Analysis of Postdischarge Interventions for Children Treated for Moderate or Severe Wasting, Growth Faltering or Failure, or Edema

Key Points Question In infants and children treated for growth failure or faltering, moderate or severe wasting, or edema, which postdischarge interventions are helpful in improving outcomes? Findings This systematic review, which included 8 intervention studies from 7 countries with 5965 participants, found that biomedical, cash transfer, and integrated interventions may improve certain outcomes in children after treatment for acute malnutrition. Meaning Given limited evidence on the efficacy of interventions to improve postdischarge outcomes following nutritional treatment for moderate or severe acute malnutrition, additional research on the effectiveness and operational feasibility is warranted to inform global guidance.


Introduction
Wasting (ie, a child being too thin for their height) affects at least 45 million children worldwide 1 and is associated with increased child morbidity and mortality. 24][5][6] A recent systematic review showed that the proportion of children who relapse after successful discharge from nutritional treatment for severe acute malnutrition (SAM) may be as high as 37%. 3 Other studies indicate postdischarge mortality risk could be as high as 9%. 4,7,8[11][12] Despite increased risks of adverse outcomes following nutritional recovery, current World Health Organization (WHO) guidelines provide no or limited recommendations for interventions to improve postdischarge outcomes. 13A recent systematic review on postdischarge interventions following hospitalization for complicated SAM concluded that medical and psychosocial interventions showed promise in reducing postdischarge mortality following hospitalization in this specific subset of children with acute malnutrition. 14An important knowledge gap exists in our understanding of which interventions are effective to improve postdischarge outcomes in most children treated on an outpatient basis for uncomplicated SAM, moderate acute malnutrition (MAM), growth failure or faltering, or edema.In addition, little is known about the subgroups of children who may benefit from postdischarge interventions.The identification of effective interventions and subgroups of children who may benefit should be used to inform the development of guidelines for postdischarge interventions to prevent relapse and other adverse outcomes after discharge and to improve targeting and the longer-term impact of standard treatment.In 2021, the WHO identified this as a priority area for guideline development and commissioned a systematic review. 15The current review aimed to evaluate the evidence on the effectiveness of postdischarge interventions for infants and children treated for moderate or severe wasting, growth failure or faltering, or edema to improve outcomes and to identify subgroups of children who may benefit from postdischarge interventions.

Methods
This systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guideline 16 and Cochrane Handbook for Systematic Reviews of Interventions 17 guidelines.The protocol was registered with Prospero (CRD42022308380).

Search Strategy and Selection Criteria
We searched PubMed, Cochrane Library, Embase, Web of Science Index Medicus, CINAHL, Latin American and Caribbean Health Sciences Literature (LILACS), e-Library of Evidence for Nutrition Actions (eLENA; WHO), and Index Medicus for the Eastern Mediterranean Region (IMEMR) from inception through December 2021 without language or geographical restrictions.The search strategy was developed using index terms along the following themes: child or infant, wasting, intervention, and discharge (eAppendix 1 in Supplement 1).References of extracted articles were reviewed for additional studies to include.
Peer-reviewed articles were included if they (1) assessed children aged 0 to 59 months treated for complicated or uncomplicated MAM or SAM, growth faltering or failure, or edema; (2) examined any intervention delivered partially or completely after discharge from nutritional treatment, where after discharge was defined as following exit from all phases of nutritional treatment; (3) study design was individually randomized clinical trial (RCT), cluster RCT, quasi-randomized study, controlled before-after study, or interrupted time series; and (4) assessed relapse, deterioration to severe wasting, readmission, anthropometric measures, all-cause mortality, or morbidity up to 6 months after discharge.Outcome definitions are provided in eAppendix 2 in Supplement 1.

