Lipid‐based nutrient supplements for maternal, birth, and infant developmental outcomes

Jai K Das; Zahra Hoodbhoy; Rehana A Salam; Afsah Zulfiqar Bhutta; Nancy G Valenzuela‐Rubio; Zita Weise Prinzo; Zulfiqar A Bhutta

doi:10.1002/14651858.CD012610.pub2

. 2018 Aug 31;2018(8):CD012610. doi: 10.1002/14651858.CD012610.pub2

Lipid‐based nutrient supplements for maternal, birth, and infant developmental outcomes

Jai K Das ^1,^✉, Zahra Hoodbhoy ¹, Rehana A Salam ¹, Afsah Zulfiqar Bhutta ², Nancy G Valenzuela‐Rubio ^3,⁴, Zita Weise Prinzo ⁵, Zulfiqar A Bhutta ^6,⁷

Editor: Cochrane Developmental, Psychosocial and Learning Problems Group

PMCID: PMC6513224 PMID: 30168868

Abstract

Background

Ready‐to‐use lipid‐based nutrient supplements (LNS) are a highly nutrient‐dense supplement, which could be a good source of macro‐ and micronutrients for pregnant women who need to supplement their nutrient intake.

Objectives

To assess the effects of LNS for maternal, birth and infant outcomes in pregnant women. Secondary objectives were to explore the most appropriate composition, frequency and duration of LNS administration.

Search methods

In May 2018, we searched CENTRAL, MEDLINE, Embase, 22 other databases and two trials registers for any published and ongoing studies. We also checked the reference lists of included studies and relevant reviews, and we contacted the authors of included studies and other experts in the field to identify any studies we may have missed, including any unpublished studies.

Selection criteria

We included randomised controlled trials (RCTs) and quasi‐RCTs that compared LNS given in pregnancy to no intervention, placebo, iron folic acid (IFA), multiple micronutrients (MMN) or nutritional counselling.

Data collection and analysis

We used standard Cochrane procedures.

Main results

We included four studies in 8018 pregnant women. All four studies took place in stable community settings in low‐ and middle‐income countries: Bangladesh, Burkina Faso, Ghana and Malawi. None were in emergency settings. The oldest trial was published in 2009. Of the four included studies, one compared LNS to IFA, one compared LNS to MMN, and two compared LNS to both IFA and MMN.

We considered the included studies to be of medium to high quality, and we rated the quality of the evidence as moderate using the GRADE approach.

LNS versus IFA

Maternal outcomes: there was no difference between the LNS and IFA groups as regards maternal gestational weight gain per week (standard mean difference (SMD) 0.46, 95% confidence interval (CI) −0.44 to 1.36; 2 studies, 3539 participants). One study (536 participants) showed a two‐fold increase in the prevalence of maternal anaemia in the LNS group compared to the IFA group, but no difference between the groups as regards adverse effects. There was no difference between the two groups for maternal mortality (risk ratio (RR) 0.53, 95% CI 0.12 to 2.41; 3 studies, 5628 participants).

Birth and infant outcomes: there was no difference between the LNS and IFA groups for low birth weight (LBW) (RR 0.87, 95% CI 0.72 to 1.05; 3 studies, 4826 participants), though newborns in the LNS group had a slightly higher mean birth weight (mean difference (MD) 53.28 g, 95% CI 28.22 to 78.33; 3 studies, 5077 participants) and birth length (cm) (MD 0.24 cm, 95% CI 0.11 to 0.36; 3 studies, 4986 participants). There was a reduction in the proportion of infants who were small for gestational age (SGA) (RR 0.94, 95% CI 0.89 to 0.99; 3 studies, 4823 participants) and had newborn stunting (RR 0.82, 95% CI 0.71 to 0.94; 2 studies, 4166 participants) in the LNS group, but no difference between the LNS and IFA groups for preterm delivery (RR 0.94, 95% CI 0.80 to 1.11; 4 studies, 4924 participants), stillbirth (RR 1.14; 95% CI 0.52 to 2.48; 3 studies, 5575 participants) or neonatal death (RR 0.96, 95% CI 0.14 to 6.51). The current evidence for child developmental outcomes is not sufficient to draw any firm conclusions.

LNS versus MMN

Maternal outcomes: one study (662 participants) showed no difference between the LNS and MMN groups as regards gestational weight gain per week or adverse effects. Another study (557 participants) showed an increased risk of maternal anaemia in the LNS group compared to the MMN group.

Birth and infant outcomes: there was no difference between the LNS and MMN groups for LBW (RR 0.92, 95% CI 0.74 to 1.14; 3 studies, 2404 participants), birth weight (MD 23.67 g, 95% CI −10.53 to 57.86; 3 studies, 2573 participants), birth length (MD 0.20 cm, 95% CI −0.02 to 0.42; 3 studies, 2567 participants), SGA (RR 0.95, 95% CI 0.84 to 1.07; 3 studies, 2393 participants), preterm delivery (RR 1.15, 95% CI 0.93 to 1.42; 3 studies, 2630 participants), head circumference z score (MD 0.10, 95% CI −0.01 to 0.21; 2 studies, 1549 participants) or neonatal death (RR 0.88, 95% CI 0.36 to 2.15; 1 study, 1175 participants).

Authors' conclusions

Findings from this review suggest that LNS supplementation has a slight, positive effect on weight at birth, length at birth, SGA and newborn stunting compared to IFA. LNS and MMN were comparable for all maternal, birth and infant outcomes. Both IFA and MMN were better at reducing maternal anaemia when compared to LNS. We did not find any trials for LNS given to pregnant women in emergency settings.

Readers should interpret the beneficial findings of the review with caution since the evidence comes from a small number of trials, with one‐large scale study (conducted in community settings in Bangladesh) driving most of the impact. In addition, effect sizes are too small to propose any concrete recommendation for practice.

Plain language summary

Effects of lipid‐based nutrient supplements (LNS) for women during pregnancy

Review question

Is giving lipid‐based nutrient supplements (LNS) to women during pregnancy good for mothers and their babies?

Background

Women's nutritional status before and during pregnancy plays a key role in fetal growth and development. It is important to address maternal undernourishment in order to improve maternal and child health. LNS aim to deliver nutrients to pregnant women and other vulnerable people, thereby providing a range of vitamins and minerals coupled with energy, protein and essential fatty acids.

Study characteristics

We found four studies with 8018 pregnant women. The oldest study was published in 2009. All studies took place in developing countries: three were in Africa (one apiece in Ghana, Malawi, and Burkina Faso), and one was in Asia (Bangladesh). All studies took place in a stable community setting; none were conducted in emergency settings. Of the four included studies, one compared LNS to iron folic acid (IFA), one compared LNS to multiple micronutrients (MMN), and two compared LNS to both IFA and MMN.

Key results

This review suggests that there may be a slight benefit of LNS on babies who are born small, and on newborn weight and length, when compared to IFA. LNS did not seem to give any additional benefit to women and newborns compared to MMN, and both IFA and MMN were better at reducing maternal anaemia than LNS. We did not find any studies on LNS for pregnant women in emergency settings.

Quality of evidence

Overall, the evidence is of moderate quality.

Currentness of evidence

The evidence is current to May 2018.

