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Table 1 Randomized controlled trials included in the systematic review

From: Review of the safety and efficacy of vitamin A supplementation in the treatment of children with severe acute malnutrition

Quality Assessment Summary of Findings GRADE Rating
  Treatment Groups (sample size) Effect  
Ref Design Indirectness Inconsistency Imprecision Study Limitations (risk of bias) Intervention Cases Control Comparison Relative Risk (95% CI) Absolute  
Sattar, 2012 [19] RCT, double-blind Pop: children 6-59 mo with SAM and diarrhea and/or ALRI SAM def: WHZ < -3 or bipedal edema No serious imprecision No differences in baseline characteristics High-dose and daily low-dose VA (n = 130) Daily low-dose VA (n = 130)    MOD-HIGH
  Aim: test the efficacy and safety of WHO protocol for VAS in treatment of SAM among children 6-59 mo VA dose: day 1: high-dose group, 200,000 IU (> 12 mo) or 100,000 IU (< 12 mo); low-dose group, placebo; day 2-15, 5000 IU daily for 15 days (both groups)    External validity: all children had diarrhea and low mean baseline serum retinol 13.15 ± 9.28 ug/dl Resolution by 48 hr of acute diarrhea, dysentery, and ALRI    NS  
   Secondary outcome examined and found no increased risk of adverse events VA toxicity and morbidities.     Duration of acute diarrhea, invasive diarrhea, cough, fever, rales, edema, and skin changes    NS  
       Changes in nutritional status, weight, length, MUAC, head circumference    NS  
       Incidence of nosocomial diarrhea   aOR 1.25 (0.67, 2.34) NS  
       and ALRI infections   aOR 0.63 (0.36-1.09) NS  
Donnen, 2007 [33] RCT, double-blind Pop: 44-48% WHZ < -2; 30-37% MUAC < 125 mm SAM def: WHZ < -2; MUAC < 125 mm No serious imprecision Age confounding: high-dose group younger Daily low-dose VA (n = 610) Single high-dose VA and placebo daily (n = 604)    MOD
  Aim: assess effect of single high-dose vs. daily low-dose VA supplements on hospitalized malnourished Senegalese children’s (0 - 14 yr) morbidity VA dose: high-dose: single 200,000 IU (> 12 mo) or 100,000 IU (< 12 mo); low-dose: 5000 IU daily until discharge    Baseline nutrition: MUAC lower in high-dose group Incidence of respiratory disease   HR 0.26 (0.07 - 0.92) p < 0.05  
   Sub-group: children with edema mortality lower in low-dose (AOR 0.21, 0.05-0.99)     Duration: respiratory disease   HR of cure 1.41 (1.05 - 1.89) p = 0.019  
       Incidence & duration of diarrhea   HR 1.02 (0.68 - 1.52) NS  
Mahalan-abis, 2004 [32] RCT, factorial Pop: children with marasmus or edema excluded No serious inconsistency Small sample Baseline nutrition: serum retinol was 0.387 μmol/L higher (P = 0.001) in VA treated group zinc + VA (n = 38) zinc (n = 39) VA (n = 38) Placebo (n = 38)    LOW-MOD
  Aim: evaluate effect of zinc and VA on clinical recovery of Indian children (2 - 24 mo) with severe acute lower respiratory infections VA dose: 10,000 μg RE 2x/d for 4d; zinc 10 mg 2x/d for 5d     Recovery rates from very ill status zinc (boys)   2.63 (1.35 - 5.10)   
       Recovery rate from fever zinc   3.12 (1.47 - 6.6) NS  
       Recovery rates for VA     
       Adverse event risk increased risk of diarrhea in VA group    p = 0.028  
       increased risk of any adverse events in VA group   RR 3.8 (1.32-10.93)   
