Preventive lipid‐based nutrient supplements given with complementary foods to infants and young children 6 to 23 months of age for health, nutrition, and developmental outcomes

Jai K Das; Rehana A Salam; Yousaf Bashir Hadi; Sana Sadiq Sheikh; Afsah Z Bhutta; Zita Weise Prinzo; Zulfiqar A Bhutta

doi:10.1002/14651858.CD012611.pub3

. 2019 May 2;2019(5):CD012611. doi: 10.1002/14651858.CD012611.pub3

Preventive lipid‐based nutrient supplements given with complementary foods to infants and young children 6 to 23 months of age for health, nutrition, and developmental outcomes

Jai K Das ¹, Rehana A Salam ¹, Yousaf Bashir Hadi ², Sana Sadiq Sheikh ¹, Afsah Z Bhutta ³, Zita Weise Prinzo ⁴, Zulfiqar A Bhutta ^5,^6,^✉

Editor: Cochrane Developmental, Psychosocial and Learning Problems Group

PMCID: PMC6497129 PMID: 31046132

Abstract

Background

One nutritional intervention advocated to prevent malnutrition among children is lipid‐based nutrient supplements (LNS). LNS provide a range of vitamins and minerals, but unlike most other micronutrient supplements, LNS also provide energy, protein and essential fatty acids. Alternative recipes and formulations to LNS include fortified blended foods (FBF), which are foods fortified with vitamins and minerals, and micronutrient powders (MNP), which are a combination of vitamins and minerals,

Objectives

To assess the effects and safety of preventive LNS given with complementary foods on health, nutrition and developmental outcomes of non‐hospitalised infants and children six to 23 months of age, and whether or not they are more effective than other foods (including FBF or MNP).

This review did not assess the effects of LNS as supplementary foods or therapeutic foods in the management of moderate and severe acute malnutrition.

Search methods

In October 2018, we searched CENTRAL, MEDLINE, Embase, 21 other databases and two trials registers for relevant studies. We also checked the reference lists of included studies and relevant reviews and contacted the authors of studies and other experts in the area for any ongoing and unpublished studies.

Selection criteria

Randomised controlled trials (RCTs) and quasi‐RCTs that evaluated the impact of LNS plus complementary foods given at point‐of‐use (for any dose, frequency, duration) to non‐hospitalised infants and young children aged six to 23 months in stable or emergency settings and compared to no intervention, other supplementary foods (i.e. FBF), nutrition counselling or multiple micronutrient supplements or powders for point‐of‐use fortification of complementary foods.

Data collection and analysis

Two review authors independently screened studies for relevance and, for those studies included in the review, extracted data, assessed risk of bias and rated the quality of the evidence using the GRADE approach. We carried out statistical analysis using Review Manager software. We used a random‐effects meta‐analysis for combining data as the interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables,.

Main results

Our search identified a total of 8124 records, from which we included 17 studies (54 papers) with 23,200 children in the review. The included studies reported on one or more of the pre‐specified primary outcomes, and five studies included multiple comparison groups.

Overall, the majority of trials were at low risk of bias for random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias, but at high risk of bias for blinding of participants and personnel due to the nature of the intervention. Using the GRADE approach, we judged the quality of the evidence for most outcomes as low or moderate.

LNS+complementary feeding compared with no intervention Thirteen studies compared LNS plus complementary feeding with no intervention. LNS plus complementary feeding reduced the prevalence of moderate stunting by 7% (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.88 to 0.98; nine studies, 13,372 participants; moderate‐quality evidence), severe stunting by 15% (RR 0.85, 95% CI 0.74 to 0.98; five studies, 6151 participants; moderate‐quality evidence), moderate wasting by 18% (RR 0.82, 95% CI 0.74 to 0.91; eight studies; 13,172 participants; moderate‐quality evidence), moderate underweight by 15% (RR 0.85, 95% CI 0.80 to 0.91; eight studies, 13,073 participants; moderate‐quality evidence), and anaemia by 21% (RR 0.79, 95% CI 0.69 to 0.90; five studies, 2332 participants; low‐quality evidence). There was no impact of LNS plus complementary feeding on severe wasting (RR 1.27, 95% CI 0.66 to 2.46; three studies, 2329 participants) and severe underweight (RR 0.78, 95%CI 0.54 to 1.13; two studies, 1729 participants). Adverse effects did not differ between the groups (RR 0.86, 95% CI 0.74 to 1.01; three studies, 3382 participants).

LNS+complementary feeding compared with FBF Five studies compared LNS plus complementary feeding with other FBF, including corn soy blend and UNIMIX. We pooled four of the five studies in meta‐analyses and found that, when compared to other FBF, LNS plus complementary feeding significantly reduced the prevalence of moderate stunting (RR 0.89, 95% CI 0.82 to 0.97; three studies, 2828 participants; moderate‐quality evidence), moderate wasting (RR 0.79, 95% CI 0.65 to 0.97; two studies, 2290 participants; moderate‐quality evidence), and moderate underweight (RR 0.81, 95% CI 0.73 to 0.91; two studies, 2280 participants; moderate‐quality evidence). We found no difference between LNS plus complementary feeding and FBF for severe stunting (RR 0.41, 95% CI 0.12 to 1.42; two studies, 729 participants; low‐quality evidence), severe wasting (RR 0.64, 95% CI 0.19 to 2.81; two studies, 735 participants; moderate‐quality evidence), and severe underweight (RR 1.23, 95% CI 0.67 to 2.25; one study, 173 participants; low‐quality evidence).

LNS+complementary feeding compared with MNP Four studies compared LNS plus complementary feeding with MNP. We pooled data from three of the four studies in meta‐analyses and found that compared to MNP, LNS plus complementary feeding significantly reduced the prevalence of moderate underweight (RR 0.88, 95% CI 0.78 to 0.99; two studies, 2004 participants; moderate‐quality evidence) and anaemia (RR 0.38, 95% CI 0.21 to 0.68; two studies, 557 participants; low‐quality evidence). There was no difference between LNS plus complementary feeding and MNP for moderate stunting (RR 0.92, 95% CI 0.82 to 1.02; three studies, 2365 participants) and moderate wasting (RR 0.97, 95% CI 0.77 to 1.23; two studies, 2004 participants).

Authors' conclusions

The findings of this review suggest that LNS plus complementary feeding compared to no intervention is effective at improving growth outcomes and anaemia without adverse effects among children aged six to 23 months in low‐ and middle‐income countries (LMIC) in Asia and Africa, and more effective if provided over a longer duration of time (over 12 months). Limited evidence also suggests that LNS plus complementary feeding is more effective than FBF and MNP at improving growth outcomes.

Plain language summary

Effect of lipid‐based nutrient supplementation on infants and young children

Review question

What is the impact of lipid‐based nutrient supplements (LNS) plus complementary foods on health, nutrition and developmental outcomes among infants and young children?

Background

LNS are food products which contain energy, minerals and vitamins that can improve growth in children. LNS provide vitamins, minerals and energy in the form of protein and essential fatty acids. We sought to assess the effect of LNS given jointly with complementary feeding, compared to no intervention, micronutrient powders (MNP; a mixture of vitamins and minerals that is sprinkled onto food) and other fortified blended food (FBF) products in healthy children.

Study characteristics

This review includes 17 studies (from 54 reports) with 23,200 children. Four of the included studies were conducted in Malawi, three in Bangladesh, two in Ghana and one each in Burkina Faso, Haiti, Honduras, Chad, Congo, Kenya, Niger, Peru, Guatemala, and Indonesia. Four included studies enrolled pregnant women and provided LNS plus complementary feeding during pregnancy and post‐partum, followed by infant supplementation starting at six months of age. The other studies provided LNS plus complementary feeding to children after six months of age. None of the included studies were conducted in emergency settings.

Key results

Findings of this review suggest that LNS plus complementary feeding is probably an effective intervention for improving growth outcomes and reducing the occurrence of children who are of short stature for their age (stunting), have low weight for their age (moderate underweight), have low weight for their height (moderate wasting) and anaemia. Additionally, LNS plus complementary feeding probably improves height and weight for age as well as mid‐upper arm circumference without adverse effects among children aged six to 23 months. The intervention seems to be more effective if provided for a duration longer than 12 months.

Evidence also suggests that LNS plus complementary probably reduces moderate stunting, moderate wasting and moderate underweight, compared to other FBF.

Furthermore, LNS plus complementary feeding is probably more effective than MNP at reducing moderate underweight and improving height and weight.

Quality of evidence

Overall, we considered most studies to be at high risk of bias for blinding of participants and personnel due to the nature of intervention. We rated the quality of the evidence for most outcomes as either low or moderate.

Currentness of evidence

The evidence is current to October 2018.

Summary of findings

Background

Description of the condition

Each year, malnutrition − including fetal growth restriction, stunting, wasting and micronutrient deficiencies −and suboptimum breastfeeding underlie nearly 3.1 million deaths of children under the age of five years worldwide, accounting for 45% of all deaths in this age group (Liu 2012). Globally in 2011, at least 165 million children were stunted (below −2 standard deviations (SD) from median height for age of reference population) and 52 million were wasted (below − 2 SD from median weight for height of reference population). Although the prevalence of stunting has decreased during the past two decades, it remains higher in South Asia (27%) and Sub‐Saharan Africa (36%) compared to high‐income countries (7%) (Black 2013; WHO 2014). Micronutrient deficiencies are also prevalent in children and these deficiencies are associated with learning disability, impaired work capacity and increased morbidity and mortality in adulthood (Black 2013). Undernutrition among children has also been associated with delayed or compromised motor and cognitive development, decreased school achievement, and consequently, reduced economic productivity (The World Bank 2006).

Disruption and displacement of populations in emergency situations pose an added threat to the existing situation of malnutrition among children. Women and children represented over three‐quarters of the estimated 80 million people in need of humanitarian assistance in 2014, and many countries with high maternal, newborn and child mortality rates are affected by humanitarian emergencies (UNICEF 2014). Malnutrition has been recorded as either a direct or an underlying cause of child mortality in emergencies (UNICEF 2014).

In order for countries to meet global targets for improved maternal, infant and child nutrition, there is a need to emphasise early prevention to address general deprivation and inequity for sustainable reductions in malnutrition (WHO 2014). Prevention is emphasised because the extent to which the effects of early damage are reversible is a complex area of ongoing research (Victora 2008). The concept of a preventive role of nutrition interventions is complex in settings with existing widespread and chronic undernutrition. However, the preventive approach aims to improve the daily nutritional intake by providing required calories, minerals and vitamins, and hence preventing undernutrition among children in vulnerable settings.

Description of the intervention

Ideally, infants are breastfed for two years or longer, with complementary food introduced at six months of age (WHO 2014). Diets of infants and young children aged six to 23 months need to include a variety of nutrient‐dense foods, preferably from local sources, to ensure their nutrient needs are met (WHO 2014). However, children's diets are likely to be deficient in macronutrients and micronutrients, specifically essential fatty acids, when nutrient‐rich diets are not available to them in resource‐poor settings (Arimond 2015). Various interventions are recommended, or have been used, to improve child malnutrition, including improved maternal nutrition, promotion of breast feeding, appropriate complementary feeding and prophylactic vitamin A and zinc supplementation in children, along with other indirect interventions, including agricultural and financial interventions (Bhutta 2013).

Supplementary feeding is a strategy that includes provision of extra food to children beyond the normal ration of their home diets and is aimed at improving the nutritional status or preventing the nutritional deterioration of the target population. One of the nutritional interventions advocated to address malnutrition among children is lipid‐based nutrient supplements (LNS). LNS are a family of products designed to deliver nutrients to vulnerable people. They are considered 'lipid‐based' because most of the energy provided by these products is from lipids (fats). All LNS provide a range of vitamins and minerals, but unlike most other micronutrient supplements, LNS also provide energy, protein and essential fatty acids (Chaparro 2010; Ilins 2015). LNS recipes can include a variety of ingredients, but typically have included vegetable fat, peanut or groundnut paste, milk powder and sugar. Based on the energy content, LNS can be small quantity (SQ LNS) providing ˜ 110 to 120 kcal/day (20 g dose), medium quantity (MQ LNS) providing ˜ 250 to 500 kcal/day (45 g to 90 g dose) or large‐quantity (LQ LNS) providing more than 280 kcal/day (> 90 g dose) (WHO 2012; WHO 2013). LNS are nutrient dense, require no cooking before use, and can be stored for months even in warm conditions (Phuka 2008).

Alternative recipes and formulations, other than LNS, are currently being explored using cereals mixed with other ingredients, including whey, soy protein isolate, dried skimmed milk, and sesame, cashew and chickpea paste, among others (Pee 2008). These are fortified with vitamins and minerals and are commonly called fortified blended foods (FBF). An example of a commonly used FBF is corn soy blend plus (CSB ++), which is a cooked blend of milled, heat‐treated corn and soybeans that is fortified with a vitamin and mineral premix. Multiple micronutrient powders (MNP) are also an alternative way of providing micronutrients. These are single‐dose packets of vitamins and minerals in powder form that can be sprinkled onto any ready to eat semi‐solid food consumed at home, school or any other point of use. The World Health Organization (WHO) recommends home fortification of foods with multiple MNP to improve iron status and reduce anaemia among infants and children aged six to 23 months of age where the prevalence of anaemia in children under five years of age is 20% or higher (WHO 2011). Besides complementary and supplementary feeding interventions, nutrition education and counselling provided to caregivers on the feeding of young children also have the potential to improve the nutritional status of children in developing countries (Lassi 2013). Nutrition education alone for improving complementary feeding practices in both food‐secure and food‐insecure populations has been shown to improve feeding practices and improve growth and anthropometric measures (Lassi 2013).

Though LNS or any other fortified food is not a replacement for breast milk or a diverse diet of local foods, the use of LNS for point‐of‐use fortification of complementary foods in infants aged six to 23 months has been proposed as a promising intervention for the prevention of malnutrition in vulnerable settings. LNS products are specifically designed to ensure nutrient adequacy (energy, protein and essential fatty acids), while simultaneously upholding other complementary feeding practices such as breastfeeding and dietary diversity.

How the intervention might work

The scope of this review is limited to assessing the effects of LNS for the prevention of malnutrition when given to children aged six to 23 months in addition to complementary foods. We did not assess the role of LNS as supplementary foods or therapeutic foods for the management of moderate and severe acute malnutrition.

LNS work by supplementing children with the required nutrients, mainly from lipids, and include energy, protein, essential fatty acids, and micronutrients in addition to the normal home diet. They provide calories as well as micronutrients. The doses and formulations of LNS can be modified according to the needs of the specific target group and, to date, there is no standard formulation (Dewey 2012). The supplements can be modified by adjusting the macronutrient content to maximise palatability and texture, and adding flavours according to regional taste preferences. It is further suggested that LNS are provided in single‐serving sachets to encourage thinking of it as a condiment, a medicine or a special food for a special group. Serving LNS in a single serving also prevents interfamily sharing since programmatic findings from studies suggest that there are issues with redistribution of the supplement within the family when feeding is home‐delivered, and much less leakage when delivered in day care centres (Kristjansson 2015). During manufacture, international guidelines need to be followed to prevent faecal contamination and fat oxidation to enhance shelf life (WHO 2012). The most commonly used formulations of fortified complementary food supplementation are Nutributter® (20 g or 108 kcal per day) and Plumpy'doz® (46 g or 246 kcal per day), both of which are produced by Nutriset, Malaunay, France, and ‘fortified spreads’ (25g to 75g or 128 to 384 kcal per day).

