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Burden and risk factors for relapse following successful treatment of uncomplicated severe acute malnutrition in young children: Secondary analysis from a randomised trial in Niger

Abstract This study aimed to quantify the burden of relapse following successful treatment for uncomplicated severe acute malnutrition (SAM) and to identify associated risk factors in rural Niger. We used data from 1490 children aged 6−59 months discharged as recovered from an outpatient nutritional programme for SAM and followed for up to 12 weeks after admission. Postdischarge SAM relapse was defined as weight‐for‐height Z‐score <−3, mid‐upper arm circumference (MUAC) <115 mm or bipedal oedema after having been discharged as recovered. Postdischarge hospitalisation was defined as admission to inpatient SAM treatment or hospitalisation for any cause after having been discharged as recovered. We used multivariate log‐binomial models to identify independent risk factors. After programmatic discharge, 114 (8%) children relapsed to SAM and 89 (6%) were hospitalised. Factors associated with SAM relapse were discharge during the lean season (relative risk [RR] = 1.80 [95% confidence interval [CI] = 1.22−2.67]) and larger household size (RR = 1.56 [95% CI = 1.01−2.41]), whereas older child age (RR = 0.94 [95% CI = 0.88−1.00]), higher child MUAC at discharge (RR = 0.93 [95% CI = 0.87−1.00]) and maternal literacy (RR = 0.54 [95% CI = 0.29−0.98]) were protective factors. Discharge during the lean season (RR = 2.27 [95% CI = 1.46−3.51]) was independently associated with postdischarge hospitalisation. Future nutritional programmes in the context of Niger may consider modification of anthropometric discharge criteria or the provision of additional home support or follow‐up during the lean season as potential interventions to prevent relapse. More research including postdischarge follow‐up is needed to better understand the sustainability of treatment outcomes after discharge and the type of intervention that may best sustain recovery over time. Clinical Trial Registration: ClinicalTrials.gov number, NCT01613547.


| INTRODUCTION
Severe acute malnutrition (SAM) is a deadly condition contributing to 8% of mortality in children under 5 years of age (Black et al., 2013).
Current community-based approaches for the treatment of SAM involve providing children with therapeutic foods and specialised clinical care on a weekly or biweekly basis until recovery (WHO, 2013;World Health Organisation et al., 2007). Recovery usually occurs between 4 and 8 weeks from admission after stabilisation of weight and clinical complications (WHO, 2013;World Health Organisation et al., 2007).
International guidelines typically evaluate the success of therapeutic feeding programmes by monitoring routine programme indicators, including recovery, death and default during treatment (Sphere Project, 2018). This practice has placed focus on measures of short-term weight gain and case fatality during treatment; however, it is becoming increasingly clear that the risk of relapse, illness and mortality after programmatic recovery from SAM treatment may remain elevated (Stobaugh et al., 2019). A recent systematic review showed that the proportion of children relapsing to SAM after successful discharge from nutritional programmes may be up to 37% (Stobaugh et al., 2019). Studies have also consistently documented elevated prevalence of postdischarge morbidities, suggesting that children's immunological recovery may lag behind anthropometric recovery and that children may remain at an increased risk of illness despite weight gain sufficient for successful programmatic discharge (Aprameya et al., 2015;Ashraf et al., 2012;Bahwere et al., 2017;Khanum et al., 1998).
A broad range of individual, case, and household factors are associated with relapse . Studies have consistently shown that lower anthropometric measures at admission to and discharge from nutritional programmes can be the primary risk factors for relapse (Stobaugh et al., 2019). Some studies have also identified measures of household socioeconomic status, sanitation practices, seasonality and child age, vaccination status and diet as factors associated with relapse (Abitew et al., 2020;Adegoke et al., 2020;Burza et al., 2016;Magnin et al., 2017;Schaefer et al., 2020;Somassè et al., 2016). Identifying risk factors for adverse outcomes following discharge, including relapse and hospitalisation, could help improve identification of children at greater risk for relapse for additional support or surveillance postdischarge and inform guidelines for programmatic discharge criteria and targeted interventions to improve the sustainability of recovery. The aim of this analysis was to evaluate the postdischarge outcomes of children recovered from SAM treatment up to 12 weeks following admission to outpatient SAM treatment in rural Niger and to identify individual and household factors associated with relapse and postdischarge hospitalisation.