Data Analysis
Two reviewers (L.B. and S.M.R.) independently screened titles, abstracts, and full texts for inclusion.
Disagreements were resolved through discussion with a third reviewer (S.I.).Data were extracted and reviewed using a standardized form.The risk of bias was assessed by 2 reviewers (L.B. and S.M.R.) using the Cochrane Risk of Bias 2 tool for RCTs and cluster RCTs 18 and the Cochrane Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool for nonrandomized studies, 19 and the certainty of the evidence using the GRADE approach. 20,21Disagreements were resolved through discussion with a third reviewer (S.I.).Authors of the original studies were not contacted for clarification or additional information.
Data were synthesized narratively by study characteristics, intervention characteristics, and outcomes assessed.Included interventions were classified by type based on the hypothesized mechanisms of action: biomedical, food supplementation, psychosocial stimulation, cash transfers, or integrated packages operating through multiple mechanisms.Results were summarized narratively and presented by intervention type.Considering that food availability is a key driver of child wasting and the provision of food supplementation likely affected outcomes, we summarized results on psychosocial stimulation alone in studies providing psychosocial stimulation with and without food supplementation.Meta-analysis was planned when at least 2 studies assessed similar interventions and predefined outcomes.Meta-analysis did not pool experimental and quasiexperimental studies. 17Subgroup meta-analysis to examine effect modification by child and study characteristics was planned (eAppendix 3 in Supplement 1) but not conducted as only 1 study reported subgroup analyses.
One study assessed daily antibiotic prophylaxis with oral co-trimoxazole compared with placebo for 6 months starting at discharge from inpatient treatment and continuing during and after outpatient treatment. 26Estimates for associations after discharge from nutritional treatment could not be extracted, as the authors did not report postdischarge estimates from all nutritional treatment (only postdischarge estimates of inpatient treatment, which included follow-up during subsequent outpatient treatment and postoutpatient discharge).Associations at 6 months and 12 months after discharge from inpatient treatment for antibiotic prophylaxis with oral co-trimoxazole are summarized in eAppendix 4 and eTable 3 in Supplement 1.
Daily supplementation with 10 mg of zinc starting at admission to inpatient treatment and continuing until 90 days after discharge was associated with higher mid-upper arm circumference (MUAC) and weight-for-age z score (WAZ) at 90 days after discharge; lower prevalence of diarrhea, skin infections, vomiting, fever, acute respiratory infection, and pallor at 30, 60, and 90 days after discharge; and lower prevalence of edema at 30 and 60 days after discharge. 23The certainty of the evidence was downgraded to moderate for all outcomes due to imprecision, ie, small sample size, few events, and wide confidence intervals (eTable 4 in Supplement 1).
Two studies assessed food supplementation. 22,24Daily food supplementation (150 kcal/d) for 3 months starting at discharge from inpatient SAM treatment was not associated with postdischarge anthropometric z scores. 24Supplementation with a nonmilk based local therapeutic food (833 kcal/d) for 6 weeks starting at discharge from inpatient SAM treatment was associated with lower proportion of children with low MUAC or low weight-for-height z score (WHZ) at 6 weeks after discharge. 22The certainty of the evidence was downgraded to moderate for anthropometric z scores due to imprecision (small sample size and wide confidence intervals) and to low for weight gain and MUAC due to high risk of bias and imprecision (small sample size and no measure of uncertainty reported) (eTable 5 in Supplement 1).
Of the 3 studies that assessed psychosocial stimulation, 2 provided psychosocial stimulation alone 25,29 and 1 provided psychosocial stimulation with and without food supplementation. 24Metaanalysis of the 2 studies that provided psychosocial stimulation alone was not conducted, as 1 study was quasi-experimental. 29Estimates for associations after discharge from nutritional treatment could not be extracted from 1 study, 25 as the authors did not provide postdischarge estimates from all nutritional treatment (only postdischarge estimates of inpatient treatment, which included follow-up during subsequent outpatient treatment and post-outpatient discharge).Associations at 6 months after discharge from inpatient treatment are summarized in eAppendix 5 and eTable 6 in Supplement 1.
Psychosocial stimulation delivered to children aged 6 to 24 months hospitalized with severe underweight (WAZ <−3 SD) through biweekly 1-hour sessions for 6 months was not associated with anthropometric z scores at 6 months after discharge. 24In contrast, psychosocial stimulation for hospitalized, severely underweight children aged 6 to 24 months starting at admission and continuing for 6 months after discharge (delivered through individual and group sessions in hospital and home visits after discharge) was associated with higher mean (SD) WAZ vs children who did not receive the intervention after 6 months of follow-up: −3.1 (0.9) vs −3.6 (1.2); P = .03. 29 The certainty certainty of the evidence was downgraded to moderate due to indirectness, related to limited generalizability of the study (eTable 8 in Supplement 1).