Studies have also explored the acceptability of LNS among infants (Adu‐Afarwuah 2011; Arimond 2015; Hess 2011), and suggest that mothers found it convenient to use, as it could be mixed with any food they preferred, and that the use of LNS could be made simpler by packaging the supplement in convenient daily doses. This shows that acceptability of LNS is similar to that of MNP, but that LNS can potentially also address general calorie deficit.

Why it is important to do this review

Recent research on smaller doses of LNS for the prevention of malnutrition has created interest in their potential use to ensure a nutritionally adequate ration for the most vulnerable groups, including children between six and 23 months of age (Chaparro 2010; Dewey 2012). Studies have shown mixed results for the impact of LNS on growth and development in infants and young children (Huybregts 2012; Iannotti 2013; Maleta 2015; Mangani 2013; Mangani 2015; Prado 2016; Thakwalakwa 2012; Thakwalakwa 2015). Furthermore, there could be potential concerns relating to LNS safety in areas where infections are common (De‐Regil 2013). A study from Malawi suggested that LNS containing iron did not increase morbidity in children and also did not affect guardian‐reported illness episodes, but may have increased malaria‐related non‐scheduled visits in one of the intervention groups (Bendabenda 2016). Other studies have suggested perceived benefits of LNS by care providers, including acceptability, adherence and willingness to pay (Iuel‐Brockdorf 2015; Segrè 2015). Several countries are implementing large‐scale projects that involve the provision of LNS as part of the interventions. An implementation survey of these interventions identified 20 projects providing LNS interventions, mostly in Sub‐Saharan Africa (UNICEF 2013). Of these, 17 were currently distributing LNS in 13 countries and three were planning to start distribution within the next 12 months. More than half (around 53%) of the implemented projects providing LNS aimed to improve complementary feeding or to prevent and treat moderate acute malnutrition (MAM), while 41% had an objective to prevent and control micronutrient malnutrition and 35% aimed to reduce stunting. Most of the planned LNS interventions that aimed to improve complementary feeding were integrated with existing infant and young child feeding programs, micronutrient prevention and control programs, humanitarian response programs and programs designed to prevent MAM (UNICEF 2013).

Reviews have evaluated supplementary feeding for children in the form of added meals, drinks or snacks, and suggest some benefit on child growth and psychosocial outcomes (Kristjansson 2015; Kristjansson 2016; Sguassero 2012). These reviews have assessed the effectiveness of community‐based supplementary feeding interventions among children under five years of age in disadvantaged population groups. Findings from one review on supplementary feeding suggested that the key for successful feeding programs for young children in low‐ and middle‐income countries (LMIC) is good implementation (Kristjansson 2015). To date, the benefits and harms of preventive LNS in infants and young children aged six to 23 months have not been systematically assessed. LNS products are more expensive to produce, transport and store compared to routine complementary food because of their composition, weight, and size. Hence, research is needed to determine the added benefit of LNS products for improved health and functional outcomes (UNICEF 2013), and studies are also needed to compare its effectiveness against natural local food sources. The retrieval, summary and assessment of the evidence for LNS compared to other supplements will assist international organisations and countries to make informed decisions about the benefits and harms of LNS in infants and young children when given with complementary foods. We have also developed a companion review on the effectiveness and safety of LNS when given to women during pregnancy on maternal, birth and infant outcomes (Das 2018), which will also guide policy makers in making informed decisions about the effectiveness and safety of LNS in pregnant women.

Objectives

To assess the effects and safety of preventive lipid‐based nutrient supplements (LNS) given with complementary foods on health, nutrition and developmental outcomes of non‐hospitalised infants and children six to 23 months of age, and whether or not LNS are more effective than other foods (including fortified blended foods (FBF) or multiple micronutrient powders (MNP)).

This review did not assess the effects of LNS as supplementary foods or therapeutic foods in the management of moderate and severe acute malnutrition.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs.

Types of participants

All non‐hospitalised infants and young children aged six to 23 months of age in stable (i.e. not in any emergency‐affected country or emergency settings according to WHO definition (Wisner 2002). We did not include infants under six months of age, as exclusive breastfeeding is recommended from birth to six months. We included studies of apparently healthy children* from the general population, although some might be at risk of having highly prevalent diseases such as malaria, diarrhoea or even malnutrition. We did not exclude studies with infants and children with HIV infection, unless they were hospitalised or had a clinical condition.

*Apparently health children are children who were described by the study authors as being healthy. We did not include studies specifically undertaken with diseased or undernourished populations.

Types of interventions

All infants and young children who were not wasted and who were given LNS with complementary food at point‐of‐use for any dose, frequency and duration compared to no intervention, placebo, or compared with other foods/supplements or nutrition intervention. Specifically, we made the following comparisons.

Provision of LNS versus no intervention or placebo
Provision of LNS versus other supplementary foods (i.e. FBF)
Provision of LNS versus nutritional counselling (counselling to mothers and caregivers for appropriate feeding of infants and young children)
Provision of LNS versus provision of multiple micronutrient supplements or powders for point‐of‐use fortification of complementary foods

We included interventions that combined provision of LNS with co‐interventions, such as education or other approaches, if the other co‐interventions were the same in both the intervention and comparison groups.

Types of outcome measures

Primary outcomes

Stunting (moderate: height/length‐for‐age (HFA) < −2 standard deviations (SD); severe: HFA < −3 SD)
Wasting (moderate: weight‐for‐height/length (WFH) < −2 SD; severe: WFH < −3 SD)
Underweight (moderate: weight‐for‐age (WFA) < −2 SD; severe: WFA < −3 SD)
Anaemia (as defined by trialists)
Psychomotor development outcomes (as defined by trialists)
Neuro‐developmental outcomes (as defined by trialists)
Any adverse effects, including allergic reactions, as diagnosed by clinical assessment (atopic dermatitis, urticaria, oedema (oral), ophthalmic pruritus, allergic rhinitis, asthma, anaphylaxis)

Secondary outcomes

Mid‐upper arm circumference (MUAC; the circumference of the left upper arm, measured at the mid‐point between the tip of the shoulder and the tip of the elbow)
Haemoglobin (g/L)
Morbidity (incidence of diarrhoea, acute respiratory illness (ARI) and fever, as defined by trialists)
Mortality

Explanatory secondary outcomes

Height/length‐for‐age z score (HAZ)
Weight‐for‐age z score (WAZ)
Weight‐for‐height/length z score (WHZ)

Search methods for identification of studies

Electronic searches

We searched the sources listed below for intervention studies in March 2017, June 2018 and October 2018. On 5 March 2019, shortly before publication, we searched MEDLINE, Embase and the Retraction Watch Database retractiondatabase.org/RetractionSearch.aspx? to identify any retraction statements or errata relating to the included studies. These searches are reported in Appendix 1

International databases

Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2) in the Cochrane Library, and which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register (searched 16 October 2018).
MEDLINE Ovid (1946 to 15 October 2018).
MEDLINE In‐Process and Other Non‐Indexed Citations Ovid (searched 15 October 2018).
MEDLINE E‐pub ahead of print Ovid (searched 15 October 2018).
Embase Ovid (1974 to 2018 week 42).
CINAHL EBSCOhost (Cumulative Index to Nursing and Allied Health Literature; 1937 to 16 October 2018).
Science Citation Index Web of Science (SCI; 1970 to 16 October 2018).
Social Sciences Citation Index Web of Science (SSCI; 1970 to 16 October 2018).
Conference Proceedings Citation Index ‐ Science Web of Science (CPCI‐S; 1990 to 16 October 2018).
Conference Proceedings Citation Index ‐ Social Science & Humanities Web of Science (CPCI‐SS&H; 1990 to 16 October 2018).
Cochrane Database of Systematic Reviews (CDSR; 2018, Issue 10), part of the Cochrane Library.
Database of Abstracts of Reviews of Effect (DARE; 2015, Issue 2) in the Cochrane Library. DARE ceased publication in 2015 (searched on 23 March 2017).
Epistemonikos (epistemonikos.org; searched 20 October 2018).
POPLINE (www.popline.org; searched 20 October 2018).
ClinicalTrials.gov (clinicaltrials.gov; searched 20 October 2018)
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; who.int/trialsearch; searched 20 October 2018).

Regional databases

IBECS (Índice Bibliográfico Español en Ciencias de la Salud;ibecs.isciii.es/cgi‐bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&base=IBECS&lang=p&form=F; searched 19 October 2018).
SciELO (Scientific Electronic Library Online; www.scielo.br; searched 19 October 2018).
AIM (Africa Global Index Medicus; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 19 October 2018).
IMEMR (Index Medicus for the Eastern Mediterranean Region Global Index Medicus ; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 19 October 2018).
LILACS (Latin American and Caribbean Health Science Information database; lilacs.bvsalud.org/en; searched 19 October 2018).
PAHO/WHO Institutional Repository for Information Sharing (iris.paho.org/xmlui; searched 19 October 2018).
WHOLIS Global Index Medicus (WHO Library Database; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 19 October 2018).
WPRIM Global Index Medicus(Western Pacific Index Medicus; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 19 October 2018).
IMSEAR Global Index Medicus (Index Medicus for the South‐East Asian Region; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 19 October 2018).
IndMED (indmed.nic.in/indmed.html; searched 19 October 2018).
Native Health Research Database (hscssl.unm.edu/nhd; searched 19 October 2018).

We searched using both keywords and controlled vocabulary (when available), using the search strategies in Appendix 2. We did not apply language or date restrictions for any source. If we identified studies written in a language other than English, we commissioned their translation into English. If necessary, we would have recorded any such studies as 'Studies awaiting classification' until a translation became available.

Searching other resources

We checked the reference lists of included studies and relevant reviews for further studies. We contacted authors of eligible studies and other relevant persons for information about ongoing or unpublished studies we might have missed or, where necessary, to provide missing data (Dewey 2016 [pers comm]; Dewey 2017 [pers comm]; Stewart 2017 [pers comm]).

Data collection and analysis

Selection of studies

Two review authors independently assessed for inclusion all records generated by the search strategy. First, they screened titles and abstracts of all records retrieved, and short‐listed those deemed relevant. Next, they obtained and assessed the full texts of all potentially relevant records, assessing each one against the inclusion criteria (Criteria for considering studies for this review), before deciding on the final list of studies to be included in the review. Both review authors resolved any disagreements regarding eligibility at each stage of the selection process through discussion or, if required, in consultation with a third author. We recorded our decisions in a PRISMA diagram (Moher 2009).

Data extraction and management

We designed a data extraction form specifically for this review (Appendix 3). Two review authors used the form to extract data on study methods, participants, intervention, control, reported outcomes, source of funding and potential conflict of interest statements from all included studies. If studies reported outcomes at multiple time points, we extracted data for each time point and pooled studies reporting similar outcomes at similar time points. When information was unclear, we attempted to contact the authors of the original report to request they provide further details. We used these details, which are presented in the Characteristics of included studies tables, to explore and make inferences for the results.

Two review authors entered the data into Review Manager 5 (RevMan 5) (Review Manager 2014), and a third review author checked the data entry for accuracy by entering the data into a separate file and comparing the results.

We resolved discrepancies at all stages through discussion or, if required, through consultation with a third review author.

Assessment of risk of bias in included studies

Randomised studies

Two review authors independently assessed the risk of bias of each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a) and set out in Appendix 4. We rated each study at high, low or unclear risk of bias, across each of the following domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective outcome reporting; and other potential sources of bias. Both review authors resolved any disagreement by discussion or by involving a third review author.

Overall risk of bias

We summarised the overall risk of bias at two levels: within studies (across domains), and across studies using the GRADE approach (Balshem 2010, GRADEpro GDT 2015). The GRADE findings are summarised in Table 1, Table 2 and Table 3.

for the main comparison.

LNS plus complementary feeding compared with no intervention
Patient or population: children aged 6 to 23 months Settings: community Intervention: LNS plus complementary feeding Comparison: no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	No intervention	LNS plus complementary feeding
*Stunting*
Moderate stunting Measured as height‐for‐age z score < −2 SD Measured at 12, 18 and 24 months of age	2618/7137	2353/7060	RR 0.93 (0.88 to 0.98)	13,372  (9 studies)	⊕⊕⊕⊝  Moderate^a	2 studies, Kumwenda 2014 and Mangani 2015, contributed data to multiple comparisons; total number of comparisons = 13
Severe stunting Measured as height‐for‐age z score < −3 SD Measured at 12, 18 and 24 months of age	471/4188	290/2868	RR 0.85 (0.74 to 0.98)	6151 (5 studies)	⊕⊕⊕⊝  Moderate^a	2 studies, Kumwenda 2014 and Mangani 2015, contributed data to multiple comparisons; total number of comparisons = 9
*Wasting*
Moderate wasting Measured as weight‐for‐height z score < −2 SD Measured at 12, 18 and 24 months of age	695/6213	624/6959	RR 0.82 (0.74 to 0.91)	13,172 (8 studies)	⊕⊕⊕⊝  Moderate^a	1 study, Kumwenda 2014, contributed data to 2 comparisons; total number of comparisons = 11
Severe wasting Measured as weight‐for‐height z score < −3 SD Measured at 12 and 18 months of age	18/1636	21/1663	RR 1.27 (0.66 to 2.46)	2329 (3 studies)	⊕⊕⊕⊕  Moderate^b	1 study, Kumwenda 2014, contributed data to 4 comparisons; total number of comparisons = 6
Underweight
Moderate underweight Measured as weight‐for‐age z score < −2 SD Measured at 12, 18 and 24 months of age	1723/7013	1525/6861	RR 0.85 (0.80 to 0.91)	13,073 (8 studies)	⊕⊕⊕⊝  Moderate^a	1 study, Kumwenda 2014, contributed data to 4 comparisons; total number of comparisons = 11
Severe underweight Measured as weight‐for‐age z score < −3 SD Measured at 12 and 18 months of age	62/1224	50/1258	RR 0.78 (0.54 to 1.13)	1729 (2 studies)	⊕⊕⊕⊕  Moderate^b	1 study, Kumwenda 2014, contributed data to 4 comparisons; total number of comparisons = 5
Anaemia Measured as haemoglobin < 10 g/dL Measured at 12, 18 and 24 months of age	697/1359	558/973	RR 0.79 (0.69 to 0.90)	2332 (5 studies)	⊕⊕⊝⊝  Low^a,c	‐
Adverse effects Defined as deaths, hospitalisations, congenital abnormalities and life‐threatening conditions requiring an immediate hospital visit Assessed at 12 and 18 months of age	314/1369	401/2333	RR 0.86 (0.74 to 1.01)	3382 (3 studies)	⊕⊕⊕⊝  Moderate^a	1 study, Kumwenda 2014, contributed data to 2 comparisons; total number of comparisons = 4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; LNS: lipid‐based nutrient supplement; RR: risk ratio; SD: standard deviation
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Method	Approach
Measures of treatment effects	Rates If rates represent events that could occur more than once per participant, we will report the rate difference using the methodologies described in Deeks 2011.
Unit of analysis issues	Cluster‐randomised trials We will follow the methods described in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), and adjust the sample sizes or standard errors of cluster‐randomised trials by using an estimate of the intra‐cluster correlation co‐efficient (ICC) derived from the study (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this in the results section, and conduct sensitivity analyses to investigate the effect of variation in the ICC. We will acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit in the future updates of the review, if applicable.
Dealing with missing data	If we find studies with high levels of missing data, we will explore the effect in the overall assessment of treatment effect by removing such studies and conducting a sensitivity analysis.
Assessment of reporting bias	If we include 10 or more studies in a meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes, we will use the test proposed by Egger 1997. For dichotomous outcomes, we will use the test proposed by Harbord 2006. If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Subgroup analysis and investigation of heterogeneity	We will conduct exploratory subgroup analyses on the primary outcomes, irrespective of heterogeneity, when there are more than three studies contributing data. We will conduct the following analyses. Breastfeeding practices (breastfed versus not breastfed) Frequency of intervention (daily versus weekly versus flexible) Living in an emergency‐affected country (Wisner 2002), or in a refugee or internally displaced persons' camp (yes verus no) Anaemic status of participants at start of intervention (anaemic (defined as haemoglobin values < 110 g/L) versus non‐anaemic or unknown status).
Sensitivity analysis	We will carry out a sensitivity analysis to examine: the effect of removing non‐randomised studies from the analysis; and the effects of different ICCs, and the randomisation unit, for cluster trials (if these are included).

