Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial

Background: Sickle cell disease increases malnutrition risk. Low arginine and nitric oxide [NO] bioavailability are implicated in sickle-related morbidity. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses: (1) supplementary arginine, citrulline and daily chloroquine increases bioavailable arginine and flow-mediated-dilatation (FMDmax%; a measure of NO-dependent endothelial function), and (2); protein energy supplementation in the form of ready-to-use supplementary-food (RUSF) improves nutritional status in children with sickle cell disease. Methods: A random-order, double-blind, cross-over trial with two four-month intervention periods (each followed by four-months wash-out) was conducted in Dar-es-Salaam, Tanzania. 119 children aged 8-12 years, naïve to hydroxyurea, were enrolled from the Muhimbili National Hospital Sickle Cohort. The random order sequence and allocation codes were generated centrally. Two formulations of RUSF (500kcal/day) were tested: ‘basic’ with weekly chloroquine (150/225mg base, depending on weight) (RUSF-b) and ‘vascular’ (RUSF-v) fortified with arginine, citrulline designed to achieve mean intakes of 0.2g/0.1g/kg/day and daily chloroquine (max 3mg base/kg/day). The primary outcomes of the comparison of the 2 RUSF formulations were mean FMDmax%, mean plasma arginine to ornithine ratio and mean plasma arginine to asymmetric-di-methylated-arginine (ADMA) ratio. The primary outcomes of the combined effect of both RUSF interventions were mean height and body mass index for age z-scores with analysis by intention to treat. Trial registration: ISRCTN74331412 Findings: 114/119 children had complete data for all reported endpoints. There was no treatment effect of RUSF-v compared to RUSF-b on the ratio of arginine to ornithine (mean within individual difference -0.09, 95% CI -0.03/0.2, p=0.12), or on FMDmax% (-1.00 95% CI -2.47/0.47, p=0.18) but the arginine:ADMA ratio was significantly increased (-0.56, 95% CI -0.81/-0.31, P<0.001). In planned analyses using random effects models to estimate the effect of each intervention compared to baseline/washout, the arginine:ADMA ratio increased following both RUSF-v or RUSF-b (+86%, p<0.001; +41%, p<0.001). Similarly, FMDmax% was higher after 2 RUSF-v (+0.92, p<0.001) but not after RUSF-b intervention (+0.39, p=0.22). Adjusted for covariates, effect estimates for FMDmax% increased: RUSF-v (+1.19, p<0.001) and RUSF-b (+0.93, p=0.008). Following either intervention (RUSF-b and RUSF-v pooled) compared to baseline/wash-outs, body-mass-index-z-score (+0.091, P=0.001) and height-for-age-z-score (+0.013, P=0.081) increased. There were 71 and 81 adverse events of which 21 and 26 were serious during intervention and washout (P=0.31) in 83 participants, 1 of whom died in the 2nd washout period. Interpretation: RUSF providing 500kcal/day results in small weight gains in children with sickle cell disease. However, RUSF even without arginine and citrulline fortification improves arginine dysregulation and may improve endothelial function. Long-term studies are required to assess if these physiological effects translate to improved clinical outcomes and better growth and development in sickle cell disease

Pre-conceptional and gestational weight trajectories and risk of delivering a small-for-gestational age baby in rural Gambia

Background: Maternal nutritional status is a key determinant of small-for-gestational age (SGA), but there remain some knowledge gaps, particularly regarding the role of energy balance entering pregnancy. Objective: This study investigates how pre-conceptional and gestational weight trajectories (summarized by individual-level traits) are associated with SGA risk in rural Gambia. Design: The sample comprised 670 women in a trial (ISRCTN49285450), with serial weight data (7,310 observations) available before and during pregnancy. Individual trajectories from six months pre-conception to 30 weeks gestation were produced using multilevel modelling. Summary traits were expressed as weight Z-scores (Zwt-3 months pre-conception, Zwt0 months (i.e., conception), Zwt+3 months post-conception, Zwt+7 months post-conception, and conditional measures representing change from the preceding time) and related to SGA risk using Poisson regression with confounder adjustment; linear splines were used to account for non-linearity. Results: Maternal weight at each time had a consistent non-linear relationship with SGA risk. For example, the Zwt-3 months estimate was stronger in women with values ≤ 0.5 Z-scores (relative risk 0.736; 95% confidence interval 0.594, 0.910) than in women with values > 0.5 Z-scores (0.920; 0.682, 1.241). The former group had the highest observed SGA prevalence. Focusing on weight change, only Conditional Zwt+7 months was associated with SGA, and only in women with values > -0.5 Z-scores (0.579; 0.463, 0.724). Conclusions: Protection against delivering an SGA neonate offered by greater pre-conceptional or gestational weight may be most pronounced among more undernourished and vulnerable women. Independently of this, greater second/third trimester weight gain beyond a threshold may be protective

Association of a prenatal lipid-based nutritional supplement with fetal growth in rural Gambia

Prenatal supplementation with protein-energy (PE) and/or multiple-micronutrients (MMN) may improve fetal growth, but trials of lipid-based nutritional supplements (LNS) have reported inconsistent results. We conducted a post-hoc analysis of non-primary outcomes in a trial in Gambia, with the aim to test the associations of LNS with fetal growth and explore how efficacy varies depending on nutritional status. The sample comprised 620 pregnant women in an individually randomized, partially blinded trial with four arms: 1) iron and folic acid (FeFol) tablet (usual care, referent group), 2) MMN tablet, 3) PE LNS, and 4) PE + MMN LNS. Analysis of variance examined unadjusted differences in fetal biometry Z-scores at 20 and 30 weeks and neonatal anthropometry Z-scores, while regression tested for modification of intervention-outcome associations by season and maternal height, BMI, and weight gain. Despite evidence of between-arm differences in some fetal biometry, Z-scores at birth were not greater in the intervention arms than the FeFol arm (e.g., birth weight Z-scores: FeFol -0.71, MMN -0.63, PE -0.64, PE + MMN -0.62; group-wise p = 0.796). In regression analyses, intervention associations with birth weight and head circumference were modified by maternal weight gain between booking and 30 weeks gestation (e.g., PE + MMN associations with birth weight were + 0.462 Z-scores (95% CI 0.097, 0.826) in the highest quartile of weight gain but - 0.099 Z-scores (-0.459, 0.260) in the lowest). In conclusion, we found no strong evidence that a prenatal LNS intervention was associated with better fetal growth in the whole sample