Summary of findings

Background

Description of the condition

The nutritional status of women prior to and during pregnancy plays a key role in fetal growth and development, and women's energy and protein requirements significantly increase during pregnancy (FAO/WHO/UNU 2004). Maternal undernutrition is still prevalent, especially in low‐ and middle‐ income countries (LMICs), with approximately 20% of women in Asia and 10% women in Africa having a low body mass index (BMI; less than 18.5 kg/m² in adult women) (Black 2013). Apart from low BMI, deficiencies of micronutrients, including iron, folate, calcium, and vitamins A and D are also prevalent in LMICs. In 2011 the global prevalence of anaemia among pregnant women was estimated to be 38.2% (WHO 2015). At least half of this anaemia burden is assumed to be due to iron deficiency, with the rest due to other conditions, including folate, vitamin B12 or vitamin A deficiencies; chronic inflammation; parasitic infections; and inherited disorders (Black 2013). Calcium and vitamin D deficiencies are also a major public health problem worldwide in all age groups; however, most countries are still lacking reliable data, particularly population representative data, with limited information on infants, children, adolescents and pregnant women (Palacios 2014). Globally, the prevalence of night blindness in pregnant women is estimated to be around 8%, affecting around 10 million women, with an estimated 15.3% of pregnant women worldwide having low serum retinol levels (Black 2013). Estimates suggest that 28.5% of the world's population, or 1.9 billion individuals, are iodine deficient (Black 2013). Additionally, undernutrition and micronutrient deficiencies increase the risk of infections, and in turn lead to further undernutrition (Black 2013).

Maternal undernutrition causes maternal and child morbidity and mortality, also contributing to low birth weight (LBW) and small‐for‐gestational‐age (SGA) births, which can lead to stunting, wasting and micronutrient deficiencies in children (Black 2013). The placenta forms the interface between maternal‐fetal circulations, which is critical for fetal nutrition and oxygenation (Belkacemi 2010), while the placental supply of nutrients to the fetus depends on its size, morphology, blood supply, and transporter abundance. An optimal maternal nutrient supply has a critical role in placental‐fetal growth and development, while a suboptimum maternal nutrition supply during pregnancy results in intrauterine growth restriction (IUGR) and newborns with LBW (Belkacemi 2010). Maternal iron deficiency anaemia has been strongly associated with adverse birth outcomes, including LBW and increased perinatal mortality, while maternal zinc and iodine deficiencies have been suggested as risk factors for adverse fetal and infant growth (Black 2013). LBW, defined by the World Health Organization (WHO) as weight‐at‐birth of less than 2500 g (5.5 lb), continues to be a significant and global public health problem. Overall, about 15% to 20% of all births worldwide are LBW, representing more than 20 million births a year (WHO 2014). LBW is not only a major predictor of mortality and morbidity in infants and children, but recent studies have found that it also increases the risk for non‐communicable diseases, such as diabetes and cardiovascular disease, in later life (Larroque 2001; Risnes 2011). Nutriton is one of the factors influencing cognitive development, and there is some evidence that these nutritional deficiencies can impair child cognition (Shenkin 2004), as well as pose adverse health outcomes in adulthood (Harder 2007). Literature suggests that there is a connection between improved nutrition and optimal brain function since nutrients provide building blocks in cell proliferation, DNA synthesis, neurotransmitter and hormone metabolism, and they are important constituents of enzyme systems in the brain (Bhatnagar 2001; De Souza 2011; Lozoff 2006; Zeisel 2006; Zimmermann 2011). Brain development is faster in the early years of life, making children more vulnerable to maternal and early life dietary deficiencies (Nyaradi 2013).

Addressing undernutrition by achieving appropriate energy intakes (in the form macronutrients) and ensuring that the intakes of specific nutrients (like vitamins and minerals) are adequate to meet maternal and fetal need, is of the utmost importance for improving maternal and child health outcomes (Imdad 2011). Early preventive measures could address general deprivation and inequity, leading to substantial and long‐term improvements in outcomes. Implementation of nutrition interventions and provision of delivery platforms for hard‐to‐reach populations is also crucial (Black 2013). Disruption and displacement of populations in emergency situations (including conflicts and natural disaster) pose an additional threat to the existing situation of undernutrition. Statistics suggest that women and children represent over three‐quarters of the estimated 80 million people in need of humanitarian assistance, and many countries with high maternal, newborn and child mortality rates are affected by humanitarian emergencies (UNICEF 2014).

Description of the intervention

Various interventions are recommended (or have been implemented) to improve maternal nutrition, including education, food provision and micronutrient supplements (iron, folic acid, multiple micronutrients) as well as other indirect interventions such as agricultural and financial interventions (Bhutta 2013). One of the nutritional interventions advocated to improve undernutrition in pregnant women is lipid‐based nutrient supplements (LNS). Adequate consumption of long‐chain, omega‐3 polyunsaturated fatty acids in the diet of pregnant women is essential, particularly the most biologically active forms (docosahexaenoic acid and eicosapentaenoic acid) (Coletta 2010), as these fatty acids support fetal growth, especially the brain and eyes, and deficiency may be associated with visual deficit and suboptimal behavioural development. However, there is not enough evidence to support the routine use of marine oil or other prostaglandin precursor supplements during pregnancy to reduce the risk of pre‐eclampsia, preterm birth, LBW or SGA (Makrides 2006).

LNS are a family of products designed to deliver nutrients to vulnerable people. There is no standard composition of LNS; however, most of the energy is supplied from fats. Three main LNS products are currently used in maternal and child nutrition: ready to‐use therapeutic foods (RUTF) or large‐quantity (LQ) LNS; ready‐to‐use supplementary foods (RUSF) or medium‐quantity (MQ) LNS; and LNS for home fortification or small‐quantity (SQ) LNS (Arimond 2015). RUTF or LQ‐LNS are designed for treatment of severe acute malnutrition, provide almost all energy requirements, and are given in large daily doses (Diop 2003); RUSF or MQ‐LNS are designed for treatment of moderate acute malnutrition and provide 50% to 100% of energy needed; while SQ‐LNS products are designed to prevent undernutrition and promote growth and development through home fortification of the local diet, and they provide less than 50% of the energy needed (Arimond 2015).

LNS provide a range of vitamins and minerals, but unlike most other micronutrient supplements they also provide energy, protein and essential fatty acids (Chaparro 2010). They are considered 'lipid‐based' because most of the energy provided by these products is from lipids (fats). There is no recommended composition for LNS, so existing projects have used different composition mixes. LNS recipes can include a variety of ingredients, but they typically include vegetable fat, peanut or groundnut paste, milk powder and sugar; other ingredients include whey, soy protein isolate, and sesame, cashew and chickpea paste (iLiNS Project 2016). Various commercial and locally available products are being used as LNS; however, researchers are exploring alternative recipes and formulations in efforts to develop affordable and culturally acceptable products for a range of settings. Similar products combining vegetable oil, groundnut paste, milk, sugar and micronutrients are being used as RUTF for managing both moderate and severe acute malnutrition in infants and children (WHO 2012; WHO 2013). Some studies have evaluated the feasibility and acceptability of LNS, suggesting that it is acceptable to infants as well as pregnant and lactating women (Adu‐Afarwuah 2011). Corn soy blends are different from LNS, as these are fortified blended foods (FBF) used as complementary foods or as supplementary foods for pregnant women.