Study	Total energy	Lipid content	Protein Content	Micronutrients
Adu‐Afarwuah 2007	108 kcal (20 g/day)	linoleic acid (1.29 g); linolenic acid (0.29 g)	Not specified	Carotene (400 μg RE); vitamin C (30 mg); folic acid (80 g); thiamine (0.3 mg); riboflavin (0.4 mg); vitamin B3 (4 mg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 g); iron sulphate (9 mg); zinc sulphate (4 mg); calcium phosphate (100 mg); potassium (152 mg); copper sulphate (0.2 mg); sodium selenite (10 ug); potassium iodate (90 ug); phosphate (82 mg); magnesium (16 mg); manganese (0.08 mg); phytate (82 mg)
Adu‐Afarwuah 2016	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.46 g); α‐linolenic acid (0.58 g); vitamin A (400 mg retinol equivalents); thiamine (0.3 mg); riboflavin (0.4 mg); niacin (4 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 mg); vitamin C (30 mg); vitamin D (5 mg); vitamin E (6 mg); vitamin K (30 mg); folic acid (80 mg); pantothenic acid (1.8 mg); iron (6 mg); zinc (8 mg); copper (0.34 mg); calcium (280 mg); phosphorus (190 mg); potassium (200 mg); magnesium (40 mg); selenium (20 mg); iodine (90 mg); manganese (1.2 mg)
Ashorn 2015	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.46 g); a‐linolenic acid (0.58 g); vitamin A (400 mg RE); vitamin C (30 mg); vitamin B1 (0.3 mg); vitamin B2 (0.4 mg); niacin (4 mg); folic acid (80 mg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 mg); vitamin D (5 mg); vitamin E (6 mg); vitamin K (30 mg); iron (6 mg); zinc (8 mg); copper (0.34 mg); calcium (280 mg); phosphorus (190 mg); potassium (200 mg); magnesium (40 mg); selenium (20 mg); iodine (90 mg); manganese (1.2 mg)
Bisimwa 2012	275 kcal (50 g/day)	Not specified	Not specified	Vitamin A (412 IU); vitamin D (307 IU); vitamin C (75 mg); thiamine (0.7 mg); riboflavin (1.0 mg); vitamin B12 (1.0 μg); pyridoxine (0.24 mg); niacin (10.3 mg); pantothenic acid (3.8 mg); folic acid (0.07 mg); vitamin K (0.01 mg); calcium (514 mg); phosphorus (265 mg); iron (9.5 mg); zinc (8.3 mg); copper (0.3 mg); iodine (0.07 mg); selenium (0.003 mg); magnesium (23.4 mg); phytic acid (0.425 mg²); phytic acid:iron molar ratio² (2.1); phytic acid:zinc molar ratio² (1.9)
Christian 2015	250 kcal (46 g/day)	Not specified	Not specified	Not specified
Dewey 2017	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.46 g); α‐linolenic acid (0.58 g); vitamin A (400 mg RE); thiamine (0.5 mg); riboflavin (0.5 mg); niacin (6 mg); folic acid (150 mg); pantothenic acid (2 mg); vitamin B6 (0.5 mg); vitamin B12 (0.9 mg); vitamin C (30 mg); vitamin D (5 mg); vitamin E (6 mg); vitamin K (30 mg); calcium (280 mg); copper (0.34 mg); iodine (90 mg); iron (9 mg); magnesium (40 mg); manganese (1.2 mg); phosphorus (190 mg); potassium (200 mg); selenium (20 mg); zinc (8 mg)
Hess 2015	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.46 g); α‐Linolenic acid (0.58 g); vitamin A (400 mg); thiamine (0.3 mg); riboflavin (0.4 mg); niacin (4 mg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 mg); folic acid (80 mg); vitamin C (30 mg); vitamin D (5 mg); vitamin E (6 mg); vitamin K (30 mg); calcium (280 mg); copper (0.34 mg); iodine (90 mg); iron (6 mg); magnesium (40 mg); manganese (1.2 mg); phosphorus (190 mg); potassium (200 mg); selenium (20 μg); zinc (0 mg)
Huybregts 2012	247 kcal (46 g/day)	16 g	5.9 g	Linoleic acid (2 g); α‐linolenic acid (0.3 g); vitamin A (400 mg); vitamin E (6 mg); thiamine (0.5 mg); niacin (6 mg); pantothenic acid (2 mg); vitamin B6 (0.5 mg); folic acid (160 mg); vitamin B12 (0.9 mg); vitamin C (30 mg); magnesium (60 mg); zinc (4 mg); iron (9 mg); copper (0.3 mg); potassium (310 mg); calcium (387 mg); phosphorus (275 mg); selenium (17 mg); manganese (0.17 mg); iodine (90 mg)
Iannotti 2014	108 kcal (20 g/day)	7.08 g	2.56 g	Linoleic acid (1.29 g); α‐linoleic acid (0.29 g); vitamin A (400 mg); thiamine (0.3 mg); riboflavin (0.4 mg); niacin (4 mg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 mg); folic acid (80 mg); vitamin C (30 mg); calcium (100 mg); copper (0.2 mg); iodine (90 mg); iron (9 mg); magnesium (16 mg); manganese (0.08 mg); phosphorus (82.2 mg); potassium (152 mg); selenium (10 mg); zinc (4 mg)
Kumwenda 2014	55 kcal (10 g/day)	4.7 g	1.3 g	Linoleic acid (2.22 g); α‐linolenic acid (0.29 g); vitamin A (400 μg RE); vitamin C (30 mg); vitamin B1 (0.3 mg); vitamin B2 (0.4 mg); niacin (4 mg); folic acid (80 μg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 μg); vitamin D (200 IU); vitamin E (6 6 mg); vitamin K (30 μg); iron (6 mg); zinc (8 mg); copper (0.34 mg); calcium (240 mg); phosphorus (208 mg); potassium (265 mg); magnesium (50 mg); selenium (20 μg); iodine (90 μg); manganese (1.2 mg); phytate (28 mg)
	17 kcal (20 g/day)	9.5 g	2.5 g	Linoleic acid (4.44 g); α‐linolenic acid (0.58 g); vitamin A (400 μg RE); vitamin C (30 mg); vitamin B1 (0.3 mg); vitamin B2 (0.4 mg); niacin (4 mg); folic acid (80 μg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 μg); vitamin D (200 IU); vitamin E (6 6 mg); vitamin K (30 μg); iron (6 mg); zinc (8 mg); copper (0.34 mg); calcium (240 mg); phosphorus (208 mg); potassium (265 mg); magnesium (50 mg); selenium (20 μg); iodine (90 μg); manganese (1.2 mg); phytate (56 mg)
	241 kcal (40 g/day)	18.9 g	5 g	Linoleic acid (8.88 g); α‐linolenic acid (1.16 g); vitamin A (400 μg RE); vitamin C (30 mg); vitamin B1 (0.3 mg); vitamin B2 (0.4 mg); niacin (4 mg); folic acid (80 μg); pantothenic acid (1.8 mg); vitamin B6 (0.3 mg); vitamin B12 (0.5 μg); vitamin D (200 IU); vitamin E (6 6 mg); vitamin K (30 μg); iron (6 mg); zinc (8 mg); copper (0.34 mg); calcium (240 mg); phosphorus (208 mg); potassium (265 mg); magnesium (50 mg); selenium (20 μg); iodine (90 μg); manganese (1.2 mg); phytate (112 mg)
Luby 2018	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.46 g); Alpha‐linolenic acid (0.58 g); Vitamin A (400 μg); Vitamin D (5 μg); Vitamin E (6 mg); Vitamin K (30 μg); Vitamin C (30 mg) Folic acid (150 μg); Thiamine (B1) (0.5 mg); Riboflavin (B2) (0.5 mg); Niacin (6 mg); Pantothenic acid (B5) (2 mg); Vitamin B6 (0.5 mg); Vitamin B12 (0.9 μg); Calcium (280 mg); Copper (0.34 mg); Iodine (90 μg); Iron (9 mg); Magnesium (40 mg); Manganese (1.2 mg); Phosphorous (190 mg); Potassium (200 mg); Selenium (20 μg); Zinc (8 mg)
Mangani 2015	Milk‐LNS 284.8 kcal (54 g/day)	17.9 g	8.2 g	Retinol (400 μg RE); folate (160 μg); niacin (6 mg); pantothenic acid (2 mg); riboflavin (0.5 mg); thiamine (0.5 mg); vitamin B6 (0.5 mg); vitamin B12 (0.9 μg); vitamin C (30 mg); vitamin D (5 μg); calcium (366 mg); copper (0.4 mg); iodine (90 μg); iron (6 mg); magnesium (78.5 mg); selenium (20 μg); zinc (6.0 mg); phosphorus (185.6 mg); potassium (318.6 mg); manganese (0.60 mg)
Mangani 2015	Soy‐LNS 276.1 kcal (54 g/day)	18.5 g	7.5 g	Retinol (400 μg RE); folate (160 μg); niacin (6 mg); pantothenic acid (2 mg); riboflavin (0.5 mg); thiamine (0.5 mg); vitamin B6 (0.5 mg); vitamin B12 (0.9 μg); vitamin C (30 mg); vitamin D (5 μg); calcium (366 mg); copper (0.4 mg); iodine (90 μg); iron (6 mg); magnesium (78.5 mg); selenium (20 μg); zinc (6.0 mg); phosphorus (185.6 mg); potassium (307.3 mg); manganese (0.60 mg)
Matias 2017	110 kcal (20 g/day)	7 g	2.6 g	Linoleic acid (1.29 g); α‐linolenic acid (0.29 g); folic acid (80 μg); niacin (4 mg); pantothenic acid (1.8 mg); riboflavin (0.4 mg); thiamine (0.3 mg); vitamin A (400 μg); vitamin B12 (0.5 μg); vitamin B6 (0.3 mg); vitamin C (30 mg); calcium (100 mg); copper (0.2 mg); iodine (90 μg); iron (9 mg); magnesium (16 mg); manganese (0,08 mg); phosphorous (82 mg); potassium (152 mg); selenium (10 μg); zinc (4 mg)
Null 2018	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.46 g); Alpha‐linolenic acid (0.58 g); Vitamin A (400 μg); Vitamin D (5 μg); Vitamin E (6 mg); Vitamin K (30 μg); Vitamin C (30 mg) Folic acid (150 μg); Thiamine (B1) (0.5 mg); Riboflavin (B2) (0.5 mg); Niacin (6 mg); Pantothenic acid (B5) (2 mg); Vitamin B6 (0.5 mg); Vitamin B12 (0.9 μg); Calcium (280 mg); Copper (0.34 mg); Iodine (90 μg); Iron (9 mg); Magnesium (40 mg); Manganese (1.2 mg); Phosphorous (190 mg); Potassium (200 mg); Selenium (20 μg); Zinc (8 mg)
Olney 2018	118 kcal (20 g/day)	9.6 g	2.6 g	Linoleic acid (4.5 g); α‐linolenic acid (0.6 g); vitamin A (400 μg); vitamin C (30 mg); vitamin D (5 mg); vitamin E (6 mg); vitamin K (30 mg); thiamine (0.5 mg); riboflavin (0.5 mg); niacin (6 mg); pantothenic acid (2 mg); vitamin B6 (0.5 mg); folic acid (150 μg); vitamin B12 (0.9 μg); iron (9 mg); zinc (8 mg); copper (0.3 mg); selenium (20 μg); iodine (90 μg); calcium (280 mg); magnesium (40 mg); manganese (1.2 mg); phosphorus (190 mg); potassium (200 mg)
Phuka 2008	130 kcal (25 g/day)	8.3 g	3.8 g	Retinol (400 mg RE); folate (160 mg); niacin (6 mg); pantothenic acid (2 mg); riboflavin (0.5 mg); thiamine (0.5 mg); vitamin B 6 (0.5 mg); vitamin B12 (0.9 mg); vitamin C (30 mg); vitamin D (5 mg); calcium (283 mg); copper (0.5 mg); iodine (90 mg); iron (8 mg); magnesium (60 mg); selenium (17 mg); zinc (8.4 mg)
Phuka 2008	264 kcal (50 g/day)	16.5 g	7.6 g	Retinol (400 mg RE); folate (160 mg); niacin (6 mg); pantothenic acid (2 mg); riboflavin (0.5 mg); thiamine (0.5 mg); vitamin B6 (0.5 mg); vitamin B12 (0.9 mg); vitamin C (30 mg); vitamin D (5 mg); calcium (366 mg); copper (0.4 mg); iodine (90 mg); iron (8 mg); magnesium (60 mg); selenium (17 mg); zinc (8.4 mg)
Siega‐Riz 2014	247 kcal (46.4 g/day)	16 g	5.9 g	Vitamin A (400 μg); vitamin B12 (0.9 μg); iron (9 mg); zinc (9 mg)

Author:
Year of publication:
Journal:
Study funded by:
Country:
Study design:
Setting (Hospital/Outpatient/Community):
Setting (Stable/Emergency):
Target population:
Baseline Indicators	Anemia:
	BMI:
	MUAC:
	Other:
Intervention/Comparison Groups	Intervention/Comparison:
	Supplementary food composition/Nutrient density:
	Produced by:
	Dose/Frequency:
	Duration of intervention:
	Period of intervention:
	Intervention given through:
	Composition of LNS/Nutrient density:
	Duration of follow‐up:
	Number of participants:
Risk of Bias	Randomization/Sequence generation	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
	Allocation concealment	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
	Assessment blinding ‐ Outcome	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
	Blinding of participants/personnel	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
	Selective reporting	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
	Attribution/ Loss to follow up	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
	Other bias	Author judgment for risk of bias: Low, High or Unclear
		Quote from the paper:
Outcomes	Primary/Secondary:
	Outcome definition:
	Units:
	Numbers (for all groups)
Limitations:
Comments:

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Moderate stunting	9	13372	Risk Ratio (Random, 95% CI)	0.93 [0.88, 0.98]
2 Severe stunting	5	6151	Risk Ratio (Random, 95% CI)	0.85 [0.74, 0.98]
3 Moderate stunting: Sensitivity analysis	7		Risk Ratio (Random, 95% CI)	0.92 [0.88, 0.96]
4 Severe stunting: Sensitivity analysis	4		Risk Ratio (Random, 95% CI)	0.84 [0.73, 0.97]
5 Moderate wasting	8	13172	Risk Ratio (Random, 95% CI)	0.82 [0.74, 0.91]
6 Severe wasting	3	2329	Risk Ratio (Random, 95% CI)	1.27 [0.66, 2.46]
7 Moderate wasting: Sensitivity analysis	6		Risk Ratio (Random, 95% CI)	0.81 [0.73, 0.90]
8 Severe wasting: Sensitivity analysis	2		Risk Ratio (Random, 95% CI)	1.24 [0.61, 2.51]
9 Moderate underweight	8	13073	Risk Ratio (Random, 95% CI)	0.85 [0.80, 0.91]
10 Severe underweight	2	1729	Risk Ratio (Random, 95% CI)	0.78 [0.54, 1.13]
11 Moderate underweight: Sensitivity analysis	6		Risk Ratio (Random, 95% CI)	0.85 [0.80, 0.90]
12 Severe underweight: Sensitivity analysis	1		Risk Ratio (Random, 95% CI)	0.79 [0.54, 1.16]
13 Anaemia	5	2332	Risk Ratio (Random, 95% CI)	0.79 [0.69, 0.90]
14 Adverse effects	3	3382	Risk Ratio (Random, 95% CI)	0.86 [0.74, 1.01]
15 Adverse effects: Sensitivity analysis	1	1932	Risk Ratio (Random, 95% CI)	0.76 [0.60, 0.95]
16 Mid‐upper arm circumference (MUAC)	6	8187	Std. Mean Difference (Random, 95% CI)	0.13 [0.05, 0.22]
17 Serum haemoglobin (g/L)	4	4518	Mean Difference (Random, 95% CI)	5.78 [2.27, 9.30]
18 Mortality	3	3321	Risk Ratio (Random, 95% CI)	0.93 [0.63, 1.37]
19 HAZ	12	15795	Std. Mean Difference (Random, 95% CI)	0.11 [0.05, 0.16]
20 WAZ	10	12188	Std. Mean Difference (Random, 95% CI)	0.09 [0.02, 0.16]
21 WHZ	10	12894	Std. Mean Difference (Random, 95% CI)	0.08 [0.04, 0.13]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe stunting	5	6151	Risk Ratio (Random, 95% CI)	0.85 [0.74, 0.98]
1.1 SQ LNS	4	4956	Risk Ratio (Random, 95% CI)	0.83 [0.70, 0.99]
1.2 MQ LNS	2	1195	Risk Ratio (Random, 95% CI)	0.88 [0.69, 1.12]
2 Moderate stunting	9	13372	Risk Ratio (Random, 95% CI)	0.93 [0.88, 0.98]
2.1 SQ LNS	7	9710	Risk Ratio (Random, 95% CI)	0.92 [0.84, 1.00]
2.2 MQ LNS	3	3662	Risk Ratio (Random, 95% CI)	0.94 [0.88, 1.02]
3 Moderate wasting	8	13172	Risk Ratio (Random, 95% CI)	0.82 [0.74, 0.91]
3.1 SQ LNS	7	9903	Risk Ratio (Random, 95% CI)	0.83 [0.73, 0.95]
3.2 MQ LNS	2	3269	Risk Ratio (Random, 95% CI)	0.78 [0.63, 0.96]
4 Severe wasting	3	2329	Risk Ratio (Random, 95% CI)	1.27 [0.66, 2.46]
4.1 SQ LNS	2	1106	Risk Ratio (Random, 95% CI)	1.74 [0.73, 4.15]
4.2 MQ LNS	2	1223	Risk Ratio (Random, 95% CI)	0.84 [0.31, 2.30]
5 Moderate underweight	8	13073	Risk Ratio (Random, 95% CI)	0.85 [0.80, 0.91]
5.1 SQ LNS	7	9880	Risk Ratio (Random, 95% CI)	0.88 [0.80, 0.96]
5.2 MQ LNS	2	3193	Risk Ratio (Random, 95% CI)	0.83 [0.76, 0.92]
6 Severe underweight	2	1729	Risk Ratio (Random, 95% CI)	0.78 [0.54, 1.13]
6.1 SQ LNS	2	1083	Risk Ratio (Random, 95% CI)	0.84 [0.52, 1.37]
6.2 MQ LNS	1	646	Risk Ratio (Random, 95% CI)	0.71 [0.41, 1.24]
7 Anaemia	5	2332	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.69, 0.90]
7.1 SQ LNS	3	1107	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.43, 0.93]
7.2 MQ LNS	2	1225	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.78, 0.94]
8 Adverse effects	3	3382	Risk Ratio (Random, 95% CI)	0.86 [0.74, 1.01]
8.1 SQ LNS	3	2576	Risk Ratio (Random, 95% CI)	0.86 [0.69, 1.06]
8.2 MQ LNS	1	806	Risk Ratio (Random, 95% CI)	0.85 [0.63, 1.15]
9 Mid‐upper arm circumference (MUAC)	6	8187	Std. Mean Difference (Random, 95% CI)	0.13 [0.05, 0.22]
9.1 SQ LNS	5	6546	Std. Mean Difference (Random, 95% CI)	0.12 [‐0.00, 0.24]
9.2 MQ LNS	2	1641	Std. Mean Difference (Random, 95% CI)	0.17 [0.08, 0.26]
10 Serum haemoglobin (g/L)	4	4518	Mean Difference (IV, Random, 95% CI)	5.78 [2.27, 9.30]
10.1 SQ LNS	2	3293	Mean Difference (IV, Random, 95% CI)	8.95 [7.66, 10.23]
10.2 MQ LNS	2	1225	Mean Difference (IV, Random, 95% CI)	3.01 [2.73, 3.28]
11 Mortality	3	3321	Risk Ratio (Random, 95% CI)	0.93 [0.63, 1.37]
11.1 SQ LNS	3	2195	Risk Ratio (Random, 95% CI)	0.88 [0.49, 1.60]
11.2 MQ LNS	1	1126	Risk Ratio (Random, 95% CI)	1.06 [0.58, 1.92]
12 HAZ	12	15795	Std. Mean Difference (Random, 95% CI)	0.11 [0.05, 0.16]
12.1 SQ LNS	9	10919	Std. Mean Difference (Random, 95% CI)	0.12 [0.04, 0.20]
12.2 MQ LNS	4	4876	Std. Mean Difference (Random, 95% CI)	0.08 [0.01, 0.15]
13 WHZ	10	12894	Std. Mean Difference (Random, 95% CI)	0.08 [0.04, 0.13]
13.1 SQ LNS	8	10631	Std. Mean Difference (Random, 95% CI)	0.08 [0.02, 0.15]
13.2 MQ LNS	3	2263	Std. Mean Difference (Random, 95% CI)	0.07 [0.00, 0.14]
14 WAZ	10	12188	Std. Mean Difference (Random, 95% CI)	0.09 [0.02, 0.16]
14.1 SQ LNS	9	10959	Std. Mean Difference (Random, 95% CI)	0.11 [0.02, 0.19]
14.2 MQ LNS	2	1229	Std. Mean Difference (Random, 95% CI)	0.05 [‐0.04, 0.14]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Moderate stunting	9	13492	Risk Ratio (Random, 95% CI)	0.93 [0.88, 0.98]
1.1 At 12 months	1	564	Risk Ratio (Random, 95% CI)	1.01 [0.86, 1.19]
1.2 At 18 months	6	7427	Risk Ratio (Random, 95% CI)	0.95 [0.88, 1.02]
1.3 At 24 months	3	5501	Risk Ratio (Random, 95% CI)	0.89 [0.81, 0.97]
2 Severe stunting	5	6151	Risk Ratio (Random, 95% CI)	0.85 [0.74, 0.98]
2.1 At 12 months	1	564	Risk Ratio (Random, 95% CI)	0.96 [0.67, 1.38]
2.2 At 18 months	2	1687	Risk Ratio (Random, 95% CI)	0.86 [0.70, 1.07]
2.3 At 24 months	2	3900	Risk Ratio (Random, 95% CI)	0.80 [0.64, 0.99]
3 Moderate wasting	8	13172	Risk Ratio (Random, 95% CI)	0.80 [0.73, 0.88]
3.1 At 18 months	6	7669	Risk Ratio (Random, 95% CI)	0.79 [0.71, 0.89]
3.2 At 24 months	3	5503	Risk Ratio (Random, 95% CI)	0.83 [0.69, 0.99]
4 Severe wasting	3	2329	Risk Ratio (Random, 95% CI)	1.27 [0.66, 2.46]
4.1 At 12 months	1	563	Risk Ratio (Random, 95% CI)	0.78 [0.12, 4.93]
4.2 At 18 months	2	1766	Risk Ratio (Random, 95% CI)	1.39 [0.67, 2.87]
5 Moderate underweight	8	13073	Risk Ratio (Random, 95% CI)	0.85 [0.81, 0.90]
5.1 At 18 months	6	7532	Risk Ratio (Random, 95% CI)	0.85 [0.78, 0.92]
5.2 At 24 months	3	5541	Risk Ratio (Random, 95% CI)	0.87 [0.79, 0.95]
6 Severe underweight: at 18 months	2	1729	Risk Ratio (Random, 95% CI)	0.78 [0.54, 1.13]
7 Anaemia	5	2332	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.69, 0.90]
7.1 At 12 months	2	1176	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.20, 1.47]
7.2 At 18 months	3	1156	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.71, 0.91]
7.3 At 36 months	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Adverse effects: At 18 months	3	3382	Risk Ratio (Random, 95% CI)	0.86 [0.74, 1.01]
9 Mid‐upper arm circumference (MUAC)	6	8187	Std. Mean Difference (Random, 95% CI)	0.13 [0.05, 0.22]
9.1 At 12 months	1	1193	Std. Mean Difference (Random, 95% CI)	0.15 [0.06, 0.24]
9.2 At 18 months	3	4355	Std. Mean Difference (Random, 95% CI)	0.12 [‐0.11, 0.34]
9.3 At 24 months	1	1601	Std. Mean Difference (Random, 95% CI)	0.04 [‐0.04, 0.12]
9.4 At 36 months	1	1038	Std. Mean Difference (Random, 95% CI)	0.2 [0.06, 0.34]
10 Serum haemoglobin (g/L)	4	4518	Mean Difference (IV, Random, 95% CI)	5.78 [2.27, 9.30]
10.1 At 12 months	1	194	Mean Difference (IV, Random, 95% CI)	8.5 [4.46, 12.54]
10.2 At 18 months	2	3342	Mean Difference (IV, Random, 95% CI)	5.96 [0.08, 11.84]
10.3 At 36 months	1	982	Mean Difference (IV, Random, 95% CI)	3.30 [1.42, 5.18]
11 Mortality	3	3321	Risk Ratio (Random, 95% CI)	0.93 [0.63, 1.37]
11.1 At 12 months	1	1932	Risk Ratio (Random, 95% CI)	0.85 [0.56, 1.30]
11.2 At 18 months	2	1389	Risk Ratio (Random, 95% CI)	1.10 [0.42, 2.89]
12 HAZ	12	15795	Std. Mean Difference (Random, 95% CI)	0.10 [0.05, 0.15]
12.1 At 12 to 15 months	3	1103	Std. Mean Difference (Random, 95% CI)	0.07 [‐0.02, 0.15]
12.2 At 18 months	6	8153	Std. Mean Difference (Random, 95% CI)	0.08 [0.00, 0.16]
12.3 At 24 months	3	5501	Std. Mean Difference (Random, 95% CI)	0.14 [0.03, 0.25]
12.4 At 36 months	1	1038	Std. Mean Difference (Random, 95% CI)	0.27 [0.10, 0.44]
13 WAZ	10	12188	Std. Mean Difference (Random, 95% CI)	0.10 [0.04, 0.16]
13.1 At 12 to 15 months	3	1103	Std. Mean Difference (Random, 95% CI)	0.09 [‐0.00, 0.19]
13.2 At 18 months	5	5544	Std. Mean Difference (Random, 95% CI)	0.05 [‐0.06, 0.17]
13.3 At 24 months	3	5541	Std. Mean Difference (Random, 95% CI)	0.13 [0.03, 0.23]
14 WHZ	10	12894	Std. Mean Difference (Random, 95% CI)	0.12 [0.02, 0.22]
14.1 At 12 to 15 months	2	809	Std. Mean Difference (Random, 95% CI)	0.10 [‐0.02, 0.22]
14.2 At 18 months	5	5544	Std. Mean Difference (Random, 95% CI)	0.13 [‐0.05, 0.31]
14.3 At 24 months	3	5503	Std. Mean Difference (Random, 95% CI)	0.09 [0.01, 0.17]
14.4 At 36 months	1	1038	Std. Mean Difference (Random, 95% CI)	0.04 [‐0.08, 0.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Moderate stunting	3	2828	Risk Ratio (Random, 95% CI)	0.89 [0.82, 0.97]
2 Severe stunting	2	729	Risk Ratio (Random, 95% CI)	0.41 [0.12, 1.42]
3 Moderate wasting	2	2290	Risk Ratio (Random, 95% CI)	0.79 [0.65, 0.97]
4 Severe wasting	2	735	Risk Ratio (Random, 95% CI)	0.64 [0.19, 2.18]
5 Moderate underweight	2	2280	Risk Ratio (Random, 95% CI)	0.81 [0.73, 0.91]
6 Severe underweight	1		Risk Ratio (Random, 95% CI)	Totals not selected
7 MUAC	2	1512	Std. Mean Difference (IV, Random, 95% CI)	0.02 [‐0.08, 0.12]
8 Haemoglobin (g/L)	1	182	Mean Difference (IV, Random, 95% CI)	0.29 [‐6.00, 6.59]
9 HAZ	4	4047	Std. Mean Difference (IV, Random, 95% CI)	0.06 [0.00, 0.13]
10 WAZ	3	1933	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.04, 0.14]
11 WHZ	3	1933	Std. Mean Difference (IV, Random, 95% CI)	0.07 [‐0.02, 0.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Moderate stunting	3	2365	Risk Ratio (Random, 95% CI)	0.92 [0.82, 1.02]
2 Moderate wasting	2	2004	Risk Ratio (Random, 95% CI)	0.97 [0.77, 1.23]
3 Moderate underweight	2	2004	Risk Ratio (Random, 95% CI)	0.88 [0.78, 0.99]
4 Anaemia	2	557	Risk Ratio (Random, 95% CI)	0.38 [0.21, 0.68]
5 Anaemia: Sensitivity analysis	1		Risk Ratio (Random, 95% CI)	0.56 [0.27, 1.14]
6 Serum haemoglobin (g/L)	2	557	Mean Difference (Random, 95% CI)	5.13 [2.00, 8.26]
7 Serum haemoglobin (g/L): Sensitivity analysis	1		Mean Difference (Random, 95% CI)	3.6 [‐0.13, 7.33]
8 HAZ	3	2362	Std. Mean Difference (IV, Random, 95% CI)	0.10 [‐0.08, 0.27]
9 HAZ: Sensitivity analysis	2	2001	Std. Mean Difference (IV, Random, 95% CI)	0.16 [0.03, 0.28]
10 WAZ	3	2362	Std. Mean Difference (IV, Random, 95% CI)	0.12 [0.02, 0.21]
11 WAZ: Sensitivity analysis	2	2001	Std. Mean Difference (IV, Random, 95% CI)	0.14 [0.05, 0.23]
12 WHZ	3	2362	Std. Mean Difference (IV, Random, 95% CI)	0.05 [‐0.06, 0.17]
13 WHZ: Sensitivity analysis	2	2001	Std. Mean Difference (IV, Random, 95% CI)	0.10 [0.01, 0.18]

