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

Kathryn Maitland,Felistas Kumwenda,Florence Alaroker,Gary Frost,Julianne Kayaga,Machpherson Mallewa,Sarah Kiguli,Cynthia Williams Musika,Sophie Uyoga,Elizabeth C George,Margaret Nakuya,Ayub Mpoya,Tonny Sennyondo,Kevin Walsh,A Sarah Walker,Diana M Gibb,George Chagaluka,Charles Engoru,Eva Nabawanuka,Imelda Bates,Denis Aromut,Cate Namayanja,Michael Boele Von Hensbroek,Julius Nteziyaremye,Neil Kennedy,Thomas N Williams ,Peter Olupot‐Olupot ,Robert O Opoka ,Margaret J Thomason ,Jennifer Evans

doi:10.1016/s2214-109x(19)30345-6

Abstract

SummaryBackgroundSevere 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.MethodsWithin 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 non-sequentially 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.FindingsFrom 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).InterpretationNeither 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.FundingMedical Research Council and Department for International Development.

Highlights

Severe anaemia, defined as haemoglobin of less than 6 g/dL, is a leading cause of hospital admission and mortality in children in sub-Saharan Africa.[1,2,3,4] Out comes remain unsatisfactory, with high rates of reported in-hospital mortality (9–10%);[2,3] long-term out comes are poor, with high additional mortality (8%), anaemia relapse (6%), and re-admission (17%) by 6 months after discharge.[4]
Our findings suggest that neither multivitamin multimineral supplements nor co-trimoxazole should be provided to children after discharge from hospital after severe anaemia
Between Sept 17, 2014, and May 15, 2017, 3986 children with severe anaemia at admission to hospital were randomly assigned to receive enhanced supplementation versus standard treatment; three declined full consent, and are excluded from all analyses. 2418 (61%) of the 3983 included children were from stratum A and had a haemoglobin concentration of less than 4 g/dL or other severity signs or both

Summary

Introduction

Severe anaemia, defined as haemoglobin of less than 6 g/dL, is a leading cause of hospital admission and mortality in children in sub-Saharan Africa.[1,2,3,4] Out comes remain unsatisfactory, with high rates of reported in-hospital mortality (9–10%);[2,3] long-term out comes are poor, with high additional mortality (8%), anaemia relapse (6%), and re-admission (17%) by 6 months after discharge.[4] transfusion alone might not be sufficient to achieve optimal outcomes for these children. In a comprehensive case-control study of children admitted to hospital with severe anaemia in Africa,[3] bacteraemia, malaria, hookworm, HIV, or vitamins A and B12 deficiency, or all six, were key associations.

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