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One study assessed an integrated package providing biomedical support (a single dose of albendazole and zinc supplementation for 14 days), food supplementation (40 g/d of lipid-based nutrient supplement, providing 200 kcal and 1 recommended daily allowance of micronutrients for 8 weeks), and malaria prevention (provision of an insecticide-treated bed net and a monthly dose of 25 mg/kg of sulfadoxine-pyrimethamine for malaria chemoprophylaxis during the peak of the rainy season) starting at discharge from MAM treatment. 28The integrated package was not associated with MAM relapse, deterioration to severe wasting, or all-cause mortality after 1, 3, or 6 months of follow-up.The intervention was associated with higher prevalence of sustained recovery after 1 month (intervention vs control: 78% vs 74%; P = .04),3 months (intervention vs control: 69% vs 63%; P = .02),and 6 months (intervention vs control: 64% vs 59%; P = .04). 28The certainty of the evidence was downgraded 2 levels for all outcomes due to risk of bias and imprecision (eTable 9 in Supplement 1).

Discussion
In this systematic review aiming to analyze postdischarge interventions for children successfully treated for complicated or uncomplicated MAM or SAM, growth failure or faltering, or edema, we included 8 studies conducted from 2003 to 2019 that evaluated biomedical, food supplementation, psychosocial stimulation, cash transfer, and integrated interventions delivered after discharge from nutritional treatment.One zinc supplementation trial was associated with improved MUAC and WAZ and reduced morbidities within 90 days after discharge. 23One of the 2 food supplementation interventions, which provided a nonmilk-based local therapeutic food, was associated with improved postdischarge weight gain, MUAC, and WHZ. 22Psychosocial stimulation was associated with improved WAZ at 6 months after discharge in one quasi-experimental study. 29One unconditional cash transfer intervention was associated with reduced MAM and SAM relapse and improved anthropometric measures. 27The integrated biomedical, nutrition, and malaria package following MAM treatment showed some evidence of benefits on sustained recovery and protection from deterioration to severe wasting within 6 months of discharge. 28None of the included interventions reduced the risk of all-cause mortality.The review did not identify studies among children treated for growth failure or faltering or edema.
Infections are a main cause of mortality during SAM recovery. 30][12]31 Zinc supplementation is effective for reducing diarrhea risk in children, 32,33 including in those recovering from protein energy malnutrition 34 and particularly in areas with high prevalence of malnutrition and zinc deficiency. 35Preventive zinc supplementation might also reduce the incidence of pneumonia. 36The postdischarge zinc supplementation intervention included in this review was associated with reduced risk of multiple morbidities, including diarrhea and acute respiratory infection, and improvement in anthropometry after discharge, 23 suggesting zinc supplementation may be an effective strategy to reduce the risk of other morbidities beyond diarrhea.While having a low risk of bias, this was a single, older study that applied a now outdated nutrition treatment protocol and discharge criterion (ie, recovery defined at WHZ >80% of expected weight).These findings should be replicated in other contemporary settings while exploring questions related to the effective dose and duration of zinc supplementation.
Current WHO guidelines for inpatient SAM treatment recommend child play activities during treatment to continue after program discharge. 37Our review included 2 RCTs 24,25  We found limited evidence of benefit of direct food supplementation.One randomized study showed no benefit of food supplementation (150 kcal/d for 3 months) on postdischarge anthropometric measures. 24Another indicated some benefits of food supplementation (833 kcal/d for 6 weeks) on postdischarge anthropometric measures. 22However, the latter was a relatively small study at serious risk of bias.International organizations, like the World Food Programme, have increasingly been shifting toward the provision of cash in emergency and humanitarian settings, as studies indicate that cash distribution can be more efficient than direct food aid, allowing more people to be reached with cash at no extra cost. 38,39A single study showed that unconditional cash transfers was associated with reduced MAM and SAM relapse and improved anthropometric measures within 6 months from admission. 27The unconditional cash transfer was hypothesized to improve child outcomes by several mechanisms, including reducing sharing of therapeutic foods during nutritional treatment, increasing household food accessibility and consumption, reducing morbidities by providing money for health care, and increasing income generating opportunities by serving as investment capital. 27However, evidence on the effectiveness of a cash intervention in one setting may not directly generalize to other contexts.The size of the cash transfer in the included study was relatively large, corresponding to 70% of the monthly household income of very poor households in this setting, 27 which likely contributed to its success in improving a range of nutritional outcomes.More research is needed on the optimal amount, duration, and any potential unintended behavioral and market consequences of postdischarge cash transfers in different settings.
Our findings also showed that an integrated package of interventions may be a promising strategy to improve certain postdischarge outcomes in children treated for MAM.The package included food and zinc supplementation, antibiotic prophylaxis, and malaria prevention and was associated with sustained recovery within 6 months after discharge, but effect sizes were overall small.The integrated package had no association with relapse, deterioration to severe wasting, or all-cause mortality, 28 which may be due to its short duration (longest intervention was food supplementation provided for 8 weeks).Although the intervention improved sustained recovery within 6 months after discharge, the authors reported that intervention effect sizes were no longer significant after 12 months of follow-up.More work is needed to understand long-term outcomes and why recovery was not sustained over the longer period of follow-up and to determine which intervention components of the package may be beneficial.Replication in other settings is also warranted to assess the feasibility and effectiveness of packaging these same interventions in different contexts.

