Interventions to improve linear growth during complementary feeding period for children aged 6-24 months living in low- and middle-income countries: a systematic review and network meta-analysis

Introduction

Linear growth is a marker of healthy childhood progression, closely linked with neurodevelopment in early life¹. Despite global improvements in maternal, newborn, and child health (MNCH), the rate of children that fail to achieve their linear growth potential in low- and middle-income countries (LMICs) is high². Prevention of linear growth faltering, also known as stunting (low height for age), during the complementary feeding period (6 to 24 months of age) is critical, since stunting during this life stage can have immediate, short- and long-term consequences that are difficult to reverse^3–5. Continued malnutrition in children experiencing stunting can result in increased susceptibility and frequency to infections, as well as enhanced likelihood of cognitive, motor, and language impairment^2,6. In later life, stunted children may also experience reduced life chances such as poor academic performance that may affect future earnings and increased risk for chronic diseases, including obesity if accompanied by excessive weight gain in adulthood^5,7–9.

As children begin to wean off breastfeeding, there is a critical and continual need to ensure proper nutrition, hygiene, control of infectious diseases, and overall care during the complementary feeding period. Despite multiple factors playing a role in child’s linear growth, the majority of the reviews concerning linear growth for children during this life period in the past have focused on a single intervention domain (e.g. micronutrients) (Table 1). The comparative effectiveness of interventions is not clear across multiple domains, such as micronutrients, food supplements, deworming, maternal education, and water, sanitation, and hygiene (WASH) that could be important solutions to optimize linear growth during this life period. Additionally, all of the existing reviews have implemented a traditional pairwise meta-analysis that only allows for comparison between two interventions that have directly been compared head-to-head in clinical trials. Given that the majority of trials have used placebo or other comparators with limited clinical interest, the utility of pairwise meta-analysis can be limiting, particularly when assessing the broad sets of interventions that could be provided during the complementary feeding period.

Network meta-analysis, as an extension of conventional pairwise meta-analysis, allows for comparisons of interventions that have not been directly compared in head-to-head randomized clinical trials within a single analysis^10,11. While network meta-analysis is new to MNCH, this technique has been endorsed by the World Health Organization (WHO) to support the development of intervention guidelines in global health¹¹, with the past WHO guidelines on HIV drug and behavioral therapies and direct acting agents against hepatitis C having been formulated using network meta-analysis^12–14. This study uses a systematic review and network meta-analysis to determine the comparative effectiveness across intervention domains in micronutrient supplements, food supplements, deworming, maternal education, and WASH interventions on HAZ and stunting for children aged 6–24 months living in LMICs.

Methods

The protocol for this study was registered on PROSPERO (CRD42018110449). The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension to network meta-analysis¹⁵.

Results

A total of 20,511 abstracts was found from our database searches and hand searches of the bibliography of published reviews (Figure 1). Of these, 1,094 studies underwent a full-text review with 96 papers reporting on 79 trials that met the inclusion criteria. The list of included studies is provided in the Extended data (Supplementary Table 4 for included and Table 5 for the list of excluded studies)¹⁸. Trial characteristics and participant characteristics of the included studies are provided in the Extended data, Supplementary Tables 6 and 7¹⁸, respectively. In total, these trials comprised of 81,786 children who were randomized to 236 unique interventions (Figure 2). Of these trials, 22 were cluster trials with 2,990 clusters (53,057 children) randomized to 80 interventions. The majority of trials were conducted in African (n = 35) and South Eastern Asian (n = 25) countries with double blinding (i.e. blinding of participants and investigators; n = 40) being the most common blinding feature. Micronutrient supplementation was the most common intervention domain studied (n = 50 trials). Only a handful of these micronutrient trials compared interventions from other domains (food supplements: n = 11 trials^46–56 and maternal education: n = 2 trial^57,58). There were four cluster trials on WASH (WASH Benefits Bangladesh⁵⁹, WASH Benefits Kenya⁶⁰, SHINE⁶¹, and Shafique et al.⁶²), and these trials also included intervention arms that consisted of food supplements (i.e. LNS) or multiple micronutrients (i.e. MMN).

Figure 1. Study selection.

Figure 2. Overall network of the comparisons between interventions for children aged 6 to 24 months.

Each node (circle) represents an intervention, each line represents a direct comparison between interventions, with the lines with width representing the number of trials with the direct comparisons in question (i.e. thicker width represents a direct comparison with larger numbers of trials). The different intervention domains are indicated with the following colors: blue for micronutrient supplements; brown for food supplements; yellow for education and counseling interventions; green for deworming interventions; and orange for WASH interventions. Vit. vitamin; IFA, iron and folic acid; LNS, lipid-based nutrient supplements; Fort, fortification; MMN, multiple micronutrients; HS, hand sanitizer.