LNS can be used as point‐of‐use food fortification or can be consumed directly during pregnancy as a source of energy, as protein and micronutrients in public health programmes, and as an intervention to improve birth weight and other pregnancy outcomes in areas where maternal undernutrition is prevalent (Arimond 2015; iLiNS Project 2016). These are usually given at a daily dose of less than 120 kcal/day. The doses and formulations of LNS can be modified according to the needs of the specific target group, and to date, there is no widely accepted, standard formulation for women during pregnancy. Some of the advantages of LNS are that they are ready‐to‐eat (no cooking required) and can be stored for as long as 18 to 24 months even in hot climates (Phuka 2008). This makes LNS especially useful in emergency settings where safe water and hygiene are common issues.

How the intervention might work

Ready‐to‐use lipid‐based nutrients could be a good source of macro‐ and micronutrients in a highly nutrient‐dense supplement, and they could be used as a dietary supplement to address the nutrient requirements of undernourished populations of pregnant women. The supplement composition can be tailored to meet the nutritional requirements of the target population. Cost is an important consideration but should be weighed against the effectiveness in maintaining and improving nutritional outcomes (Chaparro 2010).

Multiple studies have evaluated the impact of LNS when given to pregnant women and children in LMICs. The use of LNS has been associated with improved nutritional status among pregnant women and thereby improved growth and development outcomes among infants and children (Arimond 2015; Iannotti 2014; Thakwalakwa 2010), mainly by focusing on promotion of fetal growth during pregnancy through maternal supplementation. Cord leptin, produced by fetal adipocytes and placenta, has been positively associated with birth size and fetal fat mass (Clapp 1998; Forhead 2009; Lepercq 2001). Some authors hypothesise that LNS increases birth size, possibly through a change in the endocrine regulation of fetal development, and it is associated with higher cord blood leptin in primigravidae and women from the highest BMI tertile (Huybregts 2013). One study suggested that the initial effects of LNS are not sustained during infancy based on the hypothesis that fetuses adapted to better nutritional conditions in utero, which could have made them more sensitive to suboptimal nutritional and environmental factors during the postnatal period (Lanou 2014). One study from Malawi suggested that LNS did not influence the occurrence of maternal infections with Plasmodium falciparum parasitaemia, trichomoniasis or vaginal candidiasis, or of urinary tract infection (Nkhoma 2017). Other studies have suggested that LNS are palatable and acceptable to women in LMIC settings (Adu‐Afarwuah 2011; Mridha 2012; Mridha 2016a), although there were variances to adherence within the population (Harding 2014), as beneficiaries tended to make their own adaptations in terms of how much and how often to consume (Harding 2014). A study evaluating home delivery of LNS products in rural Malawi suggested that the cost of procurement, storage and weekly home delivery of LNS was largely comparable to other product delivery mechanisms currently undertaken in the public sector; however, the study also suggested that the expected health and other benefits associated with each proposed intervention strategy should be compared to the costs to set priorities (Vosti 2015).

Why it is important to do this review

LNS are currently being used in programmes targeting pregnant women in LMICs like Ghana, Malawi and Burkina Faso, with the expectation of improving birth outcomes and reducing LBW (Schofield 2009; WHO 2007). Current studies have shown mixed effects of this intervention using varying compositions, doses, frequencies and comparison groups between studies. Various types of fortified foods are currently in use, including FBF, complementary food supplements and multiple micronutrient powders (MNPs). The type and amount of nutrient varies according to the various products and formulations (Schofield 2009). This review will assess the effects and safety of LNS for women during pregnancy on maternal, birth and infant outcomes, as there is currently no systematic evaluation on this topic. The findings could inform policy and would be highly relevant for countries or areas that have a high burden of undernutrition or those facing emergency situations. We will attempt to assess the appropriate composition, frequency and duration of this intervention through various subgroup analyses. In addition, we will carry out a subgroup analysis on whether the pregnant women were identified and the LNS distributed through a facility or in a community. We are also developing a companion review to assess the effectiveness of preventive LNS plus complementary foods for health, nutrition and developmental outcomes in non‐hospitalised infants and children aged 6 to 23 months (Das in press). Together, these reviews will inform policy decisions on the effectiveness and safety of LNS compared to other interventions, and to assess which delivery platforms are effective.

Multiple micronutrient supplements and powders are currently not recommended for pregnant women (WHO 2016), but we will compare them to the provision of LNS, given the assumption that other micronutrients contained in the micronutrient powders could have an impact on pregnancy, birth and infant developmental outcomes; for example, zinc on preterm births (Ota 2015a). We will also compare LNS to antenatal nutrition education, since nutrition education conducted during the antenatal period with the aim of increasing energy and protein intake appears to be effective in reducing the risk of preterm birth and LBW, increasing head circumference at birth, increasing birth weight among undernourished women, and increasing protein intake (Ota 2015b).

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs (i.e. trials that use methods of assignment such as alternation, or assignment based on date of birth or case record number; Lefebvre 2011).

Types of participants

Women with singleton pregnancy of any age and parity, living in stable or emergency settings.

Types of interventions

Interventions involving the provision of LNS for point‐of‐use food fortification or direct consumption, irrespective of dose, frequency and duration. We included any LNS regardless of its content. Specifically, we assessed the evidence for the following comparisons.

LNS versus no intervention or placebo.
LNS versus IFA ‐ in the form of tablets or capsules. We included studies comparing LNS versus IFA and reported differences in micronutrients between groups, as described by trial authors.
LNS versus oral multiple micronutrient (MMN) supplements ‐ in the form of tablets or capsules. We included studies comparing LNS versus MMN and reported differences in micronutrients between groups, as described by trial authors.
LNS versus multiple micronutrient powders (MNPs) ‐ to be sprinkled over food. We included studies comparing LNS versus MMP and reported differences in micronutrients between groups, as described by trial authors.
LNS versus nutrition counselling ‐ WHO strategy on nutrition counselling during pregnancy focuses primarily on: promoting a healthy diet by increasing the diversity and amount of foods consumed; promoting adequate weight gain through sufficient and balanced protein and energy intake; and promoting consistent and continued use of micronutrient supplements, food supplements or fortified foods.

We included only trials that combined the provision of LNS with other cointerventions, or other approaches, provided the same cointerventions were given to both the intervention and the comparison groups.

This review excluded comparisons to FBF; these foods are given in larger quantities (more calories and nutrients) and so are difficult to compare with LNS, which are given in much smaller quantities.