Methods	Design: community‐based randomised controlled trial involving 3 intervention groups and 1 nonintervention (NI) group. Unit of randomisation: individual
Participants	Location/Setting: Koforidua, in the Eastern Region of Ghana Sample size: 409 Ghanian infants (5 months of age) Dropouts/withdrawals: 15 lost to follow‐up Sex: both male and female children included Mean age: children enrolled at 5 months of age Inclusion criteria 5 months of age Receiving any breast milk Not known to be asthmatic or allergic to peanuts Planning to stay at the study site during the next 7 months Exclusion criteria: not specified
Interventions	The infants were randomly assigned to receive either of the following until 12 months of age. Intervention Sprinkles (SP) powder (n = 105) crushable Nutritabs (NT) tablets (n = 105) Energy‐dense (108 kcal/day), fat‐based Nutributter (NB) (n = 103) Control: no intervention (n = 96)
Outcomes	Primary outcomes Weight; Head circumference Length‐for age z score (LAZ) Weight‐for‐age z score (WAZ) Weight‐for‐length z score (WLZ) Secondary outcomes Diarrhoea Fever Upper respiratory tract infection Timing of outcome assessment: at 12 months of age
Notes	Study start date: February 2004 Study end date: June 2005 Funding source: Nutriset manufactured NB. Conflicts of interest: one of the study authors was a paid consultant of Nutriset. None of the other study authors had any potential conflicts of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "we randomly selected 75% of eligible infants by entering identification numbers for all eligible infants in a dataset and using a SAS data step....The NI infants were enrolled from among the 25% of those who were originally eligible but not randomly selected for the intervention groups" Comment: not adequate
Allocation concealment (selection bias)	Low risk	Quote: "the infants were randomly assigned (with the use of opaque envelopes with group designations) to receive SP, NT, or NB until 12 mo of age" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "NT was provided to the mothers in plastic bags, and the NB (20 g/d) was provided in foil packs with screw caps" Comment: not adequate
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Comment: not clearly specified
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: SP group = 98/105; NT group = 102/105; NB group = 98/103 Comment: reasons provided for loss to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT00379158 at ClinicalTrials.gov. Outcomes described in the protocol and the methodology section reported in the results section
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a partially double‐blind, parallel, randomised, controlled trial with 3 equal‐size groups. Unit of randomisation: individual
Participants	Location/Setting: the study was conducted in several adjoining semi‐urban communities (Somany‐Odumasi‐Kpong area) in the Yilo Krobo and the Lower Manya Krobo districts in Ghana. Sample size: 1320 women at < 20 weeks of gestation, and 1228 infants Dropouts/withdrawals: 43 children dropped out Sex: both male and female children included Mean age: children were enrolled at birth and the intervention was started at 6 months of age. Inclusion criteria: pregnant women attending usual antenatal clinics in the 4 main health facilities in the area were included if they were: > 18 years old; at < 20 weeks of gestation based on the information available at the time. Exclusion criteria Not residing in the area Intention to move within the next 2 years Milk or peanut allergy Participation in another trial HIV infection Asthma Epilepsy Tuberculosis Any malignancy Unwillingness to sign or thumbprint the relevant consent forms, receive field workers, or take the study supplement
Interventions	Intervention MMN group (n = 439 women and 411 infants) SQ LNS (LNS group) (n = 440 women and 409 infants) Control: IFA group (n = 441 women and 408 infants) Interventions were provided to mothers until delivery, and then either placebo, MMN, or SQ LNS for 6 months postpartum. Infants in the LNS group received SQ LNS formulated for infants from 6 to 18 months of age (endline). SQ LNS provided 20 g/day or 118 kcal.
Outcomes	Primary outcomes Length Length‐for age z score (LAZ) Secondary outcomes Weight Mid‐upper arm circumference (MUAC) Head circumference Weight‐for‐age z score (WAZ) Weight‐for‐length z score (WLZ) Stunting Underweight Wasting Hospitalisation Deaths Timing of outcome assessment: at 18 months of age
Notes	Study start date: December 2009 Study end date: December 2011 Funding source: Bill & Melinda Gates Foundation. The funder had no role in the design of the study; data collection, analysis, and interpretation; or in the preparation of the manuscript. Conflicts of interest: one of the study authors was an employee of Nutriset SAS, which is a commercial producer of LNS products. The study authors declared that they had no conflicts of interest related to this study. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The study statistician at University of California, Davis developed group allocations with the use of a computer‐generated (SAS version 9.3; SAS Institute) randomization scheme in blocks of 9" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "At each enrollment, the study nurse offered sealed, opaque envelopes bearing group allocations, 9 envelopes at a time, and the woman picked one to reveal the allocation" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "It was not possible to blind study workers and participants to the capsules (IFA and MMN supplements) compared with the LNS supplements because of their apparent differences, but laboratory staff, anthropometrists, and data analysts had no knowledge of group assignment until all preliminary analyses had been completed" Comment: not adequate
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "It was not possible to blind study workers and participants to the capsules (IFA and MMN supplements) compared with the LNS supplements because of their apparent differences, but laboratory staff, anthropometrists, and data analysts had no knowledge of group assignment until all preliminary analyses had been completed" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: IFA group = 393/408; MMN group = 401/411; LNS group = 391/409
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT00970866 at ClinicalTrials.gov. Outcomes described in the protocol and methodology section reported in the results section
Other bias	Low risk	Comment: no other potential sources of bias reported

Trial name or title	Public title: Efficacy of a multiple micronutrient‐fortified lipid‐based nutrient supplement for children under two in Cambodia Scientific title: Efficacy of a locally‐produced multiple micronutrient‐fortified lipid‐based nutrient supplement (LNS) for children under two years in Cambodia
Methods	Design: cluster‐randomised, incomplete block, 4 × 4 cross‐over design with no blinding. Allocation ratio = 1:1 Unit of randomisation: cluster Duration: 6 months Objective: to establish the superiority of the novel RUSF, using CSB ++ and Sprinkles as active comparators and the unimproved diet as a control.
Participants	Location/setting: 4 sites in a community setting in peri‐urban Phnom Penh in Combodia Prospective sample size: 540 Sex: both male and female Age range: 6 to 11 months Inclusion criteria Normally nourished or moderately malnourished children Aged 9–23 months In good health for the past 3 days Eating solids for at least 3 months Only caregivers who have no medical complications or illness will be eligible, in order to avoid any associated appetite loss and to refer for treatment. Exclusion criteria Children who have been using Sprinkles, CSB ++ or similar supplementary foods or supplements Children with known food intolerances Any caregivers or children who become ill during the trial will be excluded and referred for treatment.
Interventions	Intervention LNS, eaten over 6 months, age 6‐12 months to age 11‐17 months CSB ++ porridge, eaten over 6 months, age 6‐12 months to age 11‐17 months Sprinkles, eaten over 6 months, age 6‐12 months to age 11‐17 months Control: no intervention
Outcomes	Primary outcomes: anthropometric status (height‐for‐age (HAZ), weight‐for‐height (WHZ) and weight‐for‐age (WAZ), calculated through monthly weight and height measurements
Starting date	February 2016 Current status: active, not recruiting
Contact information	Principal investigator 1: Bindi Borg Address: School of Public Health, Faculty of Medicine, University of Sydney, Sydney, Australia Email:bindi_borg@yahoo.com.au Principal investigator 2: Pascal Marino Address: European Union Delegation in Cameroon, Yaoundé, Cameroon Email: not provided
Notes	Trial registration number:NCT02257762 Funding source: This work is supported by UNICEF Cambodia; Department of Fisheries Post‐Harvest Technologies and Quality Control (DFPTQ), Fisheries Administration, Ministry of Agriculture, Forestry and Fisheries, Cambodia; and IRD France. Conflicts of interest: none declared