| Study setting
This study was conducted in the rural Madarounfa Health District in the Maradi Region of Niger. Households are primarily subsistence farmers with food production linked to rain-fed agriculture resulting in annual harvests of staple crops. In the months preceding this harvest, food quantity and quality decrease while infectious illnesses, such as diarrhoea, pneumonia and malaria, increase. These changes

Key messages
• Following successful discharge from a community-based nutritional programme for severe acute malnutrition (SAM) treatment in rural Niger, the prevalence of SAM relapse was 8% and the prevalence of postdischarge hospitalisation was 6% within 12 weeks from admission.
• Factors associated with SAM relapse were child age at programme admission, child mid-upper arm circumference (MUAC) at discharge, discharge from the nutritional programme during the lean season, and maternal literacy.
• Anthropometry at discharge was a primary risk factor for relapse. MUAC at discharge performed better than weight-for-height Z-score (WHZ) in classifying SAM relapse cases. 'Optimal' cut-offs, defined using the Liu method which maximises the product of the sensitivity and specificity, were MUAC of 121 mm with 66% sensitivity and 67% specificity and WHZ of −1.38 with 54% sensitivity and 57% specificity.
• Future programmes may consider additional support or follow-up of children at high risk of postdischarge relapse or hospitalisation, including those discharged during the lean season. Modification of current anthropometric discharge criteria may also be explored as an actionable target to further reduce the risk of relapse. are associated with a seasonal peak in acute malnutrition among children under 5 years of age. The Maradi Region has some of the highest rates of acute malnutrition in Niger with a wasting prevalence among children under 5 years of age of 11% (Institut National de  were enroled in a randomised controlled trial to examine the effect of routine antibiotic use on nutritional recovery from uncomplicated SAM. Study procedures have been described elsewhere (Isanaka et al., 2016(Isanaka et al., , 2020. In brief, children were randomised to receive amoxicillin (80 mg/kg/day) or placebo for 7 days. Children were seen weekly at the health centre for a minimum of 3 and a maximum of At the time the parent trial was conducted, the standard of care involved the provision of a ready-to-use therapeutic food (170 kcal/ kg/day), a single dose of vitamin A (100,000 UI for children <4 kg, 200,000 UI for children 4−8 kg and 400,000 UI for children ≥8 kg), a single dose of folic acid (5 mg tablet), deworming (200 mg of albendazole for children <8 and 400 mg for children ≥8 kg) and a measles vaccine if necessary (for children without a vaccination card at admission or at 9 months of age for children 6−8 months of age at admission). Malaria and/or anaemia treatment were also provided, if necessary. Further details on standard care in the parent trial have been previously published (Isanaka et al., 2016). At the time the parent trial was conducted, children received a protection ration at the time of discharge from SAM treatment consisting of seven sachets of a ready-to-use therapeutic food. There was no moderate acute malnutrition (MAM) treatment programme in the study area at the time of the parent trial.

| Outcome measures
The primary outcomes of interest for this analysis were postdischarge SAM relapse (defined as WHZ <−3 SD, MUAC <115 mm or bipedal oedema after recovery and up to 12 weeks from admission) and postdischarge hospitalisation (defined as admission to inpatient SAM treatment or hospitalisation for any cause, based on maternal report after recovery and up to 12 weeks from admission). Secondary outcomes of interest included the incidence of the following morbidities at any time during postdischarge follow-up: diarrhoea (≥3 loose stools in the previous 24 h), vomiting, cough, tachypnoea (respiratory rate ≥50 breaths per minute in children 6−11 months of age and ≥40 breaths per minute in children 12−59 months of age), fever (axillary temperature >38.5°C) and malaria with fever (positive rapid diagnostic test and axillary temperature >38.5°C).

