Interventions to improve linear growth during exclusive breastfeeding life-stage for children aged 0-6 months living in low- and middle-income countries: a systematic review with network and pairwise meta-analyses

Background: Exclusive breastfeeding (EBF) during the first six months of life is critical for child’s linear growth. While there is strong evidence in favor of EBF, the evidence with regards to other interventions for linear growth is unclear. We evaluated intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care, for their comparative effectiveness on linear growth. Methods: For this review, we searched for randomized clinical trials (RCTs) of the interventions provided to infants aged 0-6 months and/or their breastfeeding mothers in low- and middle-income countries reporting on length-for-age z-score (LAZ), stunting, length, and head circumference. We searched for reports published until September 17 th, 2019 and hand-searched bibliographies of existing reviews. For LAZ and stunting, we used network meta-analysis (NMA) to compare the effects of all interventions except for kangaroo care, where we used pairwise meta-analysis to compare its effects versus standard-of-care. For length and head circumference, we qualitatively summarized our findings. Results: We found 29 RCTs (40 papers) involving 35,119 mother and infant pairs reporting on the effects of aforementioned interventions on linear growth outcomes. Our NMA on LAZ found that compared to standard-of-care, multiple micronutrients administered to infants (MMN-C) improved LAZ (mean difference: 0.20; 95% credible interval [CrI]: 0.03,0.35), whereas supplementing breastfeeding mothers with MMN did not (MMN-M, mean difference: -0.02, 95%CrI: -0.18,0.13). No interventions including MMN-C (relative risk: 0.74; 95%CrI: 0.36,1.44) reduced risk for stunting compared to standard-of-care. Kangaroo care, on the other hand, improved head circumference (mean difference: 0.20 cm/week; 95% confidence intervals [CI]: 0.09,0.31 cm/week) and length (mean difference: 0.23 cm/week; 95%CI: 0.10,0.35 cm/week) compared to standard-of-care. Conclusion: Our study found important improvements for kangaroo care, but we did not find sufficient evidence for other interventions. Registration: PROSPERO CRD42018110450; registered on 17 October 2018.


Introduction
In past decades, important progress achieved in maternal, newborn, and child health (MNCH) have led to substantial reductions in maternal and child mortality rates 1,2 . However, many children still fail to reach their linear growth potential, particularly those living in low-and middle-income countries (LMICs) 3 . Linear growth in early childhood is a marker of healthy development that is closely linked with neurodevelopment 4 . The first six months of age (birth to 6 months) is a critical life stage for early child development, and exclusive breastfeeding during this life stage plays an important role in impacting the growth velocity of children. There is a strong evidence to support the benefits of exclusive breastfeeding during this life stage which includes protection against gastrointestinal infection, growth faltering, infant death syndrome etc. 5-7 . Exclusively breastfed children aged between zero to six months are known to have better growth rates and immune system. As such, mechanisms and resources to facilitate appropriate self-care in addition to psycho-social support for breastfeeding mothers is necessary to improve both health outcomes of mothers and babies. For instance, poor maternal nutrition could lead to lactation issues creating barriers for mothers to exclusively breastfeed 3 . Inadequate care, poor hygiene, and control of diseases for infants and mothers may also inadvertently limit the growth of infants who are adequately breastfed 3,8,9 .
The current evidence for other interventions, such as micronutrients, food supplements, deworming, maternal education, and kangaroo care (i.e. early skin-to-skin care) interventions is unclear for the exclusive breastfeeding life stage. Although there are numerous published reviews aimed to assess the effectiveness of these interventions that can be provided during

Amendments from Version 1
Minor change in title.
Introduction section -first paragraph re-written to improve readability.
Methods section -explanation provided in regards to the calculation of reported LAZ. Table 2 and Table � � have been interchanged -PICOS criteria reported in Table 2 and list of included studies reported in Table �.