Methods	Design: randomised, controlled, outcome‐assessor‐blinded trial Unit of randomisation: individual
Participants	Location/Setting: 1 public district hospital (Mangochi), 1 rural, semi‐private hospital (Malindi), and 1 rural public health centre (Lungwena) in Mangochi District, Southern Malawi Sample size: 869 pregnant women and their 781 children were enrolled. Dropouts/withdrawals: 22 lost to follow‐up Sex: both male and female children included Mean age: children were enrolled at birth and the intervention was started at 6 months of age Inclusion criteria Ultrasound scan confirmed pregnancy of #20 completed gestation weeks Residence in the defined catchment area Availability during the period of the study Signed or thumb‐printed informed consent Exclusion criteria < 15 years of age Need for frequent medical attention due to a chronic health condition Diagnosed asthma treated with regular medication Severe illness that warranted hospital referral History of allergy to peanuts History of anaphylaxis or serious allergic reaction to any substance that required emergency medical care Pregnancy complications evident at the enrolment visit Earlier participation in the iLiNS‐DYAD‐M trial (during a previous pregnancy), or concurrent participation in any other clinical trial
Interventions	Intervention (during pregnancy and 6 months thereafter) Women (n = 291) received 1 capsule containing 18 MMN daily, children (n = 233) received no supplement Women (n = 288) received 1 20 g sachet of SQ LNS daily (containing 21 MMN, protein, carbohydrates, essential fatty acids, and 118 kcal), children (n = 222) received SQ LNS from 6 to 18 months Control (during pregnancy and 6 months thereafter): women (n = 290) received 1 capsule of IFA daily, children (n = 223) received no supplement
Outcomes	Primary outcome length Secondary outcomes Weight Length for age z score (LAZ) Weight for age z score (WAZ) weight for height z score (WHZ) Head circumference and corresponding z score Arm circumference and corresponding z score Stunting Underweight Wasting Timing of outcome assessment: at 18 months of age
Notes	Study start date: February 2011 Study end date: August 2012 Funding source: supported, in part, by a grant to the University of California, Davis, from the Bill & Melinda Gates Foundation, with additional funding from the Office of Health, Infectious Diseases, and Nutrition, Bureau for Global Health, USAID under terms of co‐operative agreement AID‐OAA‐A‐12‐00005, through the FANTA project, managed by FHI 360. Conflicts of interest: one of the study authors works as a director of research for Nutriset SAS, a company that produces and sells LNS and which also prepared the LNS purchased for the present trial. All other study authors declared no conflict of interest. Comment: SQ LNS was provided to mothers in pregnancy and 6 months postpartum, and to their infants from 6 to 18 months of age.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Researcher not involved with the trial created individual randomisation slips (in blocks of 9) and packed them in sealed, numbered, opaque randomisation envelopes that were stored in numerical order" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "Eligible pregnant women were requested to choose 1 of the top 6 envelopes in the stack, and the contents of the envelope indicated her participant number and group allocation" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "we used single masked procedures; that is, field workers who delivered the supplements knew which mothers were receiving LNS, and the participants were advised not to disclose information about their supplements to anyone other than an iLiNS team member" Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "The data collectors who performed the anthropometric measurements or assessed other outcomes were not aware of group allocation. Researchers responsible for the data cleaning remained blind to the trial code, until the database was considered fully cleaned" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: IFA group = 220/223; MMN group = 222/233; LNS group = 214/222 Comment: reasons for loss to follow‐up mentioned
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01239693 at ClinicalTrials.gov. Published protocol reviewed
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a prospective, non‐blinded, randomised, controlled, parallel‐group trial. Unit of randomisation: individual
Participants	Location/Setting: Lwiro Pediatric Hospital, Miti Murhesa Health District, South Kivu Province, Democratic Republic of Congo Sample size: 1383 children (6 months of age) Dropouts/withdrawals: 52 lost to follow‐up Sex: both male and female children included Mean age: children were recruited at birth and the intervention initiated at 6 months of age. Inclusion criteria: full‐term‐born infants (gestational age > 37 weeks) were recruited when they were 4–5 months of age, if consent was given. Exclusion criteria Exclusively bottle‐fed children Children with any malformations or neurologic impairment
Interventions	Intervention: lipid‐based RUCF (n = 691) Control: UNIMIX (n = 692)
Outcomes	Primary outcome Stunting Secondary outcomes Underweight Weight Length Mid‐upper arm circumference (MUAC) Length‐for‐age z score (LAZ) Weight‐for‐age z score (WAZ) Weight‐for‐length z score (WLZ) Mean changes in hematocrit, cholesterol, and triglyceride concentrations Proportion of children walking unassisted (as reported by mother/caregiver) at 12 months of age Timing of outcome assessment: at 12 months of age
Notes	Study start date: October 2009 Study end date: November 2010 Funding source: supported by funds from Irish Aid, Department of Foreign Affairs, Republic of Ireland. Conflicts of interest: three study authors work for Valid Nutrition, who developed the RUCF. One study author worked for Valid International, which is Valid Nutrition’s sister company. All other study authors had no conflicts of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A computer program, with the use of a random‐number generator function, created lists for each study team that comprised 2 trained enumerators" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "On the basis of the generated randomization lists, the field supervisor who was not involved in the recruitment of participants prepared sealed envelopes labelled with consecutive numbers, with each of the envelopes containing the code of the study food that was to be assigned" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "It was not possible to blind either participants or study staff on the nature of the 2 foods, because RUCF was in paste form and was packed in 250‐g plastic jars, whereas UNIMIX was in flour form and was packed in plastic bags" Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: "It was not possible to blind either participants or study staff on the nature of the 2 foods, because RUCF was in paste form and was packed in 250‐g plastic jars, whereas UNIMIX was in flour form and was packed in plastic bags" Quote: "Only the statistician was blinded to study groups during the data analysis" Comment: not done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: RUCF group = 656/691; UNIMIX group = 675/692 Comment: reasons provided for loss to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: trial registered as ISRCTN20267635 at ISRCTN. Outcomes described in the protocol and the methodology section reported in the results section
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: an unblinded, community‐based cluster‐randomised controlled trial. Unit of randomisation: cluster (sectors)
Participants	Location/Setting: the study was conducted in the rural north‐western study site, located in 18 Unions of the Gaibandha and one Union of the Rangpur district in Bangladesh. Sample size: 5536 children (6 months of age) Dropouts/withdrawals: 872 lost to follow‐up Sex: both male and female children included Mean age: 6.22 months Inclusion criteria: families who had consented to be enrolled were visited at home for a baseline enrolment interview in the week the child turned 6 months of age, across all 5 groups. Exclusion criteria: to ensure full exposure to a year of supplementation, per protocol, consented children who were not met despite repeated visits were excluded from the study once they had reached their 7‐month birthday.
Interventions	Intervention WSB++ (n = 928) Chickpea (n = 920) Rice lentil (n = 901) Plumpy'Doz (n = 1599) Control: no food supplement (n = 1591) Children received either of the above along with nutrition counselling in all groups.
Outcomes	Primary outcomes Length length‐for‐age z score (LAZ) Stunting (LAZ < 2 SD) Weight‐for‐length z score (WLZ) Wasting (WLZ < 2 SD) Secondary outcomes: not specified Timing of outcome assessment: at 18 months of age
Notes	Study start date: September 2012 Study end date: May 2014 Funding source: this work was supported by the US Department of Agriculture, National Institute of Food and Agriculture, under the Food and Nutrition Enhancement Program (Award No. 2010‐38418‐21732). In‐kind support in the form of micronutrient premix for the food supplements was provided by DSM, Basel, Switzerland, and Plumpy’Doz was provided by Nutriset (Maulany, France). Additional support for the study was provided by the Bill & Melinda Gates Foundation (GH614) and the Johns Hopkins Sight and Life Global Nutrition Research Institute. Conflicts of interest: the study authors had no conflict of interests to declare. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A random‐number seed was selected by a statistician not involved in the study, using a random number generator, and a random number between 0 and 1 drawn from a uniform distribution was assigned to each sector" Comment: adequately done
Allocation concealment (selection bias)	Unclear risk	Comment: not specified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Our trial was unblinded" Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: "Our trial was unblinded" Comment: not done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: control group = 1312/1591; Plumpy'Doz group = 1395/1599; rice lentil group = 785/901; chickpea group = 786/920; WSB++ group = 789/928 Comment: reasons provided for loss to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: published protocol not found. Outcomes described in the methodology section reported in the results section
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a cluster‐randomised effectiveness trial within a community‐based health program. Unit of randomisation: cluster
Participants	Location/Setting: 11 rural unions of the Badarganj and Chirirbandar subdistricts in north west Bangladesh Sample size: 4011 women at < 20 weeks of gestation within 64 clusters, each comprising the supervision area of a community health worker Dropouts/withdrawals: 137 lost to follow‐up Sex: both males and females included Mean age: children were enrolled at birth and the intervention was initiated at 6 months of age. Inclusion criteria: gestational age < 20 weeks No plans to move away during pregnancy or the following 3 years Exclusion criteria: not specified.
Interventions	Intervention Women (n = 1047) and children (n = 918) both received LNS (LNS‐LNS group) Women (n = 930) received IFA and children (n = 801) received LNS (IFA‐LNS group) Women (n = 1052) received IFA and children (n = 925) received MNP (IFA‐MNP group) Control: women (n = 982) received IFA and children (n = 872) received no supplements (IFA‐control group) For this review, we used data from IFA‐LNS group and IFA‐control group.
Outcomes	Primary outcome: length‐for‐age z score (LAZ). Secondary outcomes Stunting Wasting Underweight Head circumference Weight gain Length gain Weight‐for‐age z score (WAZ) Weight‐for length z score (WLZ) Mid‐upper arm circumference (MUAC) Timing of outcome assessment: at 24 months of age.
Notes	Study start date: October 2011 Study end date: August 2012 Funding source: USAID provided funding for the study to the University of California, Davis, through the FANTA project. Conflicts of interest: none of the study authors reported a conflict of interest related to the study. Comment: we only used data from the group in which only children received LNS compared to control (IFA‐LNS group vs IFA‐Control group).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "For the randomization, the study statistician at UCD first stratified all 64 clusters in the 11 unions by subdistrict and union and then randomly assigned each cluster to 1 of the 4 arms (each containing 16 clusters)" Comment: adequately done
Allocation concealment (selection bias)	Unclear risk	Comment: not specified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "The trial was a researcher‐blind, longitudinal, cluster randomized effectiveness trial" Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "The trial was a researcher‐blind, longitudinal, cluster randomized effectiveness trial" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: LNS‐LNS group = 17%; IFA‐LNS group = 15%; IFA‐MNP group = 16%; IFA‐control = 16%
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01715038 at ClinicalTrials.gov
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a placebo‐controlled, cluster‐randomised trial Unit of randomisation: cluster
Participants	Location/Setting: 34 communities of the Dandé Health District in southwestern Burkina Faso Sample size: 2435 eligible children were randomly assigned to 1 of 4 intervention groups from 9–18 months of age. Dropouts/withdrawals: 594 lost to follow‐up Sex: both male and female children included Mean age: 9.4 months Inclusion criteria: Children aged 8.8 to 9.9 months Resided permanently in the area Planned to be available during the study period Exclusion criteria Hb < 50 g/L; Weight‐for‐length < 70% of the median of the National Center for Health Statistics/WHO growth reference Presence of bipedal oedema Other severe illness warranting hospital referral Congenital abnormalities potentially interfering with growth Chronic medical conditions requiring frequent medical attention Known HIV infection of infant or mother History of allergy towards peanuts History of anaphylaxis or serious allergic reaction to any substance requiring emergency medical care Concurrent participation in any other clinical trial
Interventions	Intervention SQ LNS without zinc, placebo tablet (LNS‐Zn0; n = 602) SQ LNS containing 5 mg zinc, placebo tablet (LNS‐Zn5; n = 613) SQ LNS containing 10 mg zinc, placebo tablet (LNS‐Zn10; n = 603) SQ LNS without zinc and 5 mg zinc tablet (LNS‐TabZn5; n = 617) Control: no intervention (NIC; n = 785) During weekly morbidity surveillance, oral rehydration salts were provided for reported diarrhoea and antimalarial therapy for confirmed malaria; 785 children in the nonintervention group did not receive SQ LNS, tablets, illness surveillance or treatment.
Outcomes	Primary outcomes Length Weight Mid‐upper arm circumference (MUAC) Head circumference Length‐for age z score (LAZ) Weight‐for‐age z score (WAZ) Weight‐for‐length z score (WLZ) Diarrhoea Malaria Zinc concentration Secondary outcomes Stunting Underweight wasting Hb C‐reactive protein Timing of outcome assessment: at 18 months of age
Notes	Study start date: April 2010 Study end date: July 2012 Funding source: the project was funded by a grant from the Bill & Melinda Gates Foundation to the University of California, Davis. The funder had no role in the design of the study, data collection and analysis, the decision to publish, or in the preparation of the manuscript. Conflicts of interest: none of the study authors had a conflict of interest to declare. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer‐generated an assignment within strata to participate in the intervention cohort .... The same statistician, who was blinded to the intervention, generated a random allocation sequence at the level of the concession for the enrollment of eligible infants in the IC" Comment: adequately done
Allocation concealment (selection bias)	Unclear risk	Comment: not clearly stated
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "The trial was partially masked, as all participants, field staff and researchers remained blinded to the four intervention groups until data analyses were completed, but were aware which communities were assigned to IC and NIC" Comment: partially blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "Treatment groups remained masked until all statistical analyses were completed and main conclusions were drawn" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: LNS‐Zn0 group = 489/602; LNS‐Zn5 group = 499/613; LNS‐Zn10 group = 491/603; LNS‐TabZn5 group = 481/617; NIC group = 666/785 Comment: reasons for loss to follow‐up mentioned
Selective reporting (reporting bias)	Low risk	Comments: protocol attached as a supplement in the study paper
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a 2‐arm cluster‐randomised controlled, pragmatic intervention study. Unit of randomisation: cluster
Participants	Location/Setting: city of Abeche, Chad Sample size: 1038 children (6 to 36 months of age) Dropouts/withdrawals: 33 lost to follow‐up Sex: both male and female children included Mean age: 24 months Inclusion criteria Non‐wasted (weight‐for‐height > 80% of the National Center for Health Statistics reference median and lack of bilateral pitting oedema) Being from a ‘‘vulnerable’’ household Exclusion criteria: not specified
Interventions	Intervention: 46 g of RUSF, given daily for 4 months (n = 613) Control: no intervention (n = 458) Both arms were included in a general food distribution program providing staple foods.
Outcomes	Primary outcomes Malnutrition; Wasting Weight‐for‐height z score (WHZ) change over time Secondary outcomes Prevalence of stunting at end point defined as height‐for‐age z score (HAZ) Mean HAZ change over time Mid‐upper‐arm‐circumference change over time Mean Hb concentration at end point Prevalence of anaemia at end point ( Hb < 110 g/L) Morbidity Timing of outcome assessment: after 4 months of intervention
Notes	Study start date: June 2010 Study end date: September 2010 Funding source: this study was funded by Action Contre la Faim, France. The World Food Programme (WFP) donated the food used to compile the food rations. WFP had no role in the design of the study, its implementation, data analysis and interpretation or preparation of the manuscript. Conflicts of interest: the study authors declared that no competing interests exist. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "random assignment was conducted through an official ceremonial gathering with officials and community members. Fourteen papers with cluster numbers were drawn blindly from a bag. Drawn clusters were alternatively assigned to the intervention group and control group" Comment: not adequate
Allocation concealment (selection bias)	High risk	Quote: "random assignment was conducted through an official ceremonial gathering with officials and community members. Fourteen papers with cluster numbers were drawn blindly from a bag. Drawn clusters were alternatively assigned to the intervention group and control group" Comment: not adequate
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "the study participants were not blinded with respect to the intervention assignment because of the type of supplement (paste) provided to children" Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "Data collectors were blinded to group assignment when measurements were taken" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: control group = 440/458; intervention group = 598/613 Comment: reasons provided for loss to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: trial protocol provided as a supplement
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a randomised controlled trial with a parallel design. Unit of randomisation: individual
Participants	Location/Setting: urban slum of Cap Haitien in Haiti Sample size: 589 healthy, singleton infants (aged 6–11 months) recruited Dropouts/withdrawals: 169 lost to follow‐up Sex: both male and female children included Mean age: 7.3 months Inclusion criteria Infant aged between 6 and 11 months Infant in good health (no fever, congenital health condition, or peanut allergy) Singleton birth Infant not severely malnourished (weight‐for‐length z score (WLZ) less than −3 SD) Household was not receiving other food aid Residence within the Fort Saint Michel catchment area Exclusion criteria: not specified
Interventions	Intervention: 3‐month LNS (n = 196); 6‐month LNS (n = 202). Control: no intervention (n = 191) The LNS provided 108 kcal and other nutrients, including vitamin A, vitamin B‐12, iron, and zinc at 80% of the recommended amounts.
Outcomes	Primary outcomes length height weight z scores for length for age, weight for age, weight for height BMI Stunting Underweight Wasting Secondary outcomes IYCF practices Dietary consumption patterns Outcomes of language and motor development Diarrhoea Respiratory infection Cough Fever Helminthes infection Eye and skin conditions Timing of outcome assessment: at 6 months and 12 months postintervention
Notes	Study start date: May 2011 Study end date: December 2012 Funding source: partners in the trial included the Ministry of Public Health and Population (MSPP) in Haiti and Meds and Food for Kids (MFK). Conflicts of interest: none of the study authors had a conflict of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Random assignment was carried out through an allocation‐concealment mechanism whereby sealed paper forms that masked group assignments were drawn from a container by mothers by using a simple random assignment ratio of 1:1:1 for group assignments" Comment: randomisation procedure not mentioned
Allocation concealment (selection bias)	Low risk	Quote: "Random assignment was carried out through an allocation‐concealment mechanism whereby sealed paper forms that masked group assignments were drawn from a container by mothers by using a simple random assignment ratio of 1:1:1 for group assignments" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: probably not done
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Comment: probably not done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: control group = 156/191; 3‐month LNS group = 126/196; 6‐month LNS group = 159/202 Comment: reasons for loss‐to‐follow‐up mentioned
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01552512 at ClinicalTrials.gov. Outcomes described in the methodology section reported in the results section
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a community‐based, controlled, single‐blind, parallel‐group clinical trial. Unit of randomisation: individual
Participants	Location/Setting: southern Malawi Sample size: 1932 healthy infants (aged between 5.5 and 6.5 months) Dropouts/withdrawals: 52 lost to follow‐up Sex: both male and female children included Mean age: 9.9 months Inclusion criteria: mother‐infant pairs were eligible if: infant was enrolled in the main iLiNS‐DOSE trial; infant was aged between 9.0 and 10.0 months of age; mother was breastfeeding the infant on demand; mother and infant would be available for the full study period of 2 weeks. Exclusion criteria Mother was breastfeeding more than 1 infant Mother or infant or both had a severe illness warranting hospital referral
Interventions	Intervention 10 g LNS/d containing milk powder (n = 321) 20 g LNS/d containing milk powder (n = 322) 40 g LNS/d containing milk powder (n = 322) 20 g milk‐free LNS/day (n = 323) 40 g milk‐free LNS/day (n = 324) Control: no supplement until 18 months of age (n = 320)
Outcomes	Primary outcomes Weight; Length; Mid‐upper‐arm circumference (MUAC) Length‐for age z score (LA)Z Weight‐for‐age z score (WAZ) Weight‐for‐length z score (WLZ) Secondary outcomes Hb Malarial parasitaemia Timing of outcome assessment: at 12 months
Notes	Study start date: November 2009 Study end date: May 2012 Funding source: this publication is based on research funded by a grant from the Bill & Melinda Gates Foundation to the University of California, Davis. Conflicts of interest: none of the study authors had a conflict of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We used block randomization and a set of opaque envelopes to assign participants to the intervention groups. The randomization list and envelopes were prepared by a study statistician not involved in trial implementation" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "We used block randomization and a set of opaque envelopes to assign participants to the intervention groups" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: Caregivers and personnel who delivered the intervention were aware whether or not they were receiving LNS.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "and the code was not disclosed to the researchers or to those assessing the outcomes until all data had been entered and verified in a database" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: 40g/day milk‐free LNS group = 239/324; 40g/day milk LNS group = 242/322; 20g/day milk‐free LNS group = 247/323; 20g/day milk LNS group = 236/322; 10g/day milk LNS group = 221/321; control group = 242/320
Selective reporting (reporting bias)	Low risk	Comment: trial protocol available on iLiNS Project website
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: cluster‐randomised trial Unit of randomisation: cluster
Participants	Location/Setting: rural Bangladesh Sample size: 5551 households Dropouts/withdrawals: 369 lost to follow‐up Sex: both male and female children included Mean age: children were enrolled in‐utero Inclusion criteria The in utero children of enrolled pregnant women (index children) were eligible for inclusion if their mother was planning to live in the study village for the next 2 years, regardless of where she gave birth. Only one pregnant woman was enrolled per compound, but if she gave birth to twins, both children were enrolled. Children who were younger than 3 years at enrolment and lived in the compound were included in diarrhoea measurements. Exclusion criteria None specified.
Interventions	Intervention: pregnant women were grouped into geographic clusters, which were randomly assigned to: chlorinated drinking water (n = 698 women); upgraded sanitation (n = 696 women); handwashing promotion (n = 688 women); combined water, sanitation and handwashing (WSH) (n = 702 women); a child nutrition intervention, including lipid‐based nutrient supplements (n = 699); combined WSH plus nutrition (n = 686). Control: no intervention (n = 1382 women) For this review; we only included outcomes from the child nutrition intervention group and the control group. The nutrition intervention targeted index children. When the index children were between 6 and 24 months of age, promoters provided a regular supply of LNS (provided by Nutriset, Malaunay, France). Promoters instructed caregivers to feed a 10 g sachet to the index child twice daily, which would provide 118 Kcal, 9.6 g of fat, 2.6 g of protein, 12 vitamins and 10 minerals.
Outcomes	Primary outcomes Mothers' reports of diarrhoea in the past 7 days among children < 36 months of age at enrolment Length‐for‐age z score (LAZ) among children born to the enrolled pregnant women Secondary outcomes: child developmental outcomes Timing of outcome assessment: at 1‐ and 2‐year follow‐up
Notes	Study start date: May 2012 Study end date: July 2013 Funding source: all study authors declared the receipt of grants and non‐financial support from the Bill & Melinda Gates Foundation during the conduct of this study. Conflicts of interest: the study authors declared no further competing interests. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation was geographically pair‐matched in blocks of 8 clusters" Comment: adequately done
Allocation concealment (selection bias)	Unclear risk	Comment: not specified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: not done due to the nature of intervention
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "Outcome and adherence was assessed by a team of university graduates who were uninvolved in delivering or promoting interventions" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: nutrition intervention group = 574/699 (17.88%); control group = 1138/1382 (17.65%)
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01590095 at ClinicalTrials.gov
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a community‐based randomised trial. Unit of randomisation: individual
Participants	Location/Setting: 2 rural, health facility catchment areas, Lungwena and Malindi in Mangochi district, southern Malawi. Sample size: 840, 6‐month‐old healthy infants residing in the study area Dropouts/withdrawals: 93 lost to follow‐up Sex: both male and female children included Mean age: 6.02 months Inclusion criteria Aged 5.5 to 6.5 months Residence in the study area Informed consent from at least 1 authorised guardian Exclusion criteria Weight‐for‐length < 80% of the WHO reference median Presence of oedema Severe illness warranting hospitalisation on the enrolment day History of peanut allergy Concurrent participation in another clinical trial Any symptoms of food intolerance within 30 minutes of ingesting a 5 g test dose of LNS (either milk or soy based) used in the trial
Interventions	Intervention Milk–LNS (n = 212) Soy–LNS (n = 210) Corn–soy blend (CBS; n = 209 Control: no intervention (n = 209) The supplements provided micronutrients and approximately 280 kcal (energy) per day.
Outcomes	Primary outcomes Severe stunting Very severe stunting Moderate‐to‐severe stunting Secondary outcomes Change in length‐for‐age z score (LAZ) Changes in weight Underweight Wasting Developmental outcomes Timing of outcome assessment: at 18 months
Notes	Study start date: January 2008 Study end date: May 2009 Funding source: the research project was supported by the Academy of Finland (grant numbers 200720,108873,111685 and 109796), the Foundation for Pediatric Research in Finland, the Medical Research Fund of Tampere University Hospital and the American people though the support of the Office of Health, Infectious Disease and Nutrition, Bureau for Global Health, USAID, under terms of Cooperative Agreement No. GHN‐A‐00‐08‐00001‐00, through the FANTA‐2 Project, and operated by the Academy for Educational Development (AED). Conflicts of interest: two study authors received personal stipends from the Nestle Foundation. All other study authors had no conflicts of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Blocked randomisation, with each block containing 16 allocations evenly distributed for the four groups, was used to assign participants to intervention groups" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "A set of identical‐appearing opaque envelopes from one randomisation block was shuffled and a guardian was requested to choose one envelope. The envelope contained an identification number and the allocation to one of the four interventions" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "The main possible causes of bias in our study design were the insufficient blinding of the field workers to the group allocation" Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "The randomisation list and envelopes were made by an individual not involved in trial implementation, and the code was not disclosed to the researchers or to those assessing the outcomes until all data had been entered and verified in a database" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: control group = 185/209; milk LNS group = 191/212; soy LNS group = 188/210; CSB group = 183/209 Comment: mentioned reasons for loss to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: key details of the protocol were published at the clinical trial registry of the National Library of Medicine
Other bias	Low risk	Comment: no other potential sources of bias reported

PERMALINK

Preventive lipid‐based nutrient supplements given with complementary foods to infants and young children 6 to 23 months of age for health, nutrition, and developmental outcomes

Jai K Das

Rehana A Salam

Yousaf Bashir Hadi

Sana Sadiq Sheikh

Afsah Z Bhutta

Zita Weise Prinzo

Zulfiqar A Bhutta

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Explanatory secondary outcomes

Search methods for identification of studies

Electronic searches

International databases

Regional databases

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Randomised studies

Overall risk of bias

for the main comparison.