Types of outcome measures

Primary outcomes

Maternal outcomes

Maternal anthropometric status (weight, BMI, gestational weight gain)
Maternal anaemia at term or near term (haemoglobin (Hb) less than 110 g/L)
Maternal mortality
Adverse effects (any); for example, allergic reactions as diagnosed by clinical assessment (atopic dermatitis, urticaria, oedema (oral), ophthalmic pruritus, allergic rhinitis, asthma, anaphylaxis) or gastrointestinal effects

Birth and infant outcomes

Low birth weight (birth weight less than 2500 g)
Weight at birth (in g)
Length at birth (in cm)
Small‐for‐gestational age (as defined by trial authors)
Preterm births (births before 37 weeks of gestation)
Development outcomes (milestones, as defined by trial authors)

Secondary outcomes

Maternal outcomes

Maternal Hb at term or near term (in g/L at 34 weeks gestation or more)
Duration of gestation
Maternal satisfaction with LNS (as defined by trial authors)
Maternal adherence or compliance with LNS (as defined by study authors)

Birth and infant outcomes

Miscarriage and stillbirths (as defined by trial authors)
Head circumference (in cm)
Mid upper arm circumference (MUAC; in cm)
Stunting at any time within the first six months (length‐for‐age is more than two standard deviations (SD) below the WHO Child Growth Standards median)
Wasting at any time within the first six months (weight‐for‐length is more than two SDs below the WHO Child Growth Standards median)
Underweight at any time within the first six months (weight‐for‐age is more than two SDs below the WHO Child Growth Standards median)
Neonatal death (death occurring between birth and 28 days of life)
Infant mortality (death occurring in the first year of life)

Search methods for identification of studies

Electronic searches

We searched the sources listed below in March 2017, and again in May 2018, using the strategies in Appendix 1. We did not apply language or date restrictions.

International databases

Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 4) in the Cochrane Library, and which includes the Cochrane Developmental, Psychosocial and Learning Problems Specialised Register (searched 29 May 2018).
MEDLINE Ovid (1946 to May Week 3 2018).
MEDLINE In‐Process and Other Non‐Indexed Citations Ovid (25 May 2018).
MEDLINE Epub ahead of print Ovid (25 May 2018).
Embase Ovid (1974 to 2018 Week 22).
CINAHL Plus EBSCOhost (Cumulative Index to Nursing and Allied Health Literature; 1937 to 29 May 2018).
Science Citation Index Web of Science (SCI; 1970 to 28 May 2018).
Social Sciences Citation Index Web of Science (SSCI; 1970 to 28 May 2018).
Conference Proceedings Citation Index ‐ Science Web of Science (CPCI‐S; 1970 to 28 May 2018).
Conference Proceedings Citation Index ‐ Social Science & Humanities Web of Science (CPCI‐SS&H; 1970 to 28 May 2018).
Cochrane Database of Systematic Reviews (CDSR; 2018, Issue 5) part of the Cochrane Library (searched 29 May 2018 ).
Database of Abstracts of Reviews of Effect (DARE; 2015, Issue 2. Final issue) part of the Cochrane Library (searched 9 March 2017).
Epistemonikos (epistemonikos.org; searched 29 May 2018).
POPLINE (www.popline.org; searched 29 May 2018).
ClinicalTrials.gov (clinicaltrials.gov; searched 4 June 2018).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; who.int/trialsearch; searched 4 June 2018).

Regional databases

IBECS (Índice Bibliográfico Español en Ciencias de la Salud; ibecs.isciii.es; searched 21 May 2018).
SciElo (Scientific Electronic Library Online; www.scielo.br; searched 21 May 2018).
AIM Africa Global Index Medicus (Africa Index Medicus; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 21 May 2018).
IMEMR Global Index Medicus (Index Medicus for the Eastern Mediterranean Region; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 21 May 2018).
LILACS (Latin American and Caribbean Health Sciences Literature; lilacs.bvsalud.org/en; searched 21 May 2018).
PAHO/WHO Institutional Repository for Information Sharing (iris.paho.org/xmlui; searched 21 May 2018).
WHOLIS Global Index Medicus (WHO Library Database; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 21 May 2018).
WPRIM Global Index Medicus (Western Pacific Index Medicus; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 21 May 2018).
IMSEAR Global Index Medicus (Index Medicus for the South‐East Asian Region; search.bvsalud.org/ghl/?lang=en&submit=Search&where=REGIONAL; searched 21 May 2018).
IndMED (Indexing of Indian Medical Journals; indmed.nic.in/indmed.html; searched 21 May 2018).
Native Health Research Database (hscssl.unm.edu/nhd; searched 21 May 2018).

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 related people for information about ongoing or unpublished studies we may have missed or, where necessary, to provide missing data (Dewey 2017a [pers comm]; Dewey 2017b [pers comm]; Moran 2016 [pers comm]; Stewart 2017 [pers comm]).

Data collection and analysis

Selection of studies

Two review authors (of ZH, AZB and RAS) independently assessed all records generated by the search strategy. First, they screened titles and abstracts of all records retrieved and short‐listed those deemed potentially relevant. Next, they obtained and assessed the full texts of all potentially relevant records, assessing each one against the inclusion criteria (see Criteria for considering studies for this review) before deciding on the final list of studies to be included. We resolved any disagreements through discussion or, if required, in consultation with a third review author (JKD).

We recorded our decisions in a PRISMA diagram (Moher 2009).

Data extraction and management

For eligible studies, two review authors (ZH, NGV, AZB and RAS) independently extracted data using a form designed for this review. We resolved any discrepancies through discussion with the entire group and documented these in the review. We completed a data collection form electronically and extracted and recorded the following information.

Study methods

Study design
Unit and method of allocation
Method of sequence generation
Masking of participants, personnel and outcome assessors

Participants

Location of study
Sample size
Age
Sex
Socioeconomic status (as defined by trialists and where such information was available)
Baseline prevalence of anaemia
Baseline BMI status
Inclusion and exclusion criteria

Intervention

Dose (SQ‐LNS providing less than 120 kcal/day; MQ‐LNS providing 120 to less than 250 kcal/day; and LQ‐LNS providing 250 to 500 kcal/day)
Formulation of LNS
Frequency of distribution of LNS to participants
Duration of intervention
Cointervention

Comparison group

No intervention or placebo
IFA
MMN supplements
MMP
Nutrition counselling

Outcomes

Primary and secondary outcomes, as outlined in the Types of outcome measures section
Exclusion of participants after randomisation and proportion of losses at follow‐up

We recorded both prespecified and non‐prespecified outcomes, although we did not use the latter to underpin the conclusions of the review.

We entered the data into Review Manager 5 (RevMan 5) software (Review Manager 2014).

Assessment of risk of bias in included studies

Using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), and set out in Appendix 2, two review authors (NGV and JKD) independently assessed the risk of bias of each included study as high, low or unclear, across the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other potential sources of bias. We resolved any disagreement by discussion or by involving a third assessor (ZH). We also summarised the risk of bias within studies (across domains). To do this, we assessed the likely magnitude and direction of the bias in each of the aforementioned domains and considered whether they were likely to impact on the findings. We considered studies to be at high risk of bias if they had poor or unclear allocation concealment and either inadequate blinding or high/imbalanced losses to follow‐up. We explored the impact of the level of bias through a Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as risk ratios (RR) with 95% confidence intervals (CI).

Continuous data

For continuous data, we used the mean difference (MD) with 95% CI if outcomes were measured in the same way between studies. We used the standardised mean difference (SMD) with 95% CI to combine studies that measured the same outcome but used different measurement methods.

When some studies reported endpoint data and others reported change from baseline data (with errors), we combined these in the meta‐analysis, provided the outcomes were reported using the same scale.