Contents of
Results section: • Effect of local food supplement for mothers has been removed from the network meta-analysis on stunting as there is no considerable impact.
• More explanation provided under kangaroo care regarding the blinding of participants. New citation inserted to support the explanation.
New supplementary data uploaded -supplementary table 7 has been updated to include average age of child (if applicable) at the time of enrolment. Revised link to access the data has been provided as well.
Reference section -reference no. 12 has been updated to include a revised link for supplementary data file.
Any further responses from the reviewers can be found at the end of the article REVISED exclusive breastfeeding period (Table 1), their scope has been limited to summarize the comparative effectiveness of a single intervention or interventions within a single domain only. Given that determinants of linear growth for exclusive breastfeeding period is multi-faceted, there is a need to summarize the evidence base of interventions from multiple intervention domains, since multi-domain intervention solutions are likely needed to tackle this problem.
This article uses a comprehensive literature review for multiple intervention domains of micronutrient, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care to summarize their effects on linear growth for LMIC-based infants in the exclusive breastfeeding period. For our quantitative summary, we have used network meta-analysis for all interventions except for kangaroo care to summarize their effects on LAZ and stunting outcomes; kangaroo care was assessed using pairwise metaanalysis. As the data was too sparse to facilitate meta-analysis, we qualitatively summarized the evidence base for outcomes length and head circumference.

Methods
Our analysis and report was designed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension to network meta-analysis 10 . The protocol for this study was registered in PROSPERO (CRD42018110450).

Search strategy and selection criteria
Our search strategy was developed after first reviewing the papers published in the Lancet 2013 Maternal and Child Nutrition series 3,11 , inclusive of the umbrella review by Bhutta and colleagues 7 , for an overview of the literature. Specifically, we hand-searched the bibliography of Bhutta et al. 7 for relevant systematic reviews, global health guidelines, and LMIC-based trials. We also performed additional searches in PubMed and the Cochrane Database of Systematic Reviews for more recent trials and other reviews published after 2013. The list of published reviews relevant to this study is provided in Table 1.
For our systematic literature search, we scanned the following databases from inception to August 28, 2019: the Cochrane Central Register of Controlled Trials, Embase, and MEDLINE (Extended data, Supplementary Tables 1-3) 12 . To increase the sensitivity of our search, we complemented our database searches with relevant trials identified from bibliographies of prior reviews. Table 2 describes the Population, Intervention, Comparator, Outcome, and Study Design (PICOS) criteria used to guide the study selection for our systematic literature review. We included randomized clinical trials on interventions of the following domains: Micronutrient supplements; Food supplements; Deworming for mothers; Maternal and breastfeeding education, and promotion; WASH; and kangaroo care (i.e. skin-to-skin care). The outcomes of interest included change in LAZ, proportions of participants with stunting (defined by LAZ below -2SD), change in length, and change in head circumference. We used LAZ reported from the individual trials that were calculated using the WHO Child Growth Standards 26 . For all intervention domains, except for kangaroo care, we excluded studies that did not report the effects of their respective interventions for at least two months. For kangaroo care, there was no restriction for time of follow-up given short duration nature of this intervention. We excluded non-English language studies.
A team of four reviewers (JJHP, ES, LD, and RM) independently reviewed all abstracts and proceedings identified in the literature searches. The same team independently conducted relevant full-text reviews of relevant papers. If any discrepancies occurred between the studies selected by the same reviewers, a third investigator (KT) provided arbitration.
Using a standardized data sheet in Microsoft Excel, four investigators (JJHP, VJ, NEZ, and HG) independently extracted data for study characteristics, interventions used, subject characteristics at baseline, and outcomes from the final list of selected eligible studies. Any discrepancies observed during data extraction were resolved through discussion between the investigators until consensus was reached.
Evidence synthesis and data analysis When sufficient data was available for quantitative assessment, a network meta-analysis or pairwise meta-analysis approach was applied. For all domains of interventions except for kangaroo care, we performed a network meta-analysis for LAZ and stunting. There was a limited number of studies that reported on length and head circumference, so we qualitatively synthesized findings from these trials as an alternative to quantitative analysis. We did not consider kangaroo care as part of the network meta-analysis since these trials involved a shorter intervention duration and follow-up (median follow-up of 2 weeks).
We performed a network meta-analysis within the Bayesian framework in R using the R2WinBUGS v14 package 27,28 . Bayesian models were performed according to the National Institute for Health and Care Excellence (NICE) in their Technical Support Document 2 (TSD2) 29 . Estimates of comparative effectiveness were measured using mean differences in LAZ with the associated 95% credible intervals (95% CrI For our primary network meta-analysis, we included both cluster and non-cluster randomized clinical trials (with the unit of randomization set at the individual level). To adjust for clustering effects of the cluster trials, we assumed a conservative intra-cluster correlation coefficient (ICC) of 0.05, and we inflated variances accordingly for continuous outcomes and adjusted the sample sizes and the number of cases for dichotomous outcomes, as recommended by Uhlmann et al. 32 We performed a sensitivity analysis by excluding cluster randomized clinical trials in our network meta-analysis. For our pairwise meta-analysis on kangaroo care, we performed a random-effects model using the Metafor R package (in R2WinBUGS v14) 33 . For our network meta-analysis, the estimates of effectiveness were measured using mean differences or relative risk with accompanying 95% credible intervals (CrIs). The estimates of effectiveness were measured using mean differences with accompanying 95% confidence intervals (CIs) for our pairwise meta-analysis on kangaroo care. As no kangaroo care trials involved cluster randomization, our pairwise meta-analysis did not need to adjust for the clustering effect.

