Interventions to reduce post-acute consequences of diarrheal disease in children: a systematic review

Pavlinac, Patricia B.; Brander, Rebecca L.; Atlas, Hannah E.; John-Stewart, Grace C.; Denno, Donna M.; Walson, Judd L.

doi:10.1186/s12889-018-5092-7

BMC Public Health

Table 2 Intervention effects on post-acute (≥7 days after enrollment) mortality, length, weight, and/or diarrhea presence

From: Interventions to reduce post-acute consequences of diarrheal disease in children: a systematic review

Reference	Intervention	Comparator	Relevant Outcomes and Results
Antimicrobial Interventions
Gilman 1980 [8]	Low dose ampicillin (50 mg/kg/day)	Standard dose ampicillin (150 mg/kg/day)	Mortality	Risk Difference (95% CI)	−0.11 (− 0.24, 0.03)ⁱ
Gilman 1980 [8]	Low dose ampicillin (50 mg/kg/day)	Standard dose ampicillin (150 mg/kg/day)	Mortality	Relative Risk (95% CI)	Undefined
Amadi 2002 [42]	5 mL of 20 g/L nitazoxanide, twice daily for 3 days	Placebo	Mortality	Risk Difference (95% CI)	−0.07 (− 0.21, 0.06)
Amadi 2002 [42]	5 mL of 20 g/L nitazoxanide, twice daily for 3 days	Placebo	Mortality	Relative Risk (95% CI)	0.58 (0.21, 1.63)
Dietary Supplements
Alam 2000 [26]	ORS with dietary fiber (Benefiber®)	WHO- ORS only	Difference in weight gain at day 7, g (95% CI)	52 (−18.73, 122.73)
Rabbani 2001 [15]	Rice-based diet with dietary fiber (green banana or pectin supplement), 7 days	Rice-based diet only	Proportions recovered from diarrhea (formed stool) at each day to day 10	Higher in banana and pectin groups than in control groupⁱⁱ
Yalcin 2004 [51]	Glutamine supplement, 0.3 g/kg/day, for 7 days	Placebo	Difference in weight gain at day 30, g (95% CI)ⁱⁱⁱ	130 (12.67, 247.33)
			Difference in weight gain at day 60, g (95% CI)	45 (−80.80, 170.80)
			Difference in weight gain at day 90, g (95% CI)	107 (−57.30, 271.30)
High Protein Diets
Datta 1990 [9]	High protein diet, length unspecified	Standard hospital diet	Difference in weight at day 15, kg (95% CI)	0.30 (−0.18, 0.78)
Datta 1990 [9]	High protein diet, length unspecified	Standard hospital diet	Difference in MUAC at day 15, cm (95% CI)	0.00 (−0.37, 0.37)
Kabir 1992 [10]	High protein diet (15% of total energy from protein), 21 days	Standard diet (7.5% of total energy from protein), 21 days	Difference in change in weight at day 21 from admission, kg (95% CI)	0.47 (0.12, 0.82)
			Difference in change in height at day 21, from admission, cm (95% CI)	0.09 (−0.57, 0.75)
			Difference in change in WAZ at day 21 from admission (95% CI)	0.30 (0.03, 0.57)
			Difference in change in WHZ at day 21 from admission (95% CI)	0.40 (0.05, 0.75)
			Difference in change in MUAC at day 21 from admission, cm (95% CI)	0.44 (0.08, 0.80)
			Difference in change in triceps skinfold thickness at day 21 from admission, cm (95% CI)	0.32 (−0.29, 0.93)
Kabir 1993 [11]	High protein diet, 21 days	Standard protein diet, 21 days	Difference in change in WAZ at day 21, from admission (95% CI)	0.23 (0.07, 0.39)
			Difference in change in WHZ at day 21, from admission (95% CI)	0.25 (0.05, 0.45)
			Difference in change in HAZ at day 21, from admission (95% CI)	0.90 (0.05, 0.13)
Mazumder 1997 [12]	High calorie & high protein milk-cereal diet, 4960 kJ/l (10 days)	Standard diet, 2480 kJ/l (10 days)	Difference in percent change in WAZ at day 10 and 40, fromadmission (95% CI)	Day 10: 3.50 (1.86, 5.14)
				Day 40: 3.11 (0.92, 5.30)
			Difference in percent change in WHZ at day 10 and 40, from admission (95% CI)	Day 10: 3.76 (1.92, 3.60)
				Day 40: 3.34 (0.76, 5.90)
