Impact of fortified versus unfortified lipid-based supplements on morbidity and nutritional status: A randomised double-blind placebo-controlled trial in ill Gambian children.

Background: Multiple micronutrients (MMN) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines. Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity. Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth. The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed. Methods and findings: We undertook a double-blind randomised controlled trial of small-quantity lipid-based nutrient supplements (SQ-LNS) fortified with 23 micronutrients in children aged 6 months (mo) to 5 years (y) presenting with an illness at a rural primary healthcare centre in The Gambia. Primary outcomes were repeat clinic presentations and growth over 24 wk. Participants were randomly assigned to receive 1 of 3 interventions: (1) supplementation with micronutrient-fortified SQ-LNS for 12 wk (MMN-12), (2) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk (MMN-6), or (3) supplementation with unfortified SQ-LNS for 12 wk (MMN-0) to be consumed in daily portions. Treatment masking used 16 letters per 6-wk block in the randomisation process. Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled. Between December 2009 and June 2011, 1,101 children (age 6–60 mo, mean 25.5 mo) were enrolled, and 1,085 were assessed (MMN-0 = 361, MMN-6 = 362, MMN-12 = 362). MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment (effect size for MMN groups combined: 0.084 SD/24 wk, 95% CI: 0.005, 0.168; p = 0.037; equivalent to 2–5 mm depending on age). No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups (MMN-0 versus MMN-6: adjusted incidence rate ratio [IRR] 1.03, 95% CI: 0.92, 1.16; MMN-0 versus MMN-12: 1.05, 95% CI: 0.93, 1.18). In post hoc analysis, clinic visits significantly increased by 43% over the first 3 wk of fortified versus unfortified SQ-LNS (adjusted IRR 1.43; 95% CI: 1.07, 1.92; p = 0.016), with respiratory presentations increasing by 52% with fortified SQ-LNS (adjusted IRR 1.52; 95% CI: 1.01, 2.30; p = 0.046). The number of severe adverse events during supplementation were similar between groups (MMN-0 = 20 [1 death]; MMN-6 = 21 [1 death]; MMN-12 = 20 [0 death]). No participant withdrew due to adverse effects. Study limitations included the lack of supervision of daily supplementation. Conclusion: Prescribing micronutrient-fortified SQ-LNS to ill children presenting for primary care in rural Gambia had a very small effect on linear growth and did not reduce morbidity compared to unfortified SQ-LNS. An early increase in repeat visits indicates a need for the establishment of evidence-based guidelines and caution with systematic prescribing of MMN. Future research should be directed at understanding the mechanisms behind the lack of effect of MMN supplementation on morbidity measures and limited effect on growth. Trial registration: ISRCTN 73571031. In a randomised double-blind placebo-controlled trial, Stefan Unger and colleagues examine the impact of fortified versus unfortified lipid-based supplements on morbidity and nutritional status in ill Gambian children. Author summary: Why was this study done?: Multiple micronutrients (MMN) are prescribed widely in low- and middle-income settings. There are currently no established evidence-based international clinical guidelines for the use of MMN in ill children. Community-wide trials of MMN within a lipid-base supplement have shown improvement in linear growth in some settings, although the effect on morbidity is underresearched. Our study was designed to investigate the effect of lipid-based MMN in ill children in relation to the frequency of subsequent primary health clinic visits and growth. What did the research do and find?: We performed a prospective, double-blind randomised controlled trial of small-quantity lipid-based MMN in ill children presenting to a rural primary healthcare clinic in West Africa. We enrolled 1,100 children aged 6 months (mo) to 5 years (y). Children were supplemented either with the lipid-base alone or a micronutrient-enriched lipid-based supplement for 6 wk or 12 wk. The trial showed no effect of small-quantity lipid-based MMN supplementation compared to unfortified supplement on subsequent all-cause morbidity as assessed by clinic visits over 6 mo, but post hoc analysis revealed a significant 43% increase in clinic presentations over the first 3 wk of supplementation. Despite a significant increase in children's reported appetite, there was only a small benefit on linear growth. What do these findings mean?: Randomised trials have so far failed to demonstrate consistent beneficial effects of MMN supplementation (lipid-based or not) on growth and morbidity, and there is some evidence of potentially harmful effects, likely related to iron in the supplements. Blanket prescribing of MMN in primary health clinics in similar settings is not supported by current evidence. [ABSTRACT FROM AUTHOR]