2.

3.

Measures of treatment effect

Dichotomous data

Continuous data

1. Unused methods.

Unit of analysis issues

Cluster‐randomised trials

Trials with more than two treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

'Summary of findings'

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Settings

Participants

Interventions

2. Composition of LNS.

Comparisons

Outcome

Funding sources

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Methods	Design: a 2‐arm, parallel‐group, randomised controlled trial Unit of randomisation: individual
Participants	Location/Setting: conducted in 5 rural districts in the Province of Ambo in the Department of Huánuco, Peru Sample size: 422 (6‐month‐old) children from 19 health centres located in the 5 study districts Dropouts/withdrawals: 61 lost to follow‐up Sex: both male and female children included Mean age: 6.1 months Inclusion criteria: not specified Exclusion criteria Chronic, congenital or severe disease that affects growth and metabolism; Not a singleton Low birth weight Not a permanent resident in the study area
Interventions	Children were screened at 5 months of age, but enrolled when they turned 6 months old at the 19 HC located in the 4 study districts and randomly selected to receive either intervention or control. Intervention: LNS (20 g) containing macronutrients and 19 micronutrients (n = 199 children) Control: MNP (also known as Sprinkles™), containing 5 micronutrients (n = 223 children)
Outcomes	Primary outcomes Hb Anaemia Secondary outcomes Gross motor development Language development Cognitive development Timing of outcome assessment: at 12 months
Notes	Study start date: July 2013 Study end date: December 2015 Funding source: this study was funded by the UBS Optimus Foundation (grant #02) and the Action Against Hunger (ACH; from its initials in Spanish) Foundation. The LNS (Nutributter®) were donated by Nutriset (Malaunay, France). UBS Optimus Foundation and Nutriset had no role in the design, analysis or writing of the report. Conflicts of interest: none declared Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "Both supplements were distributed by the MOH HC staff according to the individual‐level randomisation plan developed by ACH Peru following a standard protocol" Quote: "Due to unexpected problems in the process of customs clearance of the LNS product, the supplement was unavailable for a period of two months (September and October 2014). During that time, the probability of being enrolled in each group differed, but those already enrolled in the LNS group continued receiving their monthly LNS supply" Comment: not adequate
Allocation concealment (selection bias)	High risk	Comment: not specified; probably not done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Comment: not done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: intervention group = 161/199 (19%); control group = 200/223 (10%)
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01715038 at ClinicalTrials.gov. Outcomes specified in the protocol and methodology section reported in the results
Other bias	High risk	Quote: "Due to unexpected problems in the process of customs clearance of the LNS product, the supplement was unavailable for a period of two months (September and October 2014). During that time, the probability of being enrolled in each group differed, but those already enrolled in the LNS group continued receiving their monthly LNS supply."

Methods	Design: a cluster‐randomised trial (Kenya WASH Benefits study) Unit of randomisation: cluster
Participants	Location/Setting: conducted in rural villages in Bungoma, Kakamega, and Vihiga Counties in Kenya’s western region Sample size: 8246 households Dropouts/withdrawals: 445 lost to follow‐up Sex: both male and female children included Mean age: children were enrolled in‐utero Inclusion criteria Villages were eligible for selection into the study if they were: rural; most of the population relied on communal water sources; had unimproved sanitation facilities; no other ongoing water, sanitation, handwashing, or nutrition programmes. Participants were identified through a complete census of eligible villages. Within selected villages, women were eligible to participate if they reported that they: were in their second or third trimester of pregnancy; planned to continue to live at their current residence for the next 2 years; could speak Kiswahili, Luhya, or English well enough to respond to an interviewer administered survey. Exclusion criteria: not specified
Interventions	Intervention Nutrition intervention arm (n = 811). Study children between the ages of 6 and 24 months and their age‐eligible siblings were provided with 2 × 10 g sachets per day of a SQ LNS that could be mixed into the child’s food. LNS was manufactured by Nutriset (Malauny, France) and provided 118 kcal per day and 12 essential vitamins and 10 minerals. Control: active control group (n = 1864). Other study groups Passive control group (n = 905) Water intervention group (n = 875) Sanitation intervention group (n = 856) Handwashing intervention group (n = 885) Combined water, sanitation and handwashing group (n = 877) Combined water, sanitation, handwashing and nutrition group (n = 887) For this review, we only included outcomes from the nutrition intervention arm and the active control arm
Outcomes	Primary outcomes Caregiver‐reported diarrhoea in the past 7 days Length‐for‐age z score (LAZ) Secondary and tertiary outcomes Weight‐for‐length z score (WLZ) Weight‐for‐age z score (WAZ) Head circumference‐for‐age z score (HCZ) Prevalence of stunting (LAZ < −2 SD) Severe stunting (LAZ < −3 SD) Wasting (WLZ < −2 SD) Underweight (WAZ < −2 SD) All‐cause mortality Timing of outcome assessment: at 1‐year and 2‐year postintervention
Notes	Study start date: November 2012 Study end date: May 2014 Funding source: This research was financially supported in part by Global Development grant OPPGD759 from the Bill & Melinda Gates Foundation to the University of California, Berkeley, CA, USA, and grant AID‐OAA‐F‐13‐00040 from United States Agency for International Development (USAID) to Innovations for Poverty Action. This manuscript was made possible by the generous support of the American people through the USAID. Conflicts of interest: All study authors received funding for either salary or consulting fees through a grant from the Bill & Melinda Gates Foundation for this study.  Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Clusters were randomly allocated to treatment at the University of California, Berkeley using a random number generator with reproducible seed" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "Allocation by cluster ID was communicated directly to the field team" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Investigators remained blinded to treatment assignments. Masking participants was not possible" Comment: blinding of participants was not possible due to the nature of intervention
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: "The health promoters and staff who delivered the interventions were not involved in data collection, but the data collection team could have inferred treatment status if they saw intervention materials in study communities" Comment: not adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: nutrition intervention group = 695/811 (14.3%); active control group = 1535/1864 (17.6%)
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01704105 at ClincialTrials.gov
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a longitudinal, cluster‐randomised trial (PROCOMIDA, a Food‐assisted maternal and child health and nutrition (FA‐MCHN)). Unit of randomisation: cluster
Participants	Location/Setting: Guatemala Sample size: pregnant women with gestational age between 3 and 7 months (n = 4545) and children aged 6 to 24 months (n = 4194) Dropouts/withdrawals: 305 lost to follow‐up Sex: both male and female children included Mean age: not specified Inclusion criteria: women living in PROCOMIDA communities were eligible to enrol in the program when they became pregnant and could participate in the monthly food distributions, behaviour change communication sessions and other program activities from the time of enrolment until their children were 24 months of age. Exclusion criteria: not specified
Interventions	Intervention Full family ration (FFR) + corn soy blend (CSB) (group 1; n = 576) Reduced family ration (RFR) + CSB (group 2; n = 575) No family ration (NFR) + CSB (group 3; n = 542) FFR + lipid‐based nutrient supplement (LNS) (group 4; n = 550) FFR + micronutrient powders (MNP) (group 5; n = 587) Control: no intervention (group 6; n = 574)
Outcomes	Primary outcomes Stunting Length‐for‐age z score (LAZ) Secondary outcomes: not specified Timing of outcome assessment: at 24 months of age
Notes	Study start date: August 2011 Study end date: May 2015 Funding source: the research took place within the USAID FFP‐funded PROCOMIDA program. PROCOMIDA was implemented by Mercy Corps in Guatemala. Conflicts of interest: the study authors declared no conflict of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...eligible health convergence centers were stratified by size and randomly assigned to 1 of 6 study groups" Comment: not specified
Allocation concealment (selection bias)	Unclear risk	Comment: not specified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: probably not done
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Comment: probably not done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: group 1 = 654/693; group 2 = 651/695; group 3 = 632/705; group 4 = 630/685; group 5 = 672/718; group 6 = 650/698
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01072279 at ClinicalTrials.gov
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a randomised, controlled, single‐blind trial. Unit of randomisation: individual
Participants	Location/Setting: Lungwena, a rural Malawian population Sample size: 182 (6‐month‐old) infants Dropouts/withdrawals: 14 lost to follow‐up Sex: both male and female children included Mean age: 5.9 months Inclusion criteria Aged between 5.50 and 6.99 months Residence in the study area Informed consent from at least 1 authorised guardian Exclusion criteria Low weight‐for‐length z score (WLZ) (< −2.0 SD) Presence of oedema History of peanut allergy Severe illness warranting hospitalisation on the enrolment day Concurrent participation in another clinical trial Any symptoms of food intolerance 30 minutes after the ingestion of a 6 g test dose of the peanut‐based LNS used as a trial intervention
Interventions	Intervention 25 g/day of micronutrient fortified spread (FS25) for 1 year (n = 60) 50 g/day of micronutrient fortified spread (FS50) for 1 year (n = 61) Control: 71 g/day of micronutrient fortified maize and soy flour (Likuni Phala (LP)) for 1 year (n = 61)
Outcomes	Primary outcome: weight gain Secondary outcomes Length gain Incidence of severe stunting Underweight Wasting Timing of outcome assessment: at 12 months
Notes	Study start date: October 2004 Study end date: December 2005 Funding source: the micronutrient mixture used in the production of fortified spread was provided free of charge by Nutriset Incorporate (Malaunay, France) Conflicts of interest: two of the study authors received a stipend from Nestle Foundation. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "For group allocation, guardians picked one from a set of identically appearing opaque envelopes, each containing a paper indicating an identification number and randomly assigned allocation to one of the three interventions. The randomization list and envelopes were made by people not involved in trial implementation and the code was not disclosed to the researchers or those assessing the outcomes until all data had been entered into a database." Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "For group allocation, guardians picked one from a set of identically appearing opaque envelopes, each containing a paper indicating an identification number and randomly assigned allocation to one of the three interventions. The randomization list and envelopes were made by people not involved in trial implementation and the code was not disclosed to the researchers or those assessing the outcomes until all data had been entered into a database." Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: participants unblinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "the code was not disclosed to the researchers or those assessing the outcomes until all data had been entered into a database" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: FS50 group = 54/61; FS25 group = 57/60; LP group = 57/61 Comment: reasons provided for loss to follow‐up
Selective reporting (reporting bias)	Low risk	Quote: "Details of the protocol were published at the clinical trial registry of the National Library of Medicine, Bethesda, Md, USA"
Other bias	Low risk	Comment: no other potential sources of bias reported

Methods	Design: a cluster‐randomised controlled trial. Unit of randomisation: cluster
Participants	Location/Setting: 3 municipalities (Santa Lucia, Magdalena, and San Antonio) in the south‐western part of Intibucá, Honduras, bordering El Salvador Sample size: 300 children (aged 6–18 months) Dropouts/withdrawals: 54 lost to follow‐up Sex: both male and female children included Mean age: not provided (range = 5 to 18 months of age) Inclusion criteria: infants and caretakers (mothers/caretakers > 16 years of age) were eligible for the study if: infants were 5–18 months of age at time of recruitment; not participating in a child health brigade that provided vitamin A supplementation; residing within the 3 study municipalities; no plans to move outside of the study region in the next 2 months; no medical conditions. Exclusion criteria Infants with congenital anomalies, mental retardation, severe physical handicap, under‐nutrition caused by medical conditions, and allergy to peanuts (determined with an allergy reaction test using 5–15 g of LNS) Infant with a weight for height z score ≤ −2 SD below the norm; they were referred to a qualified healthcare provider
Interventions	Intervention: participants received a monthly supply of a LNS product (Plumpy’Doz by Nutriset, Malaunay, France) throughout the 12‐month study period, providing 247 kcal (n = 160) Control: no intervention (n = 138)
Outcomes	Primary outcomes Micronutrient status (folate, iron, zinc, riboflavin, and vitamin B12 status) Hb Secondary outcomes Growth Dietary intake Food insecurity Timing of outcome assessment: at 12 months
Notes	Study start date: March 2009 Study end date: April 2010 Funding source: this work was supported by the Mathile Institute for the Advancement of Human Nutrition and The Department of Nutrition Obesity Research Center. Conflicts of interest: the study authors reported no conflict of interest. Comment: none
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "One cluster within each pair was then randomised to intervention (n = 9) or control group (n = 9)" Comment: not clearly reported
Allocation concealment (selection bias)	High risk	Quote: "The study was blinded to study group allocation at the data entry level and at the biomarker analysis level. Given the difficulties of working in this rural setting, delivery of the intervention was not blinded for project staff conducting the assessments." Comment: not done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "The study was blinded to study group allocation at the data entry level and at the biomarker analysis level. Given the difficulties of working in this rural setting, delivery of the intervention was not blinded for project staff conducting the assessments." Comment: not done
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "The study was blinded to study group allocation at the data entry level and at the biomarker analysis level. Given the difficulties of working in this rural setting, delivery of the intervention was not blinded for project staff conducting the assessments." Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition: intervention group = 134/160; control group = 110/138 Comment: reasons for loss to follow‐up not specified
Selective reporting (reporting bias)	Low risk	Comment: trial registered as NCT01312987 at ClinicalTrials.gov. Outcomes described in the methodology section reported in the results section
Other bias	Low risk	Comment: no other potential sources of bias reported

Study	Reason for exclusion
Ackatia‐Armah 2015	This study included children with moderate acute malnutrition.
Adams 2017	This study assessed combined food security data from three of the included studies.
Adams 2018	This study is an analysis of 'willingness to pay' from the data of two studies already included in the review.
Ahmed 2014	This study only reported on the development and acceptability of various LNS.
Arimond 2017	This study reported combined results from four studies included in the review
Cercamondi 2013	This study assessed the bioavailability of iron in iron‐fortified complementary food.
Defourney 2009	This study is an uncontrolled before‐and‐after study.
Flax 2010	This study included underweight children.
Flax 2013	This study included HIV‐exposed children.
Heidkamp 2012	This study included HIV‐exposed children.
Isanaka 2009	This study included children up to 60 months of age.
Iuel‐Brockdorf 2015	This study included children with moderate acute malnutrition.
Kuusipalo 2006	This study included underweight children.
LaGrone 2012	This study included children with moderate acute malnutrition.
Langendorf 2014	The comparison of interest in this study were not randomly allocated.
Maleta 2004	This study included underweight and stunted children.
Maryam 2015	This study only reported the impact of LNS on vitamin A and zinc levels.
Muslihah 2016	The study design was not appropriate.
Rantesalu 2017	This study reported the impact of LNS on insulin‐like growth factor‐1 level (IGF‐1) only.
Schlossman 2017	This study included mildly or moderately malnourished children.
Style 2017	This study is a before‐and‐after study without a control group.
Thakwalakwa 2010	This study included moderately underweight children.
Thakwalakwa 2012	This study included underweight children.
Thakwalakwa 2015	This study included moderately underweight children.
Unger 2017	In this study the participants are sick children.
Vargas‐Vásquez 2015	This study is an uncontrolled before‐and‐after study.