Please refer to our protocol, Das 2017, and Table 3 for additional methods archived for use in future updates of this review.

1. Unused methods.

Method	Approach
Measures of treatment effect	Rates If rates represent events that could have occurred more than once per participant, we will report the rate difference using the methodologies described in Deeks 2011.
Unit of analysis issues	Cluster‐randomised studies  Where possible, we will estimate the intra‐cluster correlation co‐efficient (ICC) from trials' original data sets and will report the design effect. We will use the methods set out in the Cochrane Handbook for Systematic Reviews of Interventions to calculate the adjusted sample sizes (Higgins 2011b). We will use an estimate of the ICC derived from the study (if possible), from a similar study or from a study of a similar population. If we use ICCs from other sources, we shall report this and conduct sensitivity analyses to investigate the effect of variation in the ICC (see Sensitivity analysis). If we identify both cluster‐RCTs and individually randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit (see Sensitivity analysis).
Assessment of reporting bias	If we include 10 or more studies in the 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 any of these tests detect asymmetry, or if it is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Subgroup analysis and investigation of heterogeneity	We will conduct the following subgroup analyses. Anaemia status of the participants at baseline: anaemic versus non‐anaemic versus mixed/unknown/unreported Baseline BMI of the participants: low BMI (< 18.5 kg/m²) versus normal BMI (18.5 to 24.9 kg/m²) Delivery strategy: health facility versus provided in community versus mixed/unknown/unreported Duration of intervention: < 3 months versus 3 to < 6 months versus 6 to 9 months Setting: stable versus emergency versus mixed/unknown/unreported. We used the Inter‐Agency Standing Committee's (IASC) definition of emergency (IASC 1994): a situation threatening the lives and well‐being of a large number of people or a very large percentage of a population and often requiring substantial multi‐sectoral assistance.
Sensitivity analysis	We will conduct sensitivity analyses to assess the robustness of the results to the following. Removing studies at high risk of bias (studies with poor or unclear allocation concealment and either blinding or high/imbalanced loss to follow‐up) from the analysis Different ICC values for cluster‐randomised studies (if these were included) Studies with mixed populations in which marginal decisions were made (specifically, we aimed to conduct a sensitivity analysis for studies that were conducted in multiple settings, to assess whether the impact on any outcome was marginal) A fixed‐effect model

Lipid‐based nutrient supplements (LNS) versus iron folic acid (IFA)
Patient or population: pregnant women Settings: community Intervention: LNS Comparison: IFA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	IFA	LNS
Gestational weight gain per week (from < 20 weeks gestation till the time of delivery)	0	The mean gestational weight gain per week in the intervention group was 0.46 standard deviations higher (0.44 lower to 1.36 higher)	—	3539 participants (2 studies)	⊕⊕⊕⊝  Moderate^a
Maternal anaemia at term or near term (haemoglobin (Hb) less than 110 g/L)	38/270	88/266	RR 2.35 (1.67 to 3.30)	536 participants (1 study)	⊕⊕⊕⊝  Moderate^a
Maternal mortality (measured at six weeks postpartum)	6/3773	2/1855	RR 0.53 (0.12 to 2.41)	5628 participants (3 studies)	⊕⊕⊕⊝  Moderate^a
Low birth weight (< 2500 g)	1100/3241	396/1585	RR 0.87 (0.72 to 1.05)	4826 participants (3 studies)	⊕⊕⊕⊝  Moderate^a
Length at birth (in cm)	The mean length at birth in the control groups ranged from 47.4 cm to 49.5 cm	The mean length at birth in the intervention groups was, on average, 0.24 cm longer (0.11 longer to 0.36 longer)	—	4986 participants (3 studies)	⊕⊕⊕⊝  Moderate^a
Small‐for‐gestational age	1943/3240	772/1583	RR 0.94 (0.89 to 0.99)	4823 participants (3 studies)	⊕⊕⊕⊝  Moderate^a
Preterm births (births before 37 weeks of gestation)	426/3290	186/1634	RR 0.94 (0.80 to 1.11)	5924 participants (3 studies)	⊕⊕⊕⊝  Moderate^a
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; IFA: Iron folic acid; LNS: Lipid‐based nutrient supplements; RR: Risk ratio; SMD: Standardised mean difference
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Gestational weight gain	2	3539	Std. Mean Difference (IV, Random, 95% CI)	0.46 [‐0.44, 1.36]
2 Maternal anaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Maternal mortality	3	5628	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.12, 2.41]
4 Adverse effects	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5 Low birth weight (LBW)	3	4826	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.72, 1.05]
6 Weight at birth	3	5077	Mean Difference (IV, Random, 95% CI)	53.28 [28.22, 78.33]
7 Length at birth	3	4986	Mean Difference (IV, Random, 95% CI)	0.24 [0.11, 0.36]
8 Small‐for‐gestational age (SGA)	3	4823	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.89, 0.99]
9 Preterm births	3	4924	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.80, 1.11]
10 Duration of gestation	3	5033	Mean Difference (IV, Random, 95% CI)	0.18 [0.04, 0.32]
11 Miscarriage	2	4714	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.66, 1.14]
12 Stillbirth	3	5575	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.52, 2.48]
13 Head circumference	2	4057	Mean Difference (IV, Random, 95% CI)	0.20 [0.20, 0.20]
14 Head circumference z score	3	4982	Std. Mean Difference (IV, Random, 95% CI)	0.11 [0.04, 0.18]
15 Mid‐upper‐arm circumference (MUAC)	2	4374	Mean Difference (IV, Random, 95% CI)	0.12 [‐0.02, 0.26]
16 Newborn stunting	2	4166	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.71, 0.94]
17 Newborn underweight	2	4174	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.63, 1.13]
18 Neonatal death	3	7172	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.47, 1.10]
18.1 Early neonatal	3	5555	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.45, 1.09]
18.2 Late neonatal	2	1617	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.14, 6.51]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Gestational weight gain per week	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Maternal anaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 LBW	3	2404	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.74, 1.14]
5 Weight at birth	3	2573	Mean Difference (IV, Random, 95% CI)	23.67 [‐10.53, 57.86]
6 Length at birth	3	2567	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.02, 0.42]
7 SGA	3	2393	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.84, 1.07]
8 Preterm births	3	2630	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.93, 1.42]
9 Duration of gestation	3	2740	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.26, 0.12]
10 Head circumference	2	1627	Mean Difference (IV, Random, 95% CI)	0.08 [‐0.16, 0.31]
11 Head circumference z score	2	1549	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.01, 0.21]
12 MUAC	2	1939	Mean Difference (IV, Random, 95% CI)	0.07 [‐0.01, 0.16]
13 Newborn stunting	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
14 Newborn underweight	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
15 Neonatal death	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LBW	3	2404	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.74, 1.14]
1.1 Small quantity‐lipid‐based nutrient supplements (SQ‐LNS)	2	1384	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.66, 1.20]
1.2 Large quantity‐lipid‐based nutrient supplements (LQ‐LNS)	1	1020	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.69, 1.30]
2 Weight at birth	3	2573	Mean Difference (IV, Random, 95% CI)	23.67 [‐10.53, 57.86]
2.1 SQ‐LNS	2	1553	Mean Difference (IV, Random, 95% CI)	31.22 [‐12.66, 75.11]
2.2 LQ‐LNS	1	1020	Mean Difference (IV, Random, 95% CI)	12.0 [‐42.56, 66.56]
3 Length at birth	3	2567	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.02, 0.42]
3.1 SQ‐LNS	2	1548	Mean Difference (IV, Random, 95% CI)	0.11 [‐0.10, 0.32]
3.2 LQ‐LNS	1	1019	Mean Difference (IV, Random, 95% CI)	0.40 [0.09, 0.71]
4 SGA	3	2393	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.84, 1.07]
4.1 SQ‐LNS	2	1381	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.85, 1.17]
4.2 LQ‐LNS	1	1012	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.76, 1.07]
5 Preterm births	3	2630	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.93, 1.42]
5.1 SQ‐LNS	2	1487	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.74, 1.92]
5.2 LQ‐LNS	1	1143	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.87, 1.51]
6 Duration of gestation	3	2740	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.26, 0.12]
6.1 SQ‐LNS	2	1597	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.23, 0.23]
6.2 LQ‐LNS	1	1143	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.52, 0.12]
7 Head circumference	2	1627	Mean Difference (IV, Random, 95% CI)	0.08 [‐0.16, 0.31]
7.1 SQ‐LNS	1	608	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.01, 0.41]
7.2 LQ‐LNS	1	1019	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.25, 0.17]
8 MUAC	2	1939	Mean Difference (IV, Random, 95% CI)	0.07 [‐0.01, 0.16]
8.1 SQ‐LNS	1	928	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.02, 0.22]
8.2 LQ‐LNS	1	1011	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.07, 0.17]
9 Neonatal death: LQ‐LNS	1	1175	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.36, 2.15]