Risk of bias within and across studies
Each full text article was evaluated for reporting quality according to the Cochrane Risk of Bias Tool 34 . The risk of bias assessment within and across studies are provided in the Extended data (Supplementary Table 8) 12 .

Results
We identified 20,224 abstracts from our database searches and hand searching of reference lists from published reviews ( Figure 1). Of these, 1099 studies underwent a full-text review, and 40 papers reporting on 29 trials met our inclusion criteria. In total, these trials pertained to 35,119 participants that were randomized to 73 unique interventions ( Figure 2). The list of the final subset is provided in Table 3, and the list of excluded studies (Extended data, Supplementary Table 5) 12 is provided in the online appendix.
The trial characteristics of the included studies (Extended data, Supplementary Table 6) 12 are provided in the online appendix. Of the 29 included trials, ten were cluster randomized trials (1156 clusters; 24,389 mother-infant dyads). The majority of trials were conducted in Southeastern Asian (n = 14) and African (n = 10) countries, and involved individual randomization (i.e. non-cluster trials, n = 19) and were open-label trials (n = 9). Several trials (n = 24) focused on a single domain of interventions, with micronutrient (n = 11) and food supplements (n = 9) being the most common intervention domains investigated. There were four trials that investigated interventions from two different intervention domains 35-38 , but the scope of these trials was still limited to nutritional (micronutrient and food) supplementations. There was one trial reporting on deworming study 39 and another on WASH intervention 40 , and there were five trials on kangaroo care. There were 24 trials that investigated other intervention domains (non-kangaroo care trials), the median duration of interventions was 24 weeks (IQR: 12, 24 weeks). The kangaroo care trials entailed short follow-ups, with intervention durations that varied between one to two weeks.
The subject baseline characteristics are provided in the online appendix (Extended data, Supplementary Table 7) 12 . The median age of mothers at enrollment was 25.4 years (ranging from 21.8 to 29.8 years). For infants, the majority of trials enrolled participants from birth (after follow-up of the mother) or within the first month of life, except one trial 41 that investigated the effects of food supplements for an early weaning off breastfeeding enrolled subjects at 4 months of age (up to 7 months of age). The proportion of boys included in these trials was 51.3% on average, ranging from 36.6% 40 to 73% 42 .

Network meta-analysis on LAZ
The LAZ network (Extended data, Supplementary Figure 1) 12 included 18 trials consisting of 27,896 mother-infant dyads randomized to 52 intervention arms. The results of our primary analysis on LAZ that included both cluster and non-cluster randomized clinical trials are illustrated in Figure 3. Among micronutrient supplements, multiple micronutrients supplementation (MMN) provided to infants improved LAZ relative to standard-of-care (MMN-C, mean difference: 0.20, 95% CrI: 0.03, 0.35), whereas supplementing breasting mothers with MMN did not improve LAZ (MMN-M, mean difference: -0.02, 95% CrI: -0.18, 0.13). Compared to standard of care, other micronutrient supplements to infants, such as zinc 5 mg (zinc 5 mg C) showed a trend towards improved  Small-quantity, lipid-based nutrient supplements provided to women during pregnancy and 6 mo postpartum and to their infants from 6 mo of age increase the mean attained length of 18-mo-old children in semi-urban Ghana: a randomized controlled trial

Adu-Afarwuah 2017
Maternal supplementation with small-quantity lipidbased nutrient supplements compared with multiple micronutrients, but not with iron and folic acid, reduces the prevalence of low gestational weight gain in semi-urban ghana: A randomized controlled trial  Network meta-analysis on stunting The stunting network (Extended data, Supplementary Figure 3 Table 9 and 10) 12 . In our sensitivity analysis on LAZ, no interventions showed improvements for LAZ when compared to standard-of-care, and similarly for stunting, no interventions showed reduced risks for stunting. This is likely due to very few studies being available for sensitivity analyses; only nine trials were available for LAZ and stunting analyses.