Fawzi, 2000 [31] RCT VA dose: given on days 0 and 2, and again at 4 and 8 mo; dose after discharge, 200,000 IU (> 1 yr) or 100,000 IU (infants) SAM def: NCHS references; WHZ < -2 Statistics: few variables studied in multivariate analyses Potential seasonal bias: enrollment during 1993-1997 VA (n = 289) Placebo (n = 285)    LOW-MOD
  Aim: determine effect of VAS on risk of diarrhea and acute respiratory infections in hospitalized Tanzanian children (6 - 60 mo) Sub-group: adverse event risk normally nourished children: VA increased risk of acute diarrhea; wasted children protective against diarrhea Diarrhea def: mother’s perception; 3+ days elapsed between episode; persistent diarrhea defined as lasting 14+ days    Severe watery diarrhea   AOR 0.56 (0.32 - 0.99)   
       Hospitalization    NS  
       Adverse event risk cough and rapid respiratory rate   AOR 1.67 (1.17 - 2.36)   
Faruque, 1999 [29] RCT, factorial Pop: 34-35% WAZ < -2; acute diarrhea ≤ 3 days Diarrhea def: mother’s perception with picture No serious imprecision No differences observed by stunting at baseline Group A: VA 15d (n = 170) Group B: zinc (n = 172) Group C: VA + zinc (n = 171) Placebo (n = 171)    MOD
  Aim: to assess efficacy of zinc or VAS in Bangladeshi children (6 mo - 2 yr) with acute diarrhea VA dose: 4500 μg RE for 15d Children observed in hospital 24 h and followed at home 15d    Zinc groups Diarrhea duration reduced by 13 %    p = 0.03  
   Zinc dose: 14.2 - 40 mg zinc for 15d     Prolonged diarrhea reduced by 43%    p = 0.017  
       VA groups Prolonged diarrhea    NS  
       Overall diarrhea duration    NS  
Donnen, AJCN 1998 [26] RCT, double-blind Pop: 26-28% WHZ < -2; 20-29% MUAC < 125 mm SAM def: WHZ < -2, MUAC < 125 mm Small effect size Baseline CRP elevated in high dose group Daily low-dose VA (n = 298) High-dose VA (n = 300)    MOD
  Aim: assess effect of single high-dose vs. daily low-dose VA supplements on hospitalized pre-school aged children in Democratic Republic of Congo VA dose: high-dose: single 200,000 IU (> 12 mo) or 100,000 IU (< 12 mo) at admission; low-dose: 5000 IU daily until discharge     Sub-group: SAM (low dose VA vs. placebo) Incidence of severe diarrhea in SAM Placebo (n = 302) RR 0.21(0.07 - 0.62)   
   Adverse event risk Sub-group: children with no edema increased risk of diarrhea with high-dose VA compared to placebo (AOR 2.42, 1.15 - 5.11)     Duration of: severe diarrhea    NS  
       Acute lower respiratory infection    NS  
       Fever    NS  
Donnen, J of Nutr. 1998 [20] RCT VA dose: 60 mg oily solution of retinyl palmitate (30 mg for children < 12 mo) SAM def: WHZ < -2, MUAC < 125 mm; NCHS standards; discharged children   Failure to blind: no placebo used Group 1: VA baseline and at 6 mo (n = 118) Group 3: placebo (n = 117)    MOD
  Aim: assess effect of single high-dose VA supplements and regular antiparasitic therapy on growth of moderately malnourished children (0 - 72 mo) from eastern Zaire Pop: 4-9% WHZ < -2    Unclear why changes in Z-scores not compared Group 2: Mebendazole every 3 mo for 1 yr (n = 123)     
   Sub-group: VA boys gain more weight and height     Group 1: Annual weight gain 2.09 kg Group 3: Annual weight gain 1.18 kg   p = 0.029  
       MUAC gain 2.24 cm MUAC gain 0.95 cm   p = 0.012  
       Group 2 vs. 3 Growth    NS  
       Adverse risk: VA girls gained less height than controls. De-wormed boys and girls gained less weight than control boys and girls     
