Adherence to and acceptability of home fortification with vitamins and minerals in children aged 6 to 23 months: a systematic review

Background Vitamin and mineral deficiencies affect more than two million people worldwide. In 2011, based on recent scientific evidence and the low effectiveness of current strategies, the World Health Organization recommended home fortification of foods with multiple micronutrients in powder (MNP) as a new strategy to prevent and control anaemia during childhood. This systematic review assessed adherence to and acceptability of home fortification with multiple micronutrients in powder (MNP) in complementary feeding. Methods Adherence was assessed based on number or percentage of prescribed sachets that were consumed, and acceptability was assessed according to perceptions of caregivers and children about MNP. Results In summary, the studies indicated that home fortification with MNP has good adherence, ranging from 50 % to over 90 % of the prescribed sachets and that MNP was well accepted by caregivers. Caregivers reported side effects in 3 % to 32 % of children taking MNP in many studies; diarrhoea, vomiting, and constipation were the most common. Conclusions Home fortification with MNP has good adherence and acceptability in infants, with higher adherence in non-daily or flexible administration regimens. Characteristics of the target population and increased diarrhoea burden should be considered for planning public health programs with long term use of MNP. Acceptability of the MNP is satisfactory, when the use and perceived beneficial effects on children’s health are considered.


Background
Vitamin and mineral deficiencies affect more than two million people worldwide [1]. Young children are highly vulnerable because their high nutrient requirements need to be achieved through diet, which is sometimes inadequate in quantity and quality of nutrients, especially in developing countries.
Iron deficiency anaemia is the most common preventable nutritional problem among young children, affecting more than 750 million children worldwide [2]. According to the World Health Organization, the prevalence of iron deficiency among young children is 2.5 times the prevalence of anaemia [3]. In 2011, based on recent scientific evidence and the low effectiveness of current strategies, the World Health Organization recommended home fortification of foods with multiple micronutrients in powder (MNP) as a new strategy to prevent and control anaemia during childhood [4]. Several formulations with different compositions of micronutrients are available for use in complementary feeding. For example, Sprinkles is the most used MNP and its formulation of micronutrients was first developed in 1996 by researchers at the Children's Hospital in Toronto, to prevent micronutrient deficiencies in children [5].
Previous studies have described the efficacy of home fortification with MNP in different contexts, especially in low-income countries, where nutritional deficiencies in childhood are more prevalent. Most of these studies used increased average haemoglobin concentration as the main study outcome. However, few studies have evaluated adherence and acceptability, and when this information is available, adherence was assessed mainly by the number of sachets used. A recent systematic review of the effectiveness of MNP interventions found high acceptability with variable adherence, indicating that high acceptability does not always translate into adherence [1]. Adherence in trials has been defined as the extent to which a patient follows advice regarding the use of a supplement, for example. Studies have found that high adherence with fortified complementary foods has often been reflected in improved nutritional status, suggesting that adherence is a key factor in determining the effectiveness of the fortification strategy for MNP interventions [5,6].
It is known that adherence and acceptability are key factors in the success of an intervention. Thus, this systematic review aimed to summarize the scientific literature examining the adherence to and acceptability of home fortification with MNP in complementary feeding for planning and evaluation of public health programs to prevent childhood anemia.