Limitations
This study has limitations.First, included studies assessed various interventions that differed in intensity and duration.Some interventions started at discharge from nutritional treatment and continued for a fixed duration after discharge, while others started during treatment and continued for a varying duration after discharge, which led to variable duration of exposure.It is possible that the duration of some interventions might have been insufficient to meaningfully improve postdischarge outcomes.Second, results from some studies could not be summarized when authors reported postdischarge estimates from inpatient treatment and not postdischarge estimates from all nutritional treatment.Future studies should provide more precise documentation of all phases of nutritional treatment and the number of outcomes by phase.Third, outcomes were measured at different points, with some measured only shortly after discharge while others measured after 6

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29d 1 quasiexperimental study29of psychosocial stimulation interventions.The psychosocial stimulation interventions were of varying intensity and duration and overall showed small to no association with anthropometric measures after discharge from all nutritional treatment.When follow-up from from inpatient treatment and from all nutritional treatment were pooled in an ad hoc metaanalysis, the intervention was associated with WAZ and HAZ (eTable 7 in Supplement 1).More research could be beneficial to assess the effectiveness and cost-effectiveness of combining psychosocial stimulation with other interventions to improve postdischarge nutritional and child development outcomes.Additional work is also needed to understand and minimize any potential increased burden for caregivers and health workers' from attending or delivering psychosocial stimulation sessions.
Downloaded From: https://jamanetwork.com/ Search Terms Used in PubMed eAppendix 2. Outcome Definitions eAppendix 3. Prespecified Subgroups for Subgroup Analyses eAppendix 4. Effect of Antibiotic Prophylaxis With Co-trimoxazole eAppendix 5. Effect of Psychosocial Stimulation Postdischarge From Inpatient Treatment eFigure 1. Risk of Bias for Individually Randomized Clinical Studies Included in the Review eFigure 2. Risk of Bias for Cluster Randomized Clinical Studies Included in the Review eFigure 3. Risk of Bias for Observational Studies Included in the Review eTable 1. Excluded Records During Full-Text Review and Reasons for Exclusion eTable 2. Detailed Summary of Included Studies eTable 3. GRADE Evidence Profile for the Effect of Daily Oral Co-trimoxazole Prophylaxis Compared With Routine Care (at 12 Months After Discharge From Inpatient Treatment) eTable 4. GRADE Evidence Profile for the Effect of Zinc Supplementation Compared With Placebo eTable 5. GRADE Evidence Profile for the Effect of Food Supplementation Compared With Routine Care eTable 6. GRADE Evidence Profile for the Effect of Psychosocial Stimulation Compared With Routine Care (at 6 Months After Discharge From All Nutritional Treatment) eTable 7. GRADE Evidence Profile for the Effect of Psychosocial Stimulation Compared With Routine Care (at 6 Months After Discharge From Inpatient Treatment) eTable 8. GRADE Evidence Profile for the Effect of Unconditional Cash Transfers Compared With Routine Care eTable 9. GRADE Evidence Profile for the Effect of an Integrated Package of Medical Care, Food Supplementation, and Malaria Prevention Compared With Routine Care