Stephen-sen, 1998 [28] RCT, double-blinded VA dose: children ≤ 1 yr: 100,000 IU on day 1 and 50,000 IU on day 2; children > 1 yr: 200,000 IU on day 1 and 100,000 IU on day 2 SAM def: US reference population Small sample Potential confounding: WHZ lower in VA group at baseline VA (n = 48) Placebo (n = 49)    LOW-MOD
  Aim: test hypothesis that high-dose VA supplements will enhance recovery of Peruvian children (3 mo - 10 yrs) hospitalized with pneumonia    Statistics: univariate comparisons reported primarily without adjusting for covariates Selective reporting Adverse events: ↓ blood oxygen saturation Adverse events: ↑blood oxygen saturation   p < 0.05  
       Prevalence of retractions 37% Prevalence of retractions 15%    
       Auscultatory evidence of consolidation 28% Auscultatory evidence of consolidation 17%    
       supplemental oxygen need 21% supplemental oxygen need 8%    
       Duration of hospitalization    NS  
       Chest x-rays    NS  
Nacul, 1997 [24] RCT, double-blind placebo VA dose: 200,000 IU (< 12 mo); 400 000 IU (> 12 mo) Pop: some hospitalized while others outpatient No serious imprecision Low serum retinol at baseline in both groups likely due to infection; serum retinol in VA group higher on day 11 VA (n = 239) Placebo (n = 233)    MOD-HIGH
  Aim: evaluate impact of VAS on clinical recovery and severity of pneumonia among Brazilian children (6 - 59 mo) Subgroup analysis showed beneficial effect on those most severely affected with VA deficiency     Fever by day 3: 16 % Fever by day 3: 26.4 %   p = 0.008  
      Transitory bulging fontanelle (4%) Failure to respond to first line antibiotic   rate ratio 0.71 (0.50 - 1.01) p = 0.054  
      No effect attributable to etiological agent Duration of pneumonia    NS  
       Incidence of adverse outcomes    NS  
Julien, 1999 [30] RCT, double-blind placebo VA dose: 200,000 IU (>12 mo); 100,000 IU (< 12 mo)   Small sample size to detect morbidity differences VA deficiency high at baseline in both groups: 68.9% had serum retinol <10 μg/dL and 93.2% serum retinol < 20 μg/dL VA (n = 71) Placebo (n = 93)    LOW-MOD
  Aim: test the potential of VAS at admission to speed up recovery during hospitalization for lower respiratory infection and decrease morbidities at 6 wk in Mozambican children (6 - 72 mo) Pop: kwashiorkor and marasmus excluded     Rate of clinical discharge on day 5: 88.4% Rate of clinical discharge on day 5: 73.9% RR 1.9 (1.01 - 3.05) NS  
      No adjustment with covariates 6 wk Health care use Illness (fever, cough, or diarrhea)    NS  
Hossain, 1998 [27] RCT, double-blind Pop: excluded if WAZ ≤75% NCHS Diarrhea def: liquid stools that can be poured or contain blood or mucus; clinical cure: ≤3 formed stools without visible blood or mucus Small sample size Baseline VA status not determined, but population prevalence high VA (n = 42) Control (n = 41)    LOW-MOD
  Aim: evaluate efficacy of single oral dose VA in treating shigellosis among Bangladeshi children (1 - 7 yr)     No adjustment with covariates Clinical cure 19/24 (45%) Clinical cure 8/14 (20%) risk ratio 0.68 (0.50 - 0.93) p = 0.02  
        Bacteriological cure 16/42 (38%)    
   Bacteriological cure 16/41 (39%) risk ratio 0.98 (0.70 - 1.39) NS       
Si, 1997 [25] RCT, double-blind Pop: SAM excluded; 45% moderately underweight Nutrition def: moderate malnutrition defined as WAZ 60-80% of NCHS median No confidence intervals provided Potential selection bias: trend for greater pneumonia severity in VA group (p = 0.06) VA (n = 280) Placebo (n = 312)   NS LOW-MOD