Kangaroo care
Five randomized clinical trials investigating the effects of kangaroo care on linear growth of newborns were included in the pairwise meta-analysis 42,46,49,56,70 . The outcome reporting of these kangaroo care trials was limited to growth velocity of head circumference and length (cm per week). All kangaroo care trials were conducted in Southeastern Asian countries (i.e. India, Malaysia, and Nepal), in hospital settings and involved low birthweight neonates. Kangaroo care consisted of skin-to-skin contact between the mothers' breasts, where infants in the control group were kept under either a warmer or incubator. The effects of kangaroo care on head circumference and length growth velocities are shown in Extended data, Supplementary  Figures 12 and 13  , and 400 IU) were provided to Chinese infants from birth up to six months of age; at the 6-months assessment, differences in length between the three groups were observed. Another placebo-controlled trial 64 conducted in Bangladesh found that daily zinc supplements (5 mg) to children between the age of one month to six months did not change the length or head circumference.
There were two trials that explored the role of food supplements to children. Simondon et al. 41 was a multi-national trial (Congo, Sengal, Bolivia, and New Caledonia) that randomized four-month old infants to either cereal-based precooked porridge fortified with MMN or the control group consisting of local food. The mean consumption of supplement varied from 133 to 189 kcal/day. There were no differences in length (cm) between the supplemented and control groups in all four countries at six months of age. In Lonnerdal et al. 61 , one-month old infants of non-breastfeeding mothers were randomized to receive regular formula or formula fortified with bovine osteopontin (65 or 130 mg/L). There were no differences in length or head circumference between children who were randomized to different formula groups. This trial also recruited infants whose mothers had expressed the desire to exclusively breastfeed up to six months of age and used this breastfeeding group as a non-randomized control. The breastfeeding group had a higher mean head circumference but similar length at six months of age.

Discussion
Despite recent global achievements towards improved MNCH, the existing evidence on exclusive breastfeeding period interventions for linear growth remains unclear. Our study aimed to improve the current evidence base by assessing the comparative effectiveness of interventions across several domains: micronutrients, food supplements, maternal education, WASH, deworming, and kangaroo care. Both network meta-analysis and pairwise meta-analysis techniques were undertaken to appraise and synthesize findings from relevant studies reporting the desired outcomes for infants of age 0-6 months in LMICs (i.e. LAZ and proportion of stunted), and due to limited number of studies, length and head circumference were summarized qualitatively.
We found that MMN supplementation to infants (i.e. MMN-C) was the only intervention that showed important improvement for linear growth during the exclusive breastfeeding period. However, this finding was limited to only one trial in the study 59 . Our analysis of kangaroo care also exhibited important improvements in growth in terms of increased head circumference and length growth velocity. However, kangaroo care interventions were excluded from the network meta-analysis and were analyzed separately via pairwise meta-analysis. This was due to the specific nature of this type of intervention, consisting of skin-to-skin contact between mothers' breasts during a precise period for a limited duration (of between 1 and 6 weeks). In relation to this point was the observed heterogeneity in the intervention duration between included studies, generally, creating an added challenge when making comparisons across interventions. Deworming and WASH interventions did not show any improvements in both LAZ and stunting.
The main strength of this study was the use of network meta-analysis to assess the effectiveness of different interventions from a large network of evidence compared to standardof-care 76 . Previous reviews have focused only on intervention(s) within a single domain (Table 1). We used a broad evidence base that included multiple interventions from different domains to simultaneously analyze all potential treatment options and make full use of the available evidence within a single analysis 77,78 . Additionally, appropriate statistical adjustments were made for clustering effects of cluster randomized clinical trials to enable the convergence of cluster and noncluster trials for our network meta-analysis. Nevertheless, the narrow parameters of our PICOS criteria may have limited the breadth of our evidence base. Ethical and resource challenges associated with conducting clinical trials with neonates may have influenced investigators' decision to undertake other non-randomized methodological approaches, such as observational studies. Additionally, since our population of interest focused on newborns living in LMICs, this prevented the inclusion of several trials conducted in non-LMICs. A number of studies assessed the effectiveness of long chain poly unsaturated fatty acids [79][80][81] ; an intervention that has demonstrated some promise for improving linear growth in neonates compared to standard of care. As these trials were limited to high income settings, we were unable to incorporate this data into our analyses.
In general, our analysis revealed that the existing evidence base for improving linear growth during the exclusive breastfeeding period is limited. Our scan and appraisal of the evidence resulted in a paucity of studies focused on this early life stage. The scarcity of evidence for this early life stage could be explained by several factors. Generally, clinical trials involving neonates are considerably more difficult to perform due to a range of ethical, physiological, pharmacometric, and economic challenges 82 . Obtaining ethical clearance for enrolling neonates can be extremely tasking, particularly with the need to preserve equipoise between intervention arms through balancing risk factors across intervention groups 82 . Such complexities can complicate both the study design and recruitment, especially as it pertains to trials conducted in resource scarce settings 83 . These reasons may explain to why the current evidence base for exclusive breastfeeding period is limited.
More clinical trial research is needed for the EBF period. To enhance the quality of evidence, it will beneficial if trials in the future will utilize more efficient trial designs, such as adaptive trial designs, that can better manage the range of uncertainties that may be associated with investigations focused on neonates 84,85 . It is important for mothers and infants living in resource limited settings that our assessment of interventions is thorough and appropriate for diverse contexts and settings. This will be a critical step to achieve the global goal of achieving a 40% reduction in the number of stunted children <5 years by 2025 86 .