Methods	Randomised, single‐blind, parallel group, community‐based clinical trial in Ghana
Participants	Sample size: 1320 pregnant women and 1228 infants enrolled; 263 pregnant women excluded due to mixed exposure Mean age: 26.6 years Inclusion/exclusion criteria: pregnant women ≥ 18 years of age and ≤ 20 weeks of gestation, and children aged 6 months to 18 months were eligible. Women were excluded if their antenatal cards indicated HIV infection, asthma, epilepsy, tuberculosis, or any malignancy. Additional exclusion criteria were known milk or peanut allergy, not residing in the area, intention to move within the next 2 years, unwillingness to receive field workers or take the study supplement, or participation in another trial.
Interventions	Interventions Pregnant women were allocated to 3 groups: Group 1 (n = 441) received iron (60 mg) and folic acid (400 mg) tablets once a day Group 2 (n = 439) received MMN capsule once a day Group 3 (n = 440) received 20 g/day LNS sachets once a day Delivery/administration At enrolment, each woman received a 2‐week supply of supplement (including instruction to consume one capsule with water after a meal or one sachet mixed with any food each day), a standard nutrition message (quote: "Do not forget to eat meat, fish, eggs, fruits, and vegetables whenever you can; you still need these foods even as you take the supplement we have given you"), and a sticker on her antenatal card for identification. LNS composition Ration: 20 g/d  Total energy: 118 kcal  Protein: 2.6 g  Fat: 10 g  Linoleic acid: 4.59 g  α‐Linolenic acid: 0.59 g  Vitamin A: 800 µg RE  Vitamin C: 100 mg  Vitamin B1: 2.8 mg  Vitamin B2: 2.8 mg  Niacin: 36 mg  Folic acid: 400 µg  Pantothenic acid: 77 mg  Vitamin B6: 3.8 mg  Vitamin B12: 5.2 µg  Vitamin D: 400 IU  Vitamin E: 20 mg  Vitamin K: 45 µg  Iron: 20 mg  Zinc: 30 mg  Copper: 4 mg  Calcium: 280 mg  Phosphorus: 190 mg  Potassium: 200 mg  Magnesium: 65 mg  Selenium: 130 µg  Iodine: 250 µg  Manganese: 2.6 mg
Outcomes	Primary outcomes Infants' length (cm) at 18 months of age Length‐for‐age z score (LAZ) at 18 months of age Birth length Secondary outcomes Infants' weight (kg) at 18 months Head circumference (cm) at 18 months MUAC (cm) at 18 months Z scores for weight‐for‐age (WAZ), weight‐for‐length (WLZ), and head‐circumference‐for‐age (HCZ) at 18 months Stunting at 18 months Underweight at 18 months Wasting at 18 months Small head circumference at 18 months of age Growth from birth to 18 months of age Incidence of serious adverse events from birth to 18 months of age
Notes	Study duration: December 2009 to March 2014 Conflict of interest: authors declared that they had no conflicts of interest related to this study. Source of funding: Bill & Melinda Gates Foundation. The funder of the study had no role in the study design; data collection, analysis, and interpretation; or the preparation of the manuscript.
*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) randomisation scheme in blocks of 9" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "The study nurse offered sealed, opaque envelopes bearing group allocations, 9 envelopes at a time, and the woman picked one to reveal the allocation. Allocation information was kept securely by the field supervisor and the study statistician only." Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: it was not possible to blind the field workers and study participants to those consuming capsules versus LNS (because of the starkly different characteristics).
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "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	Comment: in IFA arm: 15/408 (3.7%) lost to follow‐up; in MMN arm: 10/411 (2.4%) lost to follow‐up; in LNS arm: 18/409 (4.4%) lost to follow‐up
Selective reporting (reporting bias)	Low risk	Comment: registered at ClinicalTrials.gov as NCT00970866. Statistical analysis plan was posted before (www.ilins.org) and all presented analyses were prespecified in the statistical analysis plan; adequately done
Other bias	Low risk	Comment: no other sources of bias were identified. The study was funded by the Bill & Melinda Gates Foundation.