Methods
We performed a systematic review of the scientific literature in December 2013, searching for indexed published articles in the electronic databases of the U.S. National Library of Medicine and the National Institutes of Health (PubMed), the Latin American and Caribbean Literature on Health Sciences (LILACS), the Scientific Electronic Library Online (SciELO), and Thomson Reuters IP & Science (Web of Knowledge).
The descriptors used to select articles were "micronutrients powder" OR "home fortification" OR "Sprinkles." Truncation symbols were used with the searched terms in Spanish and English to find words with the same root, increasing the chances of detecting a greater number of items. The selection of papers was restricted to articles published from 2003 to 2014 and written in Portuguese, Spanish, or English. The reference lists and some potentially relevant articles cited were examined and read to find additional articles or important information to the review.
The main eligibility criteria for selection of the published studies included a focus on children aged 6 months to 2 years or more and available information on adherence to and/or acceptability of home fortification of complementary feeding with MNP. Studies with either qualitative and/or quantitative methods were accepted.
Studies that used multiple micronutrients not in powder form, articles with target populations not in the age range of interest, abstracts or Congress Annals, other review articles, and technical reports were excluded for the purpose of this review.
The identification and selection of the articles were performed by two authors independently. Studies were initially selected based on their titles, and these were included in the next step of reading abstracts. Articles selected based on their abstracts were then read in full before the final selection decision, based on the criteria listed above. Discrepancies were resolved by the two authors.
A flowchart for processing and data analysis was organized to describe the steps in paper selection (Fig. 1). After all papers were read, a spreadsheet was created in Microsoft Excel 2010 to extract the relevant information from each study. Virtual Endnote Web software was used to assist in organizing the articles and writing this manuscript. Finally, descriptive tables were created with a synthesis of included articles, listing the following information: author, publication year, country, prevalence of nutritional disorders, study aim, population and design, intervention characteristics and results regarding adherence, acceptability, and side effects of home fortification with multiple micronutrients. Considering the scope of this review with a focus on available data on adherence to and acceptability for the use of MNP in complementary feeding, we did not follow strict criteria for assessing quality of the revised articles. In this review, adherence was defined as a quantitative measure of the number of sachets used compared with the expected use over a specified time frame informed in the revised studies; acceptability was considered as a subjective measure related to caregivers perceptions of the child's acceptance of the sachet, as well as perceptions of associated health benefits or side effects.

Results
Overall, 131 references were found using our search criteria. Most articles were excluded after reading their titles and abstracts based on the exclusion criteria, leaving only 19 articles eligible for full reading. Of these, two were excluded because they did not provide information on adherence to and acceptability of home fortification. The remaining 17 articles that met the inclusion criteria were selected for detailed analysis of adherence to and acceptability of home fortification with MNP in complementary feeding (Fig. 1). Tables 1 and 2 shows the main characteristics of the selected 14 clinical trials and three observational studies, respectively. Most of these studies were conducted in low-income countries: two in South America [7,8], one in Central America [9], three in North America [10][11][12], eight in Asia [13][14][15][16][17][18][19][20], and three in Africa [21][22][23].
A high prevalence of anaemia and stunting was found in children less than 2 years of age at analysed sites. The sample size in these studies ranged from 47 to 2,746 children and the duration of intervention ranged from 1 to 26 months, with a 6-month intervention in six studies [8, 10, ,1317,18,21]. Twelve studies offered MNP to children daily [7, 9-12, 15, 17, 19-23], three adopted non-daily administration, five or fewer sachets per week [8,13,14] and two articles compared daily with nondaily administration [16,18]. In addition, five studies compared MNP with other supplement types or fortified foods [9,11,12,21,23] and two studies compared different MNP formulations [7,20].
In all reviewed studies caregivers received instructions about appropriate use of the MNP sachets. One package of MNP should be added in a small portion of usual semi-solid food to be consumed fully for the child. Only in study conducted by Sampaio et al. MNP sachets were administered out of home, in childcare centre. The authors commented that the banana was the food commonly used to mix MNP sachets; in remaining studies no information on this was provided [7]. Table 3 summarizes the information collected on adherence to and acceptability of home fortification with MNP in young children. Reviewed studies assessed adherence based on number or percentage of prescribed sachets that were consumed. Acceptability was assessed according to perceptions of caregivers and children about MNP. For example, the reasons for children or caregivers like or dislike of MNP, such as taste, flavor, ease of use, ease of transportability, health benefits and others.