Nurko 1997 [36]	High protein chicken-based diet or high protein soy-based diet (Nursoy formula)^iv	Calorically equivalent standard “elemental diet” (Vivonex)	Difference in weight at end of protocol, g^v (95% CI)	Comparing soy group to control	− 204 (− 1178.40, 770.40)
			Difference in weight at end of protocol, g^v (95% CI)	Comparing chicken group to control	−445 (− 1522.70, 632.70)
			Difference in weight at discharge from enrollment, g (95% CI)	Comparing soy group to control	−92 (− 1189.60, 1005.60)
				Comparing chicken group to control	− 428 (− 1539.80, 683.80)
			Proportion with nutritional recovery^vi(RR [95%])	Comparing soy group to control	1.13 (0.79, 1.61)
			Proportion with nutritional recovery^vi(RR [95%])	Comparing chicken group to control	1.20 (0.86, 1.7)
Kabir 1998 [13]	High protein diet (15% of total energy from protein), 21 days	Standard protein diet (7.5% of total energy from protein), 21 days	Difference in change in weight at 6 mo, from post-intervention weight, kg (95% CI)	0.10 (−0.24, 0.44)
			Difference in change in height at 6 mo, from post-intervention height, cm (95% CI)	1.10 (0.56, 1.64)
			Difference in change in WAZ at 6 mo, from post-intervention WAZ (95% CI)	0.07 (−0.17, 0.31)
			Difference in change in WHZ at 6 mo, from post-intervention WHZ (95% CI)	−0.09 (− 0.35, 0.17)
			Difference in change in HAZ at 6 mo, from post-intervention HAZ (95% CI)	0.28 (0.12, 0.44)
Mazumder 2000 [14]	High calorie & protein milk-cereal formula (4960 kJ/l), 10 days	Control milk-cereal formula (2480 kJ/l), 10 days	Difference in percent change in WAZ at day 10, from admission WAZ (95% CI)	3.50 (2.08, 4.91)
Valentiner-Branth 2001 [43]	Counseling on the importance of breastfeeding and of a nutritious diet, and a high protein millet gruel with a multivitamin tablet (including zinc), until the end of a 7 day period without diarrhea	Counseling on the importance of breastfeeding and of a nutritious diet	Difference in weight gain at end of intervention and day 90, g/wk.^vii(95% CI)	Day 90	61.50 (49.20, 73.80)
				End of intervention	12.50 (7.70, 17.30)
			Difference in change in knee heel length at end of intervention and day 90, mm/y (95% CI)	Day 90	2.70 (−4.60, 10.00)
				End of intervention	7.50 (4.80, 10.20)
			Difference in change in height between groups at day 90, (cm/y)² (95% CI)^viii	0.65 (0.11, 1.19)
Rollins 2007 [44]	Standard nutritional support + extra protein to provide 150 kcal/kg/day and 4.0–5.5 g protein/kg/day	Standard nutritional support: maize porridge + milk formula	Mortality at 26 weeks	Relative risk	1.34 (95% CI: 0.79, 2.27)
			Mortality at 26 weeks	Risk difference	7.4% (−4.7%,20.5%)
			Median change in weight- SDs ^ixat 26 weeks	Greater gain in intervention group (p < 0.001)
			Median change in WAZ at 26 weeks	Greater gain in intervention group (p < 0.05)
			Proportion underweight (WAZ < −2 SDs) at 26 weeks (Prevalence Ratio [95% CI])	0.48 (0.30, 0.77)
			Proportion stunted (LAZ < − 2 SDs) at 26 weeks (Prevalence Ratio[95% CI])	0.87 (0.67, 1.13)
Lactose Free Diets
Bhan 1988 [16]	Legume and cereal-based formula (lactose-free), until recovery or 7 days min	Calorically equivalent milk-based formula, until recovery or 7 days min	Difference in weight gain at day 7, g/kg admission weight/24 h (95% CI)	−3.20 (−6.86, 0.46)
Bhan 1988 [16]			Difference in weight gain at recovery, g/kg admission weight/24 h (95% CI)	−3.80 (−7.15, −0.44)