  Aim: evaluate effect of high dose VA supplement on morbidity in hospitalized Vietnamese children (1 - 59 mo) with pneumonia VA dose: 200,000 in peanut oil (< 1 yr); 400,000 IU in peanut oil (1 - 4 yr)    No baseline VA status Mean time to normal: fever respiratory rate    NS  
   Sub-group analysis: moderately malnourished girls showed shorter duration of hospitalization    No adjustment for covariates Duration of hospitalization    NS  
Dibley, 1995 [23] RCT, double-blind Pop: 3.4% wasted; 37% stunted Morbidity def: 3+ loose stools per day; time between episodes 2+ diarrhea-free days Small effect size for acute respiratory infection; large CI for acute lower respiratory infection Baseline difference in immunization status: ever vaccinated for polio and measles higher in VA group VA (n = 396) Placebo (n = 386)    MOD-HIGH
  Aim: test efficacy of high-dose VA supplement on acute respiratory and diarrheal illnesses in Indonesian children (6 - 47 mo) VA dose: 103,000 IU (< 1 yr); 206,000 IU (≥ 1 yr) Acute respiratory episode with 2+ adjoining days for cough; time between episodes of 3+ symptom-free days    Adverse event risks Acute respiratory infection   rate ratio 1.08 (1.01 - 1.19)   
   Adverse event risk: Subgroup analysis showed VA increased diarrhea incidence in children < 30 mo     Acute lower respiratory infection   rate ratio 1.39 (1.00 - 1.93)   
       Diarrhea    NS  
Coutsou-dis, 1991 [22] RCT, double blind VA dose: 54.5 mg (< 12 mo); 109 mg (>12 mo) Nut def: WAZ by NCHS Small sample size Losses to follow-up were 20% at 6 weeks and 40% at 6 months; no characteristics of this group provided VA (n = 24) Placebo (n = 24)    MOD
  Aim: test efficacy of VAS on measles morbidity in South African children (4 - 24 mo)   Morbidity def: diarrhea: 3+ loose or watery stools per day; pneumonia: presence of tachypnea with retractions, crackles, wheezes Statistics: β set to 0.5 only to detect 30% increase in absolute recovery No adjustment for covariates; only univariate analyses IMS score 0.24 ± 0.15 IMS score 1.37 ± 0.40   p = 0.037  
    Integrated morbidity score (IMS) used    Weight gain at 6 wk 1.29 ± 0.17 kg Weight gain at 6 wk 0.90 ± 0.14 kg   P = 0.04  
       Pneumonia recovery 3.8 ± 0.40 d Pneumonia recovery 5.7 ± 0.79 d   P < 0.05  
Hussey, 1990 [21] RCT, double-blind Pop: 70/189 (37%) with WHZ < 5th% Nutrition def: percentiles of NCHS standards Rare events: mortality; pneumonia / diarrhea duration ≥10 days Differences in baseline characteristics except rash duration and lower levels of total protein and albumin in placebo VA (n = 92) Placebo (n = 97)    MOD-HIGH
  Aim: test efficacy of high dose VAS on measles complications among hospitalized South African children VA dose: 400,000 IU at admission    High prevalence of “hyporetinemia” (< 7.0 μmol /L) 76% Pneumonia recovery 6.3 d Pneumonia recovery 12.4 d   P < 0.001  
      No adjustment for covariates Diarrhea recovery 5.6 d Diarrhea recovery 8.5 d   P < 0.001  
       Croup 13 cases Croup 27 cases 0.51 (0.28 - 0.92) P = 0.01  
       Days in hospital 10.6 d Days in hospital 14.8 d 0.21 (0.05 - 0.94)   
       Mortality 2 deaths Mortality 10 deaths    
       Risk of death due to major complication   RR 0.51 (0.35, 0.74)   
  1. The table presents the included RCT studies in the review by date of publication, from most recent to oldest. For each study, the design, aim, quality assessment by GRADE criteria, findings, and GRADE rating are provided.