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.  Table 8.) • Appendix 6. The intervention networks for LAZ and stunting. (Contains Supplementary Figures 1-4.) • Appendix 7. Primary analysis leverage and consistency plots. (Contains Supplementary Figures 5-8.) • Appendix 8. Forest plots, cluster and non-cluster trials.
(Contains Supplementary Figures 9-11.) • Appendix 9. Forest plots for kangaroo care (Contains Supplementary Figures 12 and 13.) KT and EJM had full access of all of the data in the study. EJM was responsible for the integrity of the data, accuracy of the data analysis, and the final decision to submit for publication.

Glenda Courtney-Martin
Research Institute, The Hospital for Sick Children, Toronto, ON, Canada The authors state that exclusive breastfeeding during the first six months of life is critical for linear growth. Although the evidence is strong to support the benefits of exclusive breastfeeding on linear growth, the evidence for other interventions is not as clear. Numerous published reviews have assessed the effectiveness of micronutrients, food supplements, deworming, maternal education and kangaroo care during the exclusive breastfeeding period but their scope has been limited to single intervention within a single domain. Because the determinants of linear growth for the exclusive breastfeeding period is multi-faceted there is a need to summarize the evidence from multiple domains. The study therefore uses a comprehensive literature review for multiple intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene and kangaroo care with a goal to summarize their effects on linear growth during the first 6 months of life (exclusive breastfeeding period). The main outcomes of interest were LAZ, stunting, changes in linear growth and changes in head circumference. Network meta-analysis was used to analyze data except kangaroo care which was analyzed using pairwise meta-analysis. The main finding from this analysis was that micronutrient supplementation to infants was the only intervention that showed improvement in linear growth during the exclusive breastfeeding period.
This is a valuable study and generally well designed. It can be improved in the following minor areas:

Introduction:
The introduction could be tweaked to make it clearer. In the first paragraph it is not clear that linear growth is a clear benefit of exclusive breastfeeding during the first 6 months. For example "…is a critical life stage for early child development including linear growth."

Method:
Clarify how the LAZ was calculated and if the same data was used to calculate LAZ among all trials. 1.
There seems to be an error in reporting the length of the intervention among studies. For example on page 4/17 it reads "we excluded studies that did not report the effects of their respective interventions for at least three months". However in table 3 under outcomes it states "At least one of the following outcomes (reported after at least 2 months, *except for Kangaroo care)". Please clarify if this is 2 or 3 months.

2.
At the bottom of page 4/17 the last sentence states "if any discrepancies occurred between the studies selected by the same reviewers, a third investigator provided arbitration". Do you mean discrepancies in the review of the studies? 3.
Top of second column page 4/17 -should this be subject characteristics rather than patient characteristics? 4. Table 3 should likely be table 2 and vice versa, since table 3 was written first in the text. 5.
It is not clear in the methods when the respective outcomes were measured. Were they all 6.