Methods	A randomised, outcome‐assessor‐blinded, community‐based clinical trial in Malawi
Participants	Sample size: 1391 pregnant women enrolled; 84 women lost to follow‐up Mean age: 25 years Inclusion/exclusion criteria: eligible women had an ultrasound confirmed pregnancy of no more than 20 completed gestation weeks, residence in the defined catchment area, availability during the period of the study, and signed or thumb‐printed informed consent. The study excluded those: younger than 15 years of age; in need for frequent medical attention due to a chronic health condition; diagnosed asthma treated with regular medication; severe illness warranting hospital referral; history of peanut allergy; history of anaphylaxis or serious allergic reaction to any substance; requiring emergency medical care; pregnancy complications evident at enrolment visit (moderate to severe oedema, blood haemoglobin concentration 50 g/L, systolic blood pressure of 160 mmHg or more, or diastolic blood pressure 100 mmHg or more); earlier participation in the iLiNS‐DYAD‐M trial (during a previous pregnancy); or concurrent participation in any other clinical trial.
Interventions	Interventions Pregnant women were allocated to 3 groups Group 1 (n = 463) received iron (60 mg) and folic acid (400 mg) tablets Group 2 (n = 466) received MMN capsule Group 3 (n = 462) received 20 g/day LNS sachets Delivery/administration Data collectors made home visits, biweekly, to deliver the supplements and to collect information on the participant's adherence to the study intervention. LNS composition Total energy: 118 kcal  Protein: 2.6 g  Fat: 10 g  Linoleic acid: 4.59 g  α‐Linolenic acid: 0.59 g  Vitamin A: 800 mg RE  Vitamin C: 100 mg  Vitamin B1: 2.8 mg  Vitamin B2: 2.8 mg  Niacin: 36 mg  Folic acid: 400 mg  Pantothenic acid: 7 mg  Vitamin B6: 3.8 mg  Vitamin B12: 5.2 mg  Vitamin D: 10 mg  Vitamin E: 20 mg  Vitamin K: 45 mg  Iron: 20 mg  Zinc: 30 mg  Copper: 4 mg  Calcium: 280 mg  Phosphorus: 190 mg  Potassium: 200 mg  Magnesium: 65 mg  Selenium: 130 mg  Iodine: 250 mg  Manganese: 2.6 mg
Outcomes	Primary outcomes Birth weight Birth length Secondary outcomes Length at 18 months Weight at 18 months Stunting at 18 months Head circumference at 18 months MUAC at 18 months Pregnancy duration
Notes	Study duration: February 2011 to December 2015 Conflict of interest: one of the authors, Mamane Zeilani, works as a Drector of Research for Nutriset SAS, a company that produces and sells LNS supplements and also prepared the LNS supplements purchased for the current trial. The other authors declared no conflicts of interest related to this study. Source of funding: supported, in part, by a grant from the Bill & Melinda Gates Foundation, with additional funding from the Office of Health, Infectious Diseases, and Nutrition, Bureau for Global Health, US Agency for International Development (USAID) under terms of Cooperative Agreement No. AID‐OAA‐A‐12‐00005, through the Food and Nutrition Technical Assistance III Project (FANTA), managed by FHI 360. For data management and statistical analysis, the team received additional support in grants from the Academy of Finland (grant 252075) and the Medical Research Fund of Tampere University Hospital (grant 9M004). The author Yin Bun Cheung was supported by the Singapore Ministry of Health's National Medical Research Council under its Clinician Scientist Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A study statistician not involved in data collection generated 4 randomization code lists in blocks of 9." Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "In the randomisation process, each participant number was allocated one of 9 possible letter codes (A, B, C, D,E, H, J, K, or M). Each letter code corresponded to one of the 3 interventions (i.e., each intervention matched with 3 separate letter codes)." Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Quote: "The IFA and MMN interventions were provided by using double‐masked procedures—that is, the capsules looked identical,and neither the participants nor the research team members were aware of the nutrient contents of the supplement capsules. For the LNS group, we used single‐masked procedures—that is field workers who delivered the supplements knew which mothers were receiving LNS (but not a difference between IFA and MMN), and the participants were advised not to disclose information about their supplements to anyone other than an iLiNS team member." Comment: it was not possible to blind field workers due to the nature of the intervention.
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." Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: overall 6.04% similar between groups; adequately done
Selective reporting (reporting bias)	Low risk	Comment: all presented analyses were prespecified either in the trial protocol or in the statistical analysis plan. Registered at clinicaltrials.gov as NCT01239693. Adequately done
Other bias	Low risk	Comment: no other sources of bias were identified. The study was 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, US Agency for International Development (USAID).

Methods	A randomised, open‐label, community‐based clinical trial in the rural settings of Burkina Faso
Participants	Sample size: 1296 pregnant women enrolled; 32 women lost to follow‐up Mean age: 24.5 years Inclusion/exclusion criteria: women with suspected pregnancy were referred to the health centre for a formal pregnancy test and were included after confirmation of pregnancy. No exclusion criteria were used except that participants planning to leave the study area within the next 2 years were not eligible.
Interventions	Interventions Pregnant women were allocated to 2 groups: Group 1 (n = 641) received MMN tablets Group 2 (n = 655) received LNS Delivery/administration Home visitors kept both the MMN and fortified food supplement with them and visited 10 to 20 participants per day to provide and directly observe the supplement intake. LNS composition Energy: 1.56 MJ  Energy from protein: 15.8%  Energy from fat: 67.05%  Carbohydrates: 15.9 g  Protein: 14.7 g  Fat: 27.6 g  SFA: 8,1 g  MUFA: 12.1 g  PUFA: 7.3 g  x3 fatty acids: 0.4 g  x6 fatty acids: 7.0 g  Total dietary fiber: 9.1 g  Vitamin A: 881 RE  Vitamin D: 200 IU  Vitamin E: 13 mg  Thiamin: 1.6 mg  Riboflavin: 1.6 mg  Niacin: 21 mg  Vitamin B6: 2.0 mg  Folate: 461 µg  Vitamin B12: 2.6 µg  Vitamin C: 71 mg  Zinc: 17 mg  Iron: 35 mg  Copper: 2.7 mg  Selenium: 65 µg  Iodine: 150 µg  Calcium: 90 mg
Outcomes	Primary outcomes Birth weight Birth length Secondary outcomes Low birth wight Small‐for‐gestational age Large‐for‐gestational age MUAC at birth and at 12 months of age Head circumference at birth and at 12 months of age Chest circumference at birth and at 12 months of age Anthropometric indices: weight‐for‐age z score, length‐for‐age z score, and weight‐for‐length z score at 12 months of age
Notes	Study duration: March 2006 to June 2008 Conflict of interest: authors declared that none of the authors had any potential conflicts of interest. Source of funding: Supported by Nutrition Third World, the Belgian Ministry of Development under agreement 96501, and the Flemish University Council under contract ZEIN2004PR298. None of the funders had any role in the study design, data collection, data analysis, or report writing.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Individual randomisation was performed based on a computer‐generated program in permuted blocks of 4" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "Randomization numbers were sealed in opaque envelopes and when an informed consent was obtained from an eligible participant, the study physician opened the next envelope and assigned the participant to a treatment group" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Quote: "We conducted a nonblinded, individually randomized controlled trial." Comment: not clear
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Quote: "The study was organized as an open‐label" Comment: not clear
Incomplete outcome data (attrition bias)   All outcomes	High risk	Comment: 150/641 (23%) lost to follow‐up in group 1; 164/655 (25%) lost to follow‐up in group 2
Selective reporting (reporting bias)	Low risk	Comment: all presented analyses were prespecified either in the trial protocol or in the statistical analysis plan registered at Clinical.Trials.gov as NCT00909974
Other bias	Low risk	Comment: no other sources of bias were identified. The study was supported by the Flemish University Council, Nutrition Third World, and the Belgian Ministry of Development. The multiple micronutrient premix was donated by Nutriset, France.