Adherence and acceptability
Eight studies reported an average consumption of sachets ranging from 50 % to 96 % of the recommended number [7,9,10,17,[19][20][21][22]. Only one study reported unsatisfactory adherence to MNP administration. Those authors considered consumption of five to seven sachets per week to be high adherence, and this number was achieved by 31-46 % of participants in the study [11].
In the two papers that assessed adherence to consumption of sachets in a daily versus a non-daily scheme, the authors found higher rates of adherence in non-daily regimes, and in these groups the average consumption was greater than 90 % of the prescribed sachets [16,18].
In general, MNP were well accepted by caregivers and by children. Among the mentioned factors that contributed to high acceptability were transportability, ease of preparation and use, perceived benefits to children's health (increased appetite and agility), and preservation of the organoleptic characteristics of the children's meals. Nevertheless, some studies reported that MNP caused changes in the colour or taste of food, including yellowing of rice, bitterness of food after mixing with MNP, and the unpleasant taste of MNP itself. In most of these studies, the authors did not report whether the MNP had been consumed with liquids, such as broth soups or fruit juices [12,14,15,18].
Most mothers expressed interest in continuing MNP use and recommended MNP to other mothers, if these products were available in their regions. In the study by Rosado et al. 2010 MNP had lower acceptability than other supplements used in the study (iron supplement, iron and folic acid supplement, micronutrient-fortified complementary food or zinc/iron/ascorbic acid fortified  To evaluate the effect of MNP alongside infant and young child feeding education program compared with feeding education alone on anaemia, iron deficiency, vitamin A, zinc, and growth in Cambodian infants. Cluster-randomized effectiveness trial. Two groups: non-supplemented control received infant and young child feeding education alone; supplemented group received MNP alongside education.  water). According to the authors, most cases of rejection resulted from the taste of the MNP, probably because of their mineral concentrations [12].

Side effects
The most commonly reported side effects in these studies were diarrhoea, vomiting, and constipation, ranging from 3 % to 32 % of participants. Changes in the colour of stools were seen in 95 % of participants in the study by Lundeen et al.; however, this is a harmless expected effect of iron supplementation. These authors did not comment on whether differences in adherence were associated with the occurrence of side effects [19].

