Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trial

Background Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes

remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge

interventions that might improve outcomes.

Methods Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months

to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in

Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second nonsequentially

numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation

with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment

doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and

were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion

management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population;

follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry,

ISRCTN84086586, and follow-up is complete.

Findings From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed

up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement,

1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day

180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and

folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79–1·21; p=0·81) and 172 (9%) who received co-trimoxazole

versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86–1·32; p=0·56). We found no

evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180,

489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate

group (HR 0·95, 95% CI 0·84–1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children

in the no co-trimoxazole group (1·01, 0·89–1·15; p=0·85) had had one or more serious adverse events. Most serious

adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions).

Interpretation Neither enhanced supplementation with multivitamin multimineral supplement versus iron and

folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission

suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched

health services in Africa.