Methods	A cluster‐randomised, community‐based trial in Bangladesh
Participants	Sample size: 4011 pregnant women ≤ 20 weeks gestation enrolled; 93 women lost to follow‐up Mean age: 21.9 years Inclusion/exclusion criteria: the eligibility criteria included gestational age < 20 weeks and no plans to move out of the study area during pregnancy or the following 3 years (i.e. a permanent resident of the study area)
Interventions	Interventions Pregnant women were allocated to 2 groups: Group 1 (n = 2964) received iron (60 mg) and folic acid (400 mg) tablets Group 2 (n = 1047) received 20 g/day LNS sachets Delivery/administration: The first 1‐month supply of supplements for each woman enrolled was delivered by the community health worker at the safe delivery unit right after the baseline data were collected by the evaluation staff. Subsequent monthly supplies were usually delivered by the community health worker or village health volunteer to the woman's home, but occasionally delivery occurred during educational sessions given by the community health worker or village health volunteer. LNS composition Ration: 20 g/d  Total energy: 118 kcal  Protein: 2.6 g  Fat: 10 g  Linoleic acid: 4.59 g  α‐Linolenic acid: 0.59 g  Vitamin A: 800 µg RE  Vitamin C: 100 mg  Thiamin: 2.8 mg  Riboflavin: 2.8 mg  Niacin: 36 mg  Folic acid: 400 µg  Pantothenic acid: 7 mg  Vitamin B6: 3.8 mg  Vitamin B12: 5.2 µg  Vitamin D: 400 IU  Vitamin E: 20 mg  Vitamin K: 45 µg  Iron: 20 mg  Zinc: 30 mg  Copper: 4 mg  Calcium: 280 mg  Phosphorus: 190 mg  Potassium: 200 mg  Magnesium: 65 mg  Selenium: 130 µg  Iodine: 250 µg  Manganese: 2.6 mg
Outcomes	Primary outcomes Birth weight Birth length Secondary outcomes Gestational age (in weeks) at the time of delivery Birth head circumference, defined by crude head circumference (in cm) Birth head‐circumference‐for‐age z score (HCZ) BMI‐for‐age z score at birth MUAC at birth Low birth weight Newborn stunting Preterm delivery Small‐for‐gestational age
Notes	Study duration: October 2011 to August 2012 Conflict of interest: the authors declared that they had no conflicts of interest. Source of funding: US Agency for International Development's Food and Nutrition Technical Assistance III Project (FANTA), managed by Family Health International 360
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The study statistician at UC Davis first stratified the 64 clusters by sub district and union, and then assigned each cluster to 1 of 4 sets containing 16 clusters each. This procedure was then replicated several thousand times, and each randomisation was tested for balance across groups with respect to mean cluster population, number of clinics and health workers per 1000 people, number of health‐/nutrition‐related nongovernmental organizations in the cluster, and the source of funding for the CHDP, as well as the SD of the cluster population size" Comment: adequately done
Allocation concealment (selection bias)	Low risk	Quote: "The final randomisation to the 4 arms was then chosen at random from the acceptable potential randomizations; and the letters A, B, C, and D were assigned to the 4 sets, randomly permuting them by sorting on a randomly generated, uniformly distributed number (with the use of SAS for Windows, release 9.2; SAS Institute)" Comment: adequately done
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: it was not possible to blind the study participants to those consuming capsules versus LNS (because of the starkly different characteristics).
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: "The evaluation staff was not involved in supplement delivery" Comment: adequately done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: 413/2964 (13.9%) lost to follow‐up in group 1; 149/1047 (14.23%) lost to follow‐up in group 2
Selective reporting (reporting bias)	Low risk	Comment: all presented analyses were prespecified either in the trial protocol or in the statistical analysis plan registered at Clinical.Trials.gov as clinicaltrials.gov/ct2/show/NCT01715038; adequately done
Other bias	Low risk	Comment: no other sources of bias identified. The study was carried out by 3 partners: LAMB , the International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B); and the University of California, Davis (UC Davis).

Study	Reason for exclusion
Adams 2017	Reports longitudinal, household food‐insecurity data from four studies
Adams 2018	Assesses willingness to pay for small‐quantity, LNS for women and children from studies conducted in Ghana and Malawi
Flax 2012	Includes HIV‐infected women
Flax 2014	Includes HIV‐infected women
Haber 2016	LNS given to women in postpartum period to improve quality of breast milk
Hampel 2018	Assesses effects of an LNS and antiretroviral therapy on iron, copper and zinc in milk from HIV‐infected Malawian mothers
Johnson 2017	LNS not tested as a separate arm but with protein energy supplementation
Kayira 2012	Includes HIV‐infected women
Oaks 2017	A sub‐study of two included studies evaluating the effects of LNS on maternal plasma fatty acid status and lipid profile
Prado 2017	Study to determine factors associated with 18‐month language and motor development in 4 prospective cohorts of children who participated in studies conducted as part of the International Lipid‐Based Nutrient Supplements (iLiNS) Project in Ghana, Malawi and Burkina Faso
Schlossman 2017	LNS provided to mothers with no regard to pregnancy status
Young 2015	Formative research related to acceptability of LNS by women

Trial name or title	A cluster‐randomized, controlled trial of nutritional supplementation and promotion of responsive parenting in Madagascar: the MAHAY ["smart" in Malagasy] study design and rationale
Methods	A cluster‐randomised, multi‐arm, controlled trial
Participants	Number of clusters: 25 communities, 5 per arm Sample size: 1250 pregnant women; 1250 children aged 0‐6 months old; 1250 children aged 6‐18 months Inclusion/exclusion 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.
Interventions	Interventions Participants will be allocated to 5 groups (each group will comprise 1250 pregnant women, 1250 children 0‐6 months old, and1250 children 6‐18 months old); T₀: existing programme with monthly growth monitoring and nutritional/hygiene education T₁: T₀ + home visits for intensive nutrition counselling within a behaviour change framework T₂: T₁ + LNS for children aged 6‐18 months old T₃: T₂ + LNS supplementation of pregnant/lactating women T₄: T₁ + intensive home‐visiting programme to support child development For this review, we will include groups T3 as intervention arm and T0 as control arm.
Outcomes	The following outcomes will be measured at baseline, 1 year and 2 years after the baseline survey. Primary outcomes Growth: length/height‐for‐age z scores Child development: mental, motor and social development Secondary outcomes Care‐giver reported child morbidity Household food security and diet diversity Micronutrient status Maternal knowledge of child care and feeding practices, and home stimulation practices
Starting date	July 2014 to December 2019
Contact information	Name: Professor Lia Fernald Email: fernald@berkeley.edu
Notes	This study is funded by Strategic Impact Evaluation Fund (SIEF), the World Bank Innovation Grant, the Early Learning Partnership Grant, and the National Nutrition Office in Madagascar.

PERMALINK

Lipid‐based nutrient supplements for maternal, birth, and infant developmental outcomes

Jai K Das

Zahra Hoodbhoy

Rehana A Salam

Afsah Zulfiqar Bhutta

Nancy G Valenzuela‐Rubio

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

Maternal outcomes

Birth and infant outcomes

Secondary outcomes

Maternal outcomes

Birth and infant 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

Study methods

Participants

Intervention

Comparison group

Outcomes

Assessment of risk of bias in included studies

Measures of treatment effect

Dichotomous data

Continuous data

1. Unused methods.

Unit of analysis issues

Cluster‐randomised studies

Studies with more than two treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' table

Summary of findings for the main comparison. Summary of findings: lipid‐based nutrient supplements (LNS) versus iron folic acid (IFA).

Summary of findings 2. Summary of findings: lipid‐based nutrient supplements (LNS) versus multiple micronutrients (MMN).

Results

Description of studies

Results of the search

1.

Included studies

Settings

Participants

Interventions

Outcomes

Primary outcomes

Secondary outcomes

Excluded studies

Ongoing studies