Discussion
This systematic review gathered seventeen papers and analysed the main conclusions from their results. Firstly, home fortification with MNP has good adherence in regards to the percentage of sachets consumed, with higher adherence in non-daily administration regimens. Secondly, acceptability of the MNP is satisfactory, when the use and perceived beneficial effects on children's health are considered. However, limitations persist such as limited knowledge and experience of professionals and caregivers in the use of MNP, the resolution of which could increase MNP's acceptability. Finally, MNP side effects ranged from 3 % to 32 % of participants, and in general posed a low risk to health.
Higher adherence in flexible administration regimens compared to daily administration can be attributed to mothers' difficulty in remembering to offer sachets daily and the possibility that mothers discontinued administration when sachets were forgotten [10].
Adherence to non-daily regimens reached 100 % (all children consumed 100 % of prescribed MNP sachets) in the study conducted by Kounnavong et al. [18]; however, a comparison of the impact of non-daily administration versus daily administration on levels of haemoglobin and other biochemical markers would clarify the risks and benefits of different administration frequencies.
Two studies included in this review have made this comparison [16,18]. In the first, the authors concluded that in children with moderate to severe anaemia, daily administration more effectively increases haemoglobin concentration and reduces anaemia [18]. The second study found that haemoglobin levels at the end of the intervention were higher in the non-daily regimes, with a greater reduction in the prevalence of anaemia and a higher percentage of children who remained nonanaemic [16].
Other studies in the literature have also made this comparison [24,25] and concluded that providing MNP weekly with 30 mg of elemental iron produced haematological effects similar to daily administration with 12.5 mg of elemental iron in anaemic children from 6 to 23 months of age [24] as well as in nonanaemic school-age children [25].
More studies are necessary for comparing risks and benefits of different administration frequencies of MNP sachets. However evidences in this review lead us to suggest that public policies and programs with no anaemic    [23] Adherence: No data given. Acceptability: MNP sachets were found to be acceptable and beneficial by mothers. Mothers said that MNP were easy to use, and several liked that the product had no taste or smell and did not change the taste of the food. Almost all mothers, regardless of the product they used, reported some increase in appetite or weight gain in their child (data not shown).
Side effects: Several mothers reported diarrhoea in their children at the start of the study (data not shown).
Jefferds et al. (2010) [22] Adherence: At midway (at 2 weeks of 1 month-study), observations of sachets in 24 households showed an average of 15 sachets used per child per household (range, 5 to 25). Five families reportedgiving away MNP to children living in other households or older children taking and consuming MNP without permission. Acceptability: MNP's acceptability was high and most families reported that the children ate food with MNP without problems. Perceived positive effects observed in children: increased appetite and improvements in immunity, strength, activity levels, and weight gain (data not shown).
Side effects: Infrequently mentioned by some caregivers were initial adjustments to MNP, including diarrhoea, softer stool, dark stool, and vomiting. Adherence: At 12 months, median adherence (95 % CI) to treatment in the MNP group was 85.8 % (82.3-90.0). This adherence was determined as the percentage of scheduled days on which the supplement was added to the child's food. Acceptability: In the MNP group, 96.9 % of mothers liked giving the supplements to their children, 99.0 % of mothers believed that consumption of the supplements benefited their children's health, 89.6 % of mothers said that the child easily accepted food mixed with the supplement, 95.9 % of mothers did not have major problems feeding the child the supplement, and 100.0 % of them had a good impression of the supplement.
Side effects: No significant side effects were reported (data not shown). Acceptability: Most mothers reported changes in their child's behaviour (increased appetite and higher levels of activity and playfulness) after using MNP. MNPs were found to mix easily with food and had 'no' or 'mild' effects on the colour, taste, and smell of foods to which they were added. Almost all mothers preferred flexible administration over daily schedule (data not shown).
Side effects: No data given.
children adopt flexible or non-daily administration model because it has greater adherence by children and caregivers and thus it is more effective and produce haematological effects similar to daily model. Only one study, conducted by Geltmann et al. concluded that MNP had poor adherence, ranging from 30 % to 45 %. It is necessary to remember that this conclusion was based on a definition of adequate adherence as the consumption of five to seven sachets per week, a level that was considered a satisfactory range in all of the other studies [11]. However, satisfactory acceptability was hindered by several factors including inappropriate use of the sachets. In some studies, mothers reported refusal of MNP by children because of changes in the taste of food. MNP is formulated not to alter the organoleptic characteristics of food. It is possible that lack of knowledge led some mothers to use the MNP improperly, for example by mixing it with a liquid food, which is not recommended.
It is known that effectiveness of MNP depends of caregivers to be motivated to offer sachets MNP for children properly and without interruption. In this regard, additional efforts could be made to increase adherence and acceptability of the intervention. For example, high mineral concentrations in MNP sachets can be perceived by the taste; thus, careful attention must be given to the supplements' sensory characteristics during the development process to minimize cases of rejection and to increase adherence to intervention. In addition, additional efforts should be planned in providing information and training to caregivers on appropriate use of MNP sachets since type of food used to mix them can affect its taste and consequently its acceptability.