Edward J. Mills
The introduction could be tweaked to make it clearer. In the first paragraph it is not clear that linear growth is a clear benefit of exclusive breastfeeding during the first 6 months. For example "…is a critical life stage for early child development including linear growth." Thank you for your comment. We have revised the introduction to improve the readability. There seems to be an error in reporting the length of the intervention among studies. For example on page 4/17 it reads "we excluded studies that did not report the effects of their respective interventions for at least three months". However in table 3 under outcomes it states "At least one of the following outcomes (reported after at least 2 months, *except for Kangaroo care)". Please clarify if this is 2 or 3 months.
Supplementary Table 6 reports intervention duration of each trial. We have changed the text on page 4 to include "we excluded studies that did not report the effects of their respective interventions for at least two months" to keep it consistent with Table 2. ○ At the bottom of page 4/17 the last sentence states "if any discrepancies occurred between the studies selected by the same reviewers, a third investigator provided arbitration". Do you mean discrepancies in the review of the studies?
If any discrepancy occurred between the reviewers during abstract and full text screening as well as data extraction, a third investigator provided arbitration. ○ Top of second column page 4/17 -should this be subject characteristics rather than patient characteristics?
We have amended our article to include "subjects" in place of patients. ○ Table 3 should likely be table 2 and vice versa, since table 3 was written first in the text.
Thank you for the suggestion. We have amended the manuscript to include PICOS under Table 2 and list of included studies under Table 3. ○ It is not clear in the methods when the respective outcomes were measured. Were they all measured before 6 months of life?
There is variation among the trials in terms of the time when the outcomes were measured. For the purpose of our analysis, we only included outcomes that were reported within 6 months of the child's life. ○ Also not clear why 2 or 3 months (depending on which one is accurate) was chosen as the minimum length of time for each intervention (except kangaroo care).
The goal was to capture desired outcomes that were reported within 6 months of the child's age since the paper focused on the effect of exclusive breastfeeding for children aged 0-6 months. The highest length of time for intervention in the studies was 24 weeks. ○ Page 5/17 second column second paragraph the word "patients" is used rather than subjects?
We have amended our article to include "subjects" in place of patients. This is a very valuable analysis of the effects on stunting of interventions applied to mothers and infants in pregnancy and/or during the first six months of life. The methods used allow some comparisons between interventions to be made and aid interpretation of the limited data across the different type of interventions. ○ Intervention in the target age group 0-6 months is of key importance given that it is a period of very rapid relative growth, exclusive breastfeeding is not practiced to 6 months of age in many low and middle income settings, and stunting seems to occur even when exclusive breastfeeding is reported. ○ My main comments are around lack of analysis or reporting of duration of interventions and the age/timing of when they were applied.

○
In the trials in more than one domain, infant supplementation (LNS etc.) was given after 6 months of age -hence these components do not always fall within the target age range, presumably some of these components were excluded and this could be specifically mentioned under trial characteristics. ○ Timing -it would be helpful to readers to add the periods of pregnancy or during the first six months of life where interventions applied, and when LAZ was assessed as columns to Table 2. ○ In figure 2, were the lower brown nodes (local food, porridge) administered to the infants or to the mothers? If mothers, then were they before, during or after pregnancy? For infants, from what age for zinc, MMN and foods? The timing (trimesters and say 0-2m/3-5m) and recipient (mother or infant) could be indicated by shape. ○ 'Infant' rather than 'child' would be more appropriate throughout. ○ Within the target period, there are differences in timing and age between the interventions and also potentially differences in plasticity in length or head growth with age. Kangaroo care applied in a selected LBW group at the lowest end of the infant age range when head and length growth is most rapid (and possibly most plastic) and was treated separately, but pre/post-partum and timing within the first 6 months could similarly be a determinant of response. If so, this would be very important for policy. Timing and duration of intervention could be examined as covariates in the network analysis vs SOC, and the estimated effects reported. ○ For kangaroo care, the mean length and head circumference estimates are presented as absolute cm values rather than z scores and are presented as per week increment during a very short period of intervention. For the other interventions, the overall effect is reported despite varying duration. I appreciate the reasons for treating kangaroo care separately. ○ However, it would be much more valuable to readers to report all results as changes per week over n weeks (or x weeks prepartum plus y weeks postpartum). For example, the foods given from age 4 months in some studies (a maximum of 2 months of intervention before assessment at 6 months), or formula milk at 1 month (for how long?) clearly differ in terms of both timing and duration from other interventions.
Unless all studies other than kangaroo care reported measured LAZ at 6 months of age or another standardized time point, this would also need to be addressed in analysis, especially if any interventions went on for longer than the first 6 months of life.

