The Lancet Global Health (Oct 2019)

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

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

Journal volume & issue
Vol. 7, no. 10
pp. e1435 – e1447

Abstract

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Summary: 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 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. 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. Funding: Medical Research Council and Department for International Development.