement, conflicts of interest.

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Dubey, S.; Harbourne, N.; Harty, M.; Hurley, D.; Elliott-Kingston, C. Microgreens Production: Exploiting Environmental and Cultural Factors for Enhanced Agronomical Benefits. Plants 2024 , 13 , 2631. https://doi.org/10.3390/plants13182631

Dubey S, Harbourne N, Harty M, Hurley D, Elliott-Kingston C. Microgreens Production: Exploiting Environmental and Cultural Factors for Enhanced Agronomical Benefits. Plants . 2024; 13(18):2631. https://doi.org/10.3390/plants13182631

Dubey, Shiva, Niamh Harbourne, Mary Harty, Daniel Hurley, and Caroline Elliott-Kingston. 2024. "Microgreens Production: Exploiting Environmental and Cultural Factors for Enhanced Agronomical Benefits" Plants 13, no. 18: 2631. https://doi.org/10.3390/plants13182631

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