Trial name or title	Public title: Improving child development in children in Madagascar Scientific title: A cluster‐randomised, controlled trial of nutritional supplementation and promotion of responsive parenting in Madagascar: the MAHAY
Methods	Design: multi‐arm, randomised controlled trial Unit of randomisation: cluster Duration: one year Objective: to test the effects and cost‐effectiveness of combined interventions to address chronic malnutrition and poor child development.
Participants	Location/setting: Madagascar Prospective sample size: 25 communities in each arm (n = 1250 pregnant women, n = 1250 children aged 0 – 6 months, n = 1250 children aged 6–18 months) Sex: both male and female children Age range: birth to 18 months Inclusion criteria: all pregnant women and women with age‐eligible children living in the catchment area of a project site are eligible to participate in the standard growth monitoring and nutritional education that occurs in a group setting in a community centre in all sites. Exclusion criteria: severe malnutrition (will be referred for treatment)
Interventions	The arms of the trial are: (T0) existing program with monthly growth monitoring and nutritional/hygiene education (T1) T0 + home visits for intensive nutrition counselling within a behavior change framework (T2) T1 + lipid‐based supplementation (LNS) for children 6–18 months old (T3) T2 + LNS supplementation of pregnant/lactating women (T4) T1 + intensive home visiting program to support child development There are anticipated to be 25 communities in each arm (n = 1250 pregnant women, n = 1250 children 0–6 months old, and n = 1250 children 6–18 months old)
Outcomes	Primary outcomes Height‐for‐age and stunting Measures of child development including language, cognitive development Secondary outcomes Wasting Being underweight Iron deficiency and anaemia Intermediate indicators of nutrition and development pathway outcomes including Dietary diversity Household food security Maternal knowledge of child care and feeding practices Home stimulation practices
Starting date	July 2014 Current status: no longer recruiting
Contact information	Principal investigator: Dr Lia Fernald Address: School of Public Health, University of California, Berkeley, 50 University Hall, MC 7360, Berkeley, CA 94720‐7360, USA Email:fernald@berkeley.edu
Notes	Trial registration number:ISRCTN14393738 Funding source: Strategic Impact Evaluation Fund; The World Bank Conflicts of interest: none declared

Trial name or title	Public title: The effect of integrated prevention and treatment on child malnutrition and health in Burkina Faso, a cluster‐randomised intervention (PROMIS‐BF) Scientific title: The effect of integrated prevention and treatment on child malnutrition and health in Burkina Faso: a cluster‐randomised intervention study
Methods	Design: a two‐arm, cluster‐randomised, non‐masked, community‐based trial Unit of randomisation: cluster Duration: 24 months Objective: to assess the effect of an integrated approach consisting of higher screening coverage and preventive Behavior Change Communication (BCC) + SQ‐LNS on both prevention and treatment of child undernutrition.
Participants	Location/setting: Burkina Faso and Mali Prospective sample size: 2400 participants in Burkina Faso and 2304 participants in Mali Sex: both male and female children Age range: children aged 6 to 23.9 months Inclusion criteria Child aged from birth to 1.4 months Mother living in the study area since the index child's delivery Singleton infants Exclusion criteria Congenital malformations that make anthropometric measurements impossible Mother planning to leave the study area in the coming year Children aged 1.5 months or older at study inclusion WHZ < −2 both at enrolment and at the first follow‐up
Interventions	Intervention: the PROMIS intervention provides an integrated package that consists of 2 key components. Small group, Behavior Change Communication (BCC) on Essential Nutrition Actions (ENA), Infant and Young Child Feeding (IYCF) and Water, Sanitation and Hygiene (WASH) is provided during monthly well‐baby visits for children 0‐17 months of age; Caregivers with children 0‐17 months of age that attend the well‐baby visit will be provided with a monthly dose of LNS (20 g/day). Control: monthly well‐baby visits, as prescribed by national policy. This arm is the basic comparison arm. Caregivers are invited to frequent the health centre once a month for well‐baby visits. During these visits necessary vaccinations are administered, child growth and nutrition status is evaluated and preventive counselling on child nutrition and health is provided in large groups of caregivers.
Outcomes	Primary outcomes Prevalence of acute child malnutrition (defined by WHZ < −2, MUAC < 125 mm or bilateral pitting oedema in children aged from birth to 17 months) (time frame: after 24 months of program implementation) Screening coverage of acute child malnutrition (proportion of children monthly screened/total number of eligible children (aged from birth to 17 months)) (time frame: monthly from study inclusion at birth to 17 months of age and at study endline) Incidence of child acute malnutrition (defined by WHZ < −2 or MUAC < 125 mm) (time frame: monthly from study inclusion at birth to 17 months of age) Compliance to treatment of acute malnutrition (% of cases that complete treatment over total admitted) (time frame: monthly from study inclusion at birth to 17 months of age and at study endline) Secondary outcomes Prevalence of child stunting (defined by HAZ < −2 in children aged from birth to 17 months) (time frame: after 24 months of program implementation) Mean WHZ score in children (aged from birth to 17 months) (time frame: after 24 months of program implementation) Mean HAZ score in children (aged from birth to 17 months) (time frame: after 24 months of program implementation) Mean MUAC in children (aged from birth to 17 months) (time frame: after 24 months of program implementation) Mean Hb concentration in children (aged from 3 to 17 months) (time frame: after 24 months of program implementation). Hemocues will be used to measure Hb concentration Prevalence of child anaemia (Hb concentration < 10 g/dL) in children (aged from 3 to 17 months) (time frame: after 24 months of program implementation) Prevalence of severe acute child malnutrition (defined by a WHZ < −3, bilateral pitting oedema or a MUAC < 115 mm in children aged from birth to 17 months) (time frame: after 24 months of program implementation) Prevalence of severe stunting (defined by a HAZ < −3 in children aged from birth to 17 months) (time frame: after 24 months of program implementation) Caregiver's knowledge and practices related to IYCF, ENA and WASH (time frame: after 24 months of program implementation) Incidence of child stunting (defined by HAZ < −2 in children aged from birth to 17 months) (time frame: monthly from inclusion at birth to 17 months of age) Linear growth velocity (HAZ increment/month) (time frame: monthly from inclusion at birth to 17 months of age) Ponderal growth velocity (WHZ increment/month) (time frame: monthly from inclusion at birth to 17 months of age) Weight gain (weight increment/month) (time frame: monthly from inclusion at birth to 17 months of age) MUAC (increment/month) (time frame: monthly from inclusion at birth to 17 months of age) Infant morbidity (acute respiratory infections, fever, malaria (RDT), vomiting, diarrhoea) (time frame: monthly from inclusion at birth to 17 moths of age). Malaria will be tested in case of fever (or recalled fever over last 24 hours) using rapid tests Relapse rate after treatment of MAM/SAM (proportion WHZ < −2, MUAC < 125 mm or bilateral pitting oedema after discharge from MAM or SAM treatment program over total number of children treated) (time frame: monthly from inclusion at birth to 17 months of age)
Starting date	February 2015 Current status: recruitment complete
Contact information	Principle investigator: Lieven Huybregts Address: International Food Policy Research Institute Email:L.Huybregts@cgiar.org
Notes	Trial registration number:NCT02323815; NCT02245152 Funding source: Global Affairs Canada, award number 52308/5252/0200. Co‐funding was kindly provided by the CGIAR Research Program on Agriculture for Nutrition and Health (A4NH), led by the International Food Policy Research Institute.). Conflicts of interest: none declared

Trial name or title	Public title: Ready to use supplementary foods (RUSF) to prevent stunting among children under five years in Kurram Agency Scientific title: A community‐based cluster‐controlled trial to evaluate the effectiveness of ready to use supplementary foods (RUSF) and proportional contribution of multi‐sectoral interventions in the prevention of stunting among children under five years in Kurram Agency, Pakistan
Methods	Design: community‐based, cluster‐randomised controlled trial Unit of randomisation: cluster Duration: from pregnancy until 36 months of age. Objective: the aim of this study is to evaluate the effectiveness of selected nutrition‐specific interventions in improving childhood length‐for‐age scores.
Participants	Location/setting: Pakistan Prospective sample size: 7200 Sex: both male and female children Age range: pregnant women aged 15‐49 years; children aged 6‐23 months Inclusion criteria Group 1: pregnant women in their first trimester (preferably 1st 2 months of pregnancy) will be invited and those between the ages of 15‐49 years will be recruited Group 2: lactating women within the early days following delivery (preferably within 2 months of delivery) will be invited and recruited Group 3: children between 6‐18 months of age will be invited and children aged 6‐23 months will be recruited Group 4: children with ages between 24‐48 months will be invited and children aged 24‐59 month will be recruited Preferably these children will be recruited from the households from which pregnant and lactating women were invited. Exclusion criteria* Children with SAM or MAM (will be referred for treatment) Similar nutrition specific interventions currently being implemented in the selected cluster Participants planning to move from the study area during the study timelines
Interventions	Intervention LNS for pregnant and lactating women (Local name: Maamta). These RUSF are given to pregnant and lactating women in Group 1 and Group 2. Supplementation will start from conception/earliest confirmation of pregnancy, or during the first 6 months of lactation for lactating women. Active ingredients include roasted chickpeas, roasted yellow lentils, roasted peanuts, soybean oil, palm olein oil, hydrogenated vegetable fat as stabiliser, skimmed milk powder, sugar, maltodextrin, vitamins and minerals, emulsifier and antioxidant. The daily ration is a 75 g sachet. One sachet per day is recommended for maintenance of nutritional status, throughout pregnancy and the first 6 months of lactation. Maamta is manufactured within a quality and food safety management environment in accordance with latest version of recognised international standards and best practices and/or guidelines. LNS for children (Local name: Wawa‐mum). These RUSF are given to children aged 6‐23 months (Group 3 in the trial). The active ingredients include roasted chickpeas, vegetable oil, dry skimmed milk, sugar, vitamins and minerals, emulsifier and antioxidant. The daily ration is a 50 g sachet. One sachet per day is recommended. The average duration of the intervention is 18 months under stunting prevention, depending on the age of the child at the time of assistance, starting from 6 months till 23 months age. Wawa‐mum is manufactured within a quality and food safety management environment in accordance with latest version of recognised international standards and best practices and/or guidelines. Micronutrient Powder (MNP) for children (Local name: Vita‐Mixe). These RUSF are given to children aged 24‐59 months (i.e. group 4 of the trial). MNP is homogeneous, stable and dry packaged in a 1 g sachet. The daily ration is 1 g sachet. One sachet per alternate day is recommended under stunting prevention (1 sachet for 2 days). Control: no intervention
Outcomes	Primary outcome measures Change in LAZ, measured using the height boards (SECA) at each month in the intervention vs control arms, compared to the baseline LAZ score against WHO 2006 growth standards (time frame: baseline and thereafter monthly, till the end of the study (3 years)). Change in WAZ, measured using the digital weighing scales (SECA) at each month in intervention vs control arms, compared to the baseline WAZ score against WHO 2006 growth standards (time frame: baseline and thereafter monthly, till the end of the study (3 years)). Change in WHZ, measured using the digital weighing scales (SECA) and height boards (SECA) at each month in intervention vs control arms, compared to the baseline WHZ score against WHO 2006 growth standards (timeframe: baseline and thereafter monthly, till the end of the study (3 years)). Secondary outcome measures Infant and Young Child Feeding (IYCF) indicators, measured using a questionnaire (WHO guideline‐based) at baseline and at the end of the study in the intervention vs control arm (time frame: baseline and at the end of the study). Birth weight of live newborns, measured using digital weighing scales (SECA) at 24 hours of birth in the intervention vs control arm (time frame: within 24 hours of delivery). Nutritional intake (energy and protein), measured using 24‐hour dietary recall method (FAO guideline‐based) at baseline and at the end of the study (time frame: baseline and at the end of the study). Maternal weight gain during pregnancy, measured using digital weighing scales (SECA) at baseline and thereafter monthly, till delivery, in the intervention vs control arm (time frame: baseline, thereafter monthly till delivery). Hb, albumin and micronutrients, like iron, zinc, iodine and vitamins, measured using blood samples at baseline and thereafter yearly, until the end of the study (3rd year end), in a subsample in the intervention vs control arm (time frame: baseline, thereafter yearly till the end of the study (3rd year end)).
Starting date	December 2017 Current status: ongoing; no longer recruiting
Contact information	Principal investigator: Muhammad Naseem Khan Address: Institute of Public Health & Social Sciences, Khyber Medical University, Phase 5, Hayatabad 25000, Peshawar, Pakistan Email:drnasim@kmu.edu.pk
Notes	Trial registration number:ISRCTN94319790 Funding source: United Nations World Food Programme (WFP) Conflicts of interest: not specified

Trial name or title	Public title: SHINE sanitation, hygiene, infant nutrition efficacy project (SHINE) Scientific title: Sanitation, Hygiene Infant Nutrition Efficacy Project
Methods	Design: 2 × 2 factorial, cluster‐randomised, community‐based trial Unit of randomisation: cluster Duration: 18 months Objective: to assess the impact of sanitation, hygiene, infant nutrition on infant length and Hb
Participants	Location/setting: 2 rural districts of Zimbabwe Prospective sample size: 4800 pregnant women (1200 in each of the 4 trial arms, each of which is comprised of 53 clusters) Sex: both male and female Age range: pregnant women and their infants till 18 months of age Inclusion criteria Pregnant women residing in the study districts Pregnancy confirmed by a urine pregnancy test Exclusion criteria Women residing in the study districts who become pregnant during the enrolment period but do not consent to join the trial Women who reside in urban areas of these two districts Infants with major non‐fatal abnormalities will not be excluded from study procedures, but will be excluded from the final analytic sample if the abnormality is likely to directly affect gut health/function or stature (e.g. neural tube defects, cerebral palsy, Down syndrome).
Interventions	Intervention Water, Sanitation, and Hygiene (WASH) intervention (n = 1200): a package of interventions to improve household sanitation and hygiene Infant and Young Child fFeding (IYCF) intervention (n = 1200): a package of interventions to improve infant and young child feeding and Dietary Supplement Sanitation/Hygiene AND nutrition (WASH + IYCF) (n = 1200): this arm will receive a combination of all standard care interventions, all WASH and all IYCF interventions Control: standard care (n = 1200). The standard care intervention is the blanket intervention as routine.
Outcomes	Primary outcomes LAZ ‐ recumbent length, measured by length board Hb level, measured by Hemocue Timing of outcome assessment: 18 months of age
Starting date	November 2012 Current status: completed
Contact information	Principal investigator: Jean H Humphrey, ScD Address: Johns Hopkins Bloomberg School of Public Health Email: not specified
Notes	Trial registration number:NCT01824940 Funding source: Johns Hopkins Bloomberg School of Public Health Conflicts of interest: not specified