One study cited the need for MNP to be mixed with food as a barrier to its use given the food situation in some of the countries in which these strategies have been implemented [23]. This study demanded public policies for food availability and distribution. As an alternative approach to address these issues, the Ministry of Health in Brazil developed the "NutriSUS" program, using fortification with MNP in young children attending day-care centres, in a sustainable and multisector strategy integrated with the cash transfer program "Bolsa Família." [26].
Some studies reported that a lack of knowledge and experience with MNP generated concerns among caregivers about its use and safety [11,22]. It is possible that these problems related to the product distribution model and the monitoring of children who participated in intervention, problems that could be resolved through training directed at health professionals and a greater dialogue between professionals and caregivers to address possible doubts and encourage caregivers about the importance of MNP in promoting health of their children. Furthermore, the reported concern and uncertainty of participants about the use of MNP is normal considering it is a new product. In the study conducted by Geltman et al. the mothers who completed the intervention had the greatest understanding about the importance of vitamins and minerals for their children [11].
The main side effects cited in these studies were diarrhoea, vomiting, and constipation, ranging 3-32 % of participants. These problems were more prevalent in the early days of MNP use. However, it must be cautiously interpreted when considering the possible side effects of MNP such as diarrhoea or other gastrointestinal diseases common in young children.
In a recent study by Soofi et al. in a malaria-endemic region of Pakistan with a stunting prevalence of 42 % among children under 5 years of age, the authors found strong evidence of an increase in the proportion of days with diarrhoea and an increase in bloody diarrhoea in the groups receiving MNP [20,27]. That study found that MNP had a modest effect on micronutrient deficiencies, and very little effect on growth (p = 0 · 0017) [20]. Table 3 Summary of results regarding adherence to and acceptability and side effects of home fortification with multiple micronutrients in powder (MNP) (Continued) Menon et al. (2007) [9] Adherence: An estimated mean 57.6 of the planned 60 sachets were consumed (SD, 4.9; range, 27-60). Acceptability: No data given. CI confidence interval, IRR incidence rate ratio, OR odds ratio, RR relative risk, SD standard deviation Another concern discussed in one study [23] is the need to mix MNP in semi-solid food because such food is not always available in low-income countries. The lack of knowledge and experience of professionals and caregivers in the use of MNP, the lack of availability of MNP, and its cost were also considered limitations in another study [22].
Despite of the described limitations, factors such as practicality of use increase in children's appetite, weight gain, and increased activity level, among others, contributed to the high acceptability of MNP. In most studies, participants expressed an interest in continuing MNP use and recommended it to other mothers, which leads us to believe in the potential success of future interventions of home fortification with MNP.
Given these findings, the authors recommend that despite the demonstrated effect of MNP in preventing iron deficiency anaemia, future studies on home fortification with MNP should pay special attention to the definitions and strategies for monitoring adherence and acceptability . This evaluation should account for issues affecting adherence and acceptability of MNPs, highlighting once again the need to direct strategies to the particular characteristics of the target population. Acceptability rates for MNPs have generally been above 83 % in studies in developing countries, although rates are somewhat lower in studies performed in developed countries such as Canada (60 %) [ 1]. Because the use of the MNP requires their addition to foods suitable for young children, the home fortification strategy offers an opportunity to promote healthy complementary feeding, further improving the benefits of fortification [6]. However, it is likely that increased adherence to the use of MNP could result in greater impact on child health outcomes in future studies. Both adherence and acceptability can be increased when providing better guidance to caregivers and integration with the actions already performed by the healthcare team [6].

Conclusions
This systematic review suggests that home fortification of complementary feeding with MNP has good adherence and acceptability. However, both adherence and acceptability could be increased with adjustments in the distribution model, such as better guidance to caregivers, and in MNP administration frequency. Special attention is necessary when monitoring MNP use in malnourished populations with a high incidence of diarrhoea. Additionally, more studies are needed examining the efficacy of MNP related to adherence and acceptability to compare the positive and negative aspects of various intervention models, for the success of future programs and public policies.

Ethics approval and consent to participate
Not applicable. This review was reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.
Abbreviations MNP: multiple micronutrients in powder.

Competing interest
The authors declare that they have no competing interests.
Authors' contributions SFB contributed to the selection of studies, data analysis and data interpretation, and to drafting the initial version of the manuscript. MAC developed the study design and protocol, and contributed to study selection, data interpretation, and to drafting and critical review of the manuscript. Both authors read and approved the final manuscript.