○
In the qualitative summary please specifically comment on blinding in the kangaroo care studies since these measurements are operator dependent and knowledge of the randomization at measurement could be a problem. In the trials in more than one domain, infant supplementation (LNS etc.) was given after 6 months of age -hence these components do not always fall within the target age range, presumably some of these components were excluded and this could be specifically mentioned under trial characteristics.
Thank you for your comment. For the purpose of our analysis, we included outcomes that were reported within 6 months of age. Supplementary tables 6 and 7 report age of mother/child during enrolment and the intervention duration. ○ Timing -it would be helpful to readers to add the periods of pregnancy or during the first six months of life where interventions applied, and when LAZ was assessed as columns to Table 2.  figure 2, were the lower brown nodes (local food, porridge) administered to the infants or to the mothers? If mothers, then were they before, during or after pregnancy? For infants, from what age for zinc, MMN and foods? The timing (trimesters and say 0-2m/3-5m) and recipient (mother or infant) could be indicated by shape.

Supplementary
Interventions provided to mothers have been indicated as "maternal" on the nodes. Thus, the lower brown nodes show interventions that were administered to infants. Supplementary Table 7 indicates the ages of mother and child at enrolment as well as the average gestational age during recruitment. The network diagram was drawn from a treatment network generated from our Bayesian network meta-analysis tool which shows multiple treatment comparison among all the trials. Treatments have not been segregated according to duration for data analysis purposes. ○ 'Infant' rather than 'child' would be more appropriate throughout.
Thank you for the suggestion. We decided to use the term "child" specifying the age range in order to be more specific. Infants usually indicate young children between the age of 0-1 year (https://www.cdc.gov/ncbddd/childdevelopment/positiveparenting/infants.html) ○ Within the target period, there are differences in timing and age between the interventions and also potentially differences in plasticity in length or head growth with age. Kangaroo care applied in a selected LBW group at the lowest end of the infant age range when head and length growth is most rapid (and possibly most plastic) and was treated separately, but pre/post-partum and timing within the first 6 months could similarly be a determinant of response. If so, this would be very important for policy. Timing and duration of intervention could be examined as covariates in the network analysis vs SOC, and the estimated effects reported.
For kangaroo care, the mean length and head circumference estimates are presented as absolute cm values rather than z scores and are presented as per week increment during a very short period of intervention. For the other interventions, the overall effect is reported despite varying duration. I appreciate the reasons for treating kangaroo care separately. However, it would be much more valuable to readers to report all results as changes per week over n weeks (or x weeks prepartum plus y weeks postpartum). For example, the foods given from age 4 months in some studies (a maximum of 2 months of intervention before assessment at 6 months), or formula milk at 1 month (for how long?) clearly differ in terms of both timing and duration from other interventions.
Thank you for this comment. We acknowledge that there is substantial heterogeneity observed in the duration of the interventions and the timing of outcome assessments. To address the heterogeneity in trials, we employed random-effects model for our network meta-analysis. For kangaroo care studies, our outcomes reporting has been limited to growth velocity of head circumference and length (cm per week). Given the heterogeneity in timing and duration of interventions, we calculated pooled estimates of growth velocities. ○ Unless all studies other than kangaroo care reported measured LAZ at 6 months of age or another standardized time point, this would also need to be addressed in analysis, especially if any interventions went on for longer than the first 6 months of life.
The highest duration of intervention in the studies was 24 weeks (i.e. 6 months). Among those studies that reported an intervention duration of 24 weeks, some recruited mothers during pregnancy, while the children were recruited within a few days of birth. For the purpose of analysis, outcomes reported within the first 6 months of life were included. ○ In the qualitative summary please specifically comment on blinding in the kangaroo care studies since these measurements are operator dependent and knowledge of the randomization at measurement could be a problem.
Thank you for pointing this out. We have added one paragraph under kangaroo care, which is as follows: We do not use terms such as "statistically significant or insignificant" to avoid ○