Bhutta 1991 [50]	Soy milk (lactose-free) for 7 days, followed by khitchri and yogurt for 7 days	Khitchri and yogurt for 14 days	Difference in weight gain at day 7 and 14, g/wk. (95% CI)	Day 7: −400 (− 559.40, − 240.60)
Bhutta 1991 [50]		Khitchri and yogurt for 14 days	Difference in weight gain at day 7 and 14, g/wk. (95% CI)	Day 14: 385.7 (209.60, 561.80)
Lozano 1994 [38]	Corn-based (lactose-free) formula, 21 days	Milk-based formula, 21 days	Difference in weight increment at 6 weeks, kg (95% CI)	−0.02 (− 0.30, 0.26)
Bhatnagar 1996 [17]	Rice-based formula with egg white protein (lactose-free), until discharge	Rice-based formula with milk protein, until discharge	Proportion of patients whose weight on day 7 was lower than at rehydration (Prevalence Ratio [95% CI])	0.97 (0.06, 15.19)
Bhatnagar 1996 [17]		Rice-based formula with milk protein, until discharge	Probability of continuing diarrhea at each day to day 12	No significant difference (p = 0.76)^x
de Mattos 2009 [37]	Amino-acid based diet, isolated soy-based, or hyrolyzed casein-based diet; until discharge	Yogurt-based diet^xi until discharge	Difference in weight gain at discharge among groups at discharge	No difference among groups^xii
de Mattos 2009 [37]		Yogurt-based diet^xi until discharge	Change in WHZ at discharge	Similar improvement in all groups^xiii
Other Dietary Interventions
Eichenberger 1984 [35]	Semi-elemental diet with low osmolarity and high hydrolyzed lactalbumin, at least 21 days	Standard hospital diet	Weight at day 21 compared to weight at beginning of therapy	Better in intervention group^xiv
van der Kam 2016 (Uganda) [45]	RUTF, plus instructions to feed the child an extra meal/day for 14 d; or micronutrient powder plus instructions to feed the child an extra meal/day for 14 d	An instruction to feed the child an extra meal/day for 14 d	Relative Risk of first event of malnutrition (95% CI)	RUTF vs micronutrient group	0.68 (0.37, 1.22)
				RUTF vs control group	0.62 (0.35, 1.10)
				Micronutrient group vs control	0.92 (0.54, 1.54)
van der Kam 2016 (Nigeria) [46]	RUTF, plus instructions to feed the child an extra meal/day for 14 d; or micronutrient powder plus instructions to feed the child an extra meal/day for 14 d	An instruction to feed the child an extra meal/day for 14 d	Relative Risk of first event of malnutrition (95% CI)	RUTF vs micronutrient group	1.12 (0.84, 1.50)
				RUTF vs control group	0.91 (0.69, 1.20)
				Micronutrient group vs control	0.81 (0.61,1.09^xv)
ORS Formulations
Santosham 1983 [39]	High potassium/ high chloride ORS, or standard WHO-ORS, with regular diet	Standard diet for diarrhea management	Difference in weight at day 14, kg (95% CI)	Comparing high potassium/chloride to control	−0.3 (−1.45, 0.85)
			Difference in weight at day 14, kg (95% CI)	Comparing standard ORS to control	−0.50 (− 1.86, 0.76)
			Difference in percent weight gain at day 14 (95% CI)	Comparing high potassium/chloride to control	2.00 (1.57, 2.42)
			Difference in percent weight gain at day 14 (95% CI)	Comparing standard ORS to control	2.30 (1.82, 2.77)
Ribeiro 1991 [40]	Alanine-based ORS	Standard WHO-ORS	Difference in weight gain at day 7, g (95% CI)	18 (−94.37, 130.38)
Faruque 1997 [21]	Glucose-based ORS	Rice powder-based ORS, equivalent in electrolyte content	Proportion with diarrhea at day 14 (RR [95% CI])	0.80 (0.21, 2.95)
Faruque 1997 [21]	Glucose-based ORS	Rice powder-based ORS, equivalent in electrolyte content	Difference in weight gain at day 16, g	Similar between groups^xvi
Alam 2009 [55]	Glucose-based ORS, or glucose-based ORS with amylase-resistant starch (