Height-for-age z-score (HAZ)

The network of evidence pertaining to the analysis of the outcome HAZ included 67 trials (69,223 children randomized to 220 intervention arms; Extended data, Supplementary Figure 1)¹⁸. Of these, 16 were cluster trials that randomized 1,440 clusters (36,032 children) to 62 intervention arms. Key results of the primary analysis that included both cluster and non-cluster randomized clinical trials are illustrated using a forest plot (Figure 3). Among micronutrient supplementations, iron + folic acid (IFA) (mean difference =0.08 95% CrI: 0.01, 0.15), and multiple micronutrients (MMN) (mean difference =0.06; 95% CrI: 0.01, 0.11) showed improvements in HAZ in comparison to standard-of-care. Iron (mean difference =0.03; 95% Crl: -0.02, 0.08) showed a trend towards HAZ improvement versus standard-of-care, but its credible intervals contained the null effect of 0. No food supplements showed improvements for HAZ versus standard-of-care. Similarly, no deworming interventions during the complementary feeding period or WASH interventions showed improvements in HAZ compared to standard-of-care.

Figure 3. Forest plot for the effects of interventions on HAZ (mean difference), primary analysis.

Vit. vitamin; IFA, iron and folic acid; LNS, lipid-based nutrient supplements; Fort, fortification; MMN, multiple micronutrients; WASH, – water treatment, toilet facilities, and handwashing. * Denotes mean difference values that do not contain the null effect of 0.

Stunting (HAZ < -2SD)

The network of evidence for the primary analysis of the stunting outcome consisted of 20 trials with 40,193 children randomized to 77 intervention arms (Extended data, Supplementary Figure 3)¹⁸. Of these, 12 were cluster trials with 1,608 clusters (33,660 children) randomized to 50 intervention arms. A forest plot for the comparative effects of interventions on stunting (RRs) is provided in Figure 4. Among micronutrient supplements, MMN (RR: 0.86, 95% CrI: 0.73, 0.98) demonstrated superiority over standard-of-care, whereas IFA (RR: 0.92, 95% CrI: 0.64, 1.23) did not reduce the risks of stunting relative to standard-of-care; however, intake of Iron (RR: 0.91; 95% Crl: 0.76, 1.06) showed trend towards reducing risks for stunting. For food supplements, fortified lipid-based nutrient supplements (LNS) containing 220–285 kcal (RR: 0.80, 95% CrI: 0.66, 0.97) and flour containing 270 – 340 kcal (RR: 0.73, 95% CrI: 0.51, 1.00) showed reduced risks of stunting versus standard-of-care. Among other intervention domains, compared to standard-of-care, Maternal education also showed a trend towards decreasing the risks of stunting (RR: 0.91, 95% CrI: 0.75, 1.08); but no deworming or WASH interventions showed reduced risks for stunting except for WASH combined + fortified LNS containing 118 kilocalories that had showed a trend towards reducing the risks of stunting (RR: 0.91, 95% CrI: 0.73, 1.10).

Figure 4. Forest plot for the effects of interventions on stunting (risk ratio), primary analysis.

Vit. vitamin; IFA, iron and folic acid; LNS, lipid-based nutrient supplements; Fort, fortification; MMN, multiple micronutrients; WASH, – water treatment, toilet facilities, and handwashing. * Denotes values of risk ratio that do not contain the null effect of 1.

Discussion

In this study, systematic literature review and network meta-analysis were used to determine the comparative effectiveness of interventions for linear growth under the domains of micronutrients, food supplements, deworming, maternal education, and WASH interventions for LMIC-based children in the age group of 6 to 24 months. During the complementary feeding period life stage, micronutrient supplements such as IFA and MMN showed improvements for HAZ compared to standard-of-care, with iron showing some trends towards improved HAZ. Deworming, maternal education, food supplements, and WASH interventions, on the other hand, did not show improvements in HAZ versus standard-of-care. For stunting, food supplements of fortified LNS 220–280 kcal and flour 270–340 kcal showed reduced risks of stunting, with other interventions such as iron, MMN, and MMN combined with maternal education, demonstrating trends towards reduced stunting risks, in comparison to standard-of-care.

