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

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. 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 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 la Statistique, 2019), within the WHO ‘high’ prevalence category of 10%−15% (de Onis et al., 2019). Médecins Sans Frontières (MSF), in collaboration with the Ministry of Health of Niger, has supported paediatric care in the Madarounfa Health District since 2001. Project activities were transferred to local control and implemented through a Nigerien nongovernmental organisation, Forum Santé Niger (FORSANI) in collaboration with the Ministry of Health from 2009 to March 2014. FORSANI provided care and treatment to over 30,000 children in the Madarounfa Health District each year with MSF support. From October 2012 to November 2013, children aged 6−59 months with uncomplicated SAM (defined as weight‐for‐height Z‐score [WHZ] <−3 SD or mid‐upper arm circumference (MUAC) <115 mm) 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, 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 8 weeks until they reached nutritional recovery. Nutritional recovery was defined as WHZ ≥−2 SD and MUAC ≥115 mm and the absence of acute complications or bipedal oedema for at least 7 days, per the national protocol for integrated SAM management at the time of the study. Per the trial protocol, children had scheduled follow‐up visits at 4, 8 and 12 weeks post‐admission regardless of their treatment/recovery status. Caregivers were also invited to return to the health centres at any time in the event of a clinical deterioration. During each follow‐up visit, anthropometry (weight to the nearest 100 g; length in children <24 months of age or standing height in children ≥24 months of age to the nearest 0.1 cm; and MUAC to the nearest 0.1 cm) was assessed and a study physician performed a physical exam and took a medical history. All children received standard medical care for outpatient treatment of uncomplicated SAM as specified by the national guidelines of the Ministry of Health of Niger. 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. 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). 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, 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 cut‐offs 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). Statistical analysis was conducted in R version 4.1.2. (R Development Core Team, 2017).