| Statistical analysis
The analytic sample included 1490 children with WHZ ≥−2 SD and MUAC ≥115 mm discharged from the outpatient SAM treatment programme as recovered. The present analysis excluded 41 children who were discharged as 'recovered' but did not achieve both anthropometric criteria for discharge. First, to describe the burden of postdischarge relapse and hospitalisation, we reported the number and proportion of children with postdischarge events. Second, to explore whether children were immunologically recovered at the time of discharge, we compared the incidence of individual morbidities before and after discharge, assuming similar or increased morbidity postdischarge would suggest insufficient immunological recovery.
The incidence of morbidity during and after discharge from treatment was examined using generalised estimating equations with an unstructured correlation matrix, a log-Poisson link to derive incidence rate ratios and person-time since admission as an offset. Third, to identify risk factors for postdischarge SAM relapse and hospitalisation, we considered individual and household characteristics at admission into the nutritional programme and case characteristics at admission and discharge. Child characteristics included child age, sex and breastfeeding status at admission. Household characteristics included household food insecurity score based on the Household Food Insecurity Access Scale (Coates et al., 2007), number of children in the household, whether the child slept under a bednet the previous night, household wealth (calculated using principal components analysis using nine items for household asset and livestock ownership, and housing quality), maternal age and literacy. Case characteristics included child anthropometry at admission and discharge: WHZ, BLIZNASHKA ET AL. | 3 of 11 height-for-age Z-score (HAZ), stunting (HAZ <−2 SD), severe stunting (HAZ <−3 SD), weight-for-age Z-score (WAZ), severe underweight (WAZ <−3 SD) and MUAC, calculated using the 2006 WHO child growth standards (World Health Organisation, 2006), and length of stay in the programme, weight gain during the programme (g/kg/ day) and season at discharge (lean season: July to September vs. harvest season: October to June). We used log-binomial models to identify independent risk factors for SAM relapse and hospitalisation.
Crude models adjusted for the parent trial regimen (amoxicillin vs. placebo). Multivariable models adjusted for the trial regimen and for risk factors with a significant crude association at p < 0.20.
Finally, to further explore the predictive value and optimal cutoffs of WHZ and MUAC at discharge for SAM relapse and postdischarge hospitalisation at 12-weeks since admission, we constructed receiver operating characteristic curves and calculated the area under the curve (AUC). AUCs were compared using a bootstrap test with 10,000 replications, which we considered significant at p < 0.05. While there are several ways to define 'optimal' cut-offs for MUAC and WHZ at discharge to predict SAM relapse and hospitalisation, we defined the optimal cut-off in this analysis using the Liu method which maximises the product of the sensitivity and specificity (Liu, 2012

| RESULTS
Recovered children included in this analysis were 17 months of age on average and 52% were female (Table 1)  We found that the incidence of any morbidity, vomiting, cough and tachypnoea was similar during and after treatment, whereas the incidence of fever and malaria with fever was significantly higher postdischarge (Table 2). Only the incidence of diarrhoea was significantly lower postdischarge versus during treatment.
In multivariable analysis, independent risk factors for SAM relapse included younger child age, discharge during the lean season, and living in a household with two children compared to living in a household with one child (Table 3). Higher MUAC at discharge and maternal literacy were independent protective factors against SAM relapse. Discharge during the lean season was similarly independently associated with postdischarge hospitalisation (Table 4).
Lastly, to better understand anthropometry at discharge as a predictor of adverse events postdischarge, we examined the We found that several individual, case and household factors were associated with postdischarge SAM relapse and hospitalisation.
Older children were at lower risk of relapse in line with recent evidence from Ethiopia (Lambebo et al., 2021). Older children may be protected from relapse due to fewer nutritional and health problems often associated with improper introduction of complementary foods in younger children (Lambebo et al., 2021). In terms of case characteristics, our results showed that season of discharge predicted SAM relapse and postdischarge hospitalisation. These findings are consistent with prior reports. In Bihar, India, Burza et al. (2016) found that children discharged into a season of low food security were more likely to relapse than children discharged during a season of high food security. A study in Malawi which followed children discharged from MAM treatment over the course of a year also found that 60% of the poor outcomes were observed in children discharged during the lean season (Chang et al., 2013). However, a third study from Burkina Faso found no differences in relapse risk between children who faced a food scarcity period and those who did not (Somassè et al., 2016).  (Stobaugh et al., 2017). More work is needed to understand whether this type of comprehensive package could also be effective in sustaining long-term recovery and reducing relapse following SAM treatment. The feasibility, acceptability and cost-effectiveness of integrating these services in the Niger context should also be assessed.
In addition to the season of discharge, we found that anthropometry at discharge predicted SAM relapse, consistent with prior studies (Binns et al., 2016;Burrell et al., 2017;Burza et al., 2016;Magnin et al., 2017;Somassè et al., 2016). In our analysis, higher MUAC at discharge was protective against relapse, and MUAC of 121 mm at discharge (somewhat lower than international guidance recommending discharge at MUAC of 125 mm) was found to be optimal in predicting no SAM relapse at 12 weeks of admission.
It is worth noting that the optimal WHZ cut-off of −1.38 identified in the present analysis was higher than the internationally used cut-off of −2 SD. The 'optimal' cut-offs presented in the current analysis, however, reflect one statistical optimisation maximising the product of the sensitivity and specificity. Other approaches could be used to determine optimal cut-offs that may better serve other programme objectives. For programmes seeking to otherwise maximise and that additional support during the postdischarge period may be helpful to reduce vulnerability to infection. Our study builds on existing evidence by demonstrating elevated incidence of fever and malaria with fever after discharge from outpatient treatment, although the incidence of diarrhoea was lower in the postdischarge period than during nutritional treatment. We do, however, note the possibility for higher incidence of fever and malaria with fever may have resulted from increased presentation of fever after recovery compared to during treatment when the immune system may be compromised, resulting in increased malaria testing in the postdischarge period. The lower incidence of diarrhoea in the postdischarge period is likely unrelated to the trial amoxicillin regimen, which had only a transient effect on diarrhoea within the first week of admission to the programme (Isanaka et al., 2016). More research is needed to better understand immunological recovery as it relates to anthropometry during treatment and at the time of discharge, as well as to determine additional interventions that may specifically improve immune recovery and reduce postdischarge morbidity.
Our study is subject to limitations. We did not have a community control group and were unable to calculate excess risk of SAM and hospitalisation after discharge, as has been done elsewhere (Adegoke et al., 2020). Any excess risk might be attributed to the fact that children with SAM come from subgroups of the general population with a higher risk or vulnerability. In addition, we had a shorter period of follow-up relative to other studies (i.e., up to 12 weeks after admission and mean 7.8 weeks after programmatic recovery) and were unable to capture long-term risk of relapse and hospitalisation.
Prior studies have shown that the risk of relapse and death is highest during the period immediately after discharge, with most events occurring within the first 12 weeks after initial recovery (Burza et al., 2016;Guesdon et al., 2021).
Despite these limitations, our study has important implications for nutritional programmes in Niger and other low-resource settings.
Continued focus on short-term outcomes alone may not adequately

| CONCLUSION
In conclusion, we found that 8% of children discharged as nutritionally recovered from outpatient treatment of uncomplicated SAM in rural Niger relapsed to SAM and 6% were hospitalised within 12 weeks of admission. We found elevated morbidity in the postdischarge period, suggesting children may remain immunologically vulnerable even after programmatic recovery. Discharge during the lean season was a risk factor for postdischarge SAM relapse and hospitalisation, while younger child age and larger household size were also risk factors for SAM relapse. Higher child MUAC at discharge and maternal literacy were protective factors for relapse.
MUAC at discharge performed better than WHZ in identifying cases Abbreviations: CI, confidence interval; HAZ, height-for-age Z-score; MUAC, mid-upper arm circumference; WHZ, weight-for-height Z-score. a All models adjusted for trial regimen (amoxicillin vs. placebo).
F I G U R E 1 Receiver operating characteristic curves showing predictive value of mid-upper arm circumference (MUAC) and weight-forheight Z-score (WHZ) at discharge for postdischarge relapse to severe acute malnutrition (left) and postdischarge hospitalisation (right) at 12 weeks after admission of SAM relapse, with statistically optimal cut-offs of 121 mm MUAC