The key strengths of this study were the consideration of multiple intervention domains and the use of network meta-analysis. The approach undertaken for this study differed from previous reviews (Table 1) that have had limited scopes of single intervention or single intervention domains; these reviews have all used pairwise meta-analysis, thus being limited to trials and interventions that have only been directly compared to one another. The use of network meta-analysis allowed for consideration of a broader evidence base to estimate the comparative effectiveness of multiple interventions under multiple treatment domains. By incorporating statistical adjustments for clustering effects, this study was able to incorporate cluster randomized clinical trials that mostly did not report information on clustering effects (i.e. ICC or design effects) into the statistical analyses.

Nonetheless, the existing evidence base limited our analyses. The majority of the randomized clinical trial evidence base was confined to the micronutrient supplementation domain (n = 50), and the evidence base for intervention domains for food supplements, deworming, maternal education, and WASH being limited. This imbalance in intervention class could partly be explained by the narrow bounds in the population criterion (i.e. the age criteria of 6 to 24 months) of our PICOS criteria. For instance, there were a number of trials that recruited children using a wider age eligibility criterion (e.g. 6 months up to 5 years of age) that encompassed children in the complementary feeding life stage, but these trials were excluded since growth rates and determinants of children older than 24 months are different than children in the complementary feeding period age group. While this age restriction limited the number of eligible trials for our analysis, it is important to note that the population criteria was determined a priori before the screening was initiated for this systematic review since we recognized that growth determinants and rates can vary substantially for children between these ages⁶³. Another limitation related to our categorisation of interventions is that we combined interventions into broad categories to assist with interpretation and acknowledge that a different approach to categorisation might have altered the results.

This study has shown that the existing evidence base on interventions aimed to improve linear growth in children during the complementary feeding period is limited and inconsistent. Generally, investigation of interventions outside of the domain of micronutrient supplements was limited. There were only two trials on deworming^64,65 and four WASH trials^59–62 reporting on linear growth outcomes in our analyses. There were eight trials under the maternal education domains^{57,58,62,66–70}, but the components and the delivery of these educational interventions varied considerably between these trials. For food supplement trials, poor adherence and household food insecurity that may promote family sharing could influence why these interventions did not show improvements in linear growth. Moreover, the food supplements in these trials were all based on a single type of food, so children may have refused to consume as they have become tired of consuming same type of food over time. There were no trials that investigated nutritional strategies that aimed to improve dietary diversity in order to improve linear growth in children during this life stage, nor were there any trials that aimed to address household food insecurity. It is also important to note that there was randomness in the data as well as substantial heterogeneity observed in the duration of the interventions and the timing of outcome assessments that can be attributed to the variation in impact on HAZ and stunting.

A previous report from Bangladesh has shown that the taste of LNS is generally acceptable, and at least in shorter-term, adherence to LNS was high and sharing of these food supplements could be minimized in the household⁷¹. However, acceptability and adherence to LNS in other settings are not clear; the long-term acceptability and adherence to LNS or other types of food supplements that consist of a single food on daily basis over long-term are also questionable. Additionally, our analysis did not show that supplementing children with high caloric food supplements result in improved linear growth when compared to standard of care or to other lower caloric food supplements. Aside from previously described issues associated with tolerability of nutritional supplementation that may be exacerbated by high caloric formulations, it is possible that in households with food insecurity, caregivers may choose to share these supplements with other children or members of the household who are not enrolled in the trial. Understanding compliance and the influence that this may have on our analyses was not possible, as we found that compliance was usually not measured or reported in the included food supplement trials^72–76.

Our findings identified several directions for future research. There is a need to combine interventions across multiple domains as a package. Instead of singling out interventions from one domain, there is a need for comparisons between different packaged interventions because a combined set of interventions will likely result in the greatest improvements in linear growth. Strategies should consider local contexts and challenges. The feasibility of conducting trials that incorporate food supplement strategies aimed to improve dietary diversity and address household food insecurities is undoubtedly difficult. However, it is important to recognize these factors will be important for long-term acceptability and adherence to food interventions, and interventional strategies that incorporate diverse local foods will have higher acceptability and adherence in the long run. Trials with longer follow-up are also needed, as the median follow-up among the trials included for this review was only 6 months. Lastly, there is a need for more innovative trial approaches⁷⁷. The majority of the trials identified for this review used a conventional trial approach with a fixed sample size design, where the assessment of interventions occurred only after the number of participants recruited reached the sample size target. It is important to recognize that such approach can be inefficient, and adopting adaptive trial design approaches that allow for pre-specified modifications, with the decision being made based on accumulating trial data may improve both the efficiencies of the trial evaluation in this avenue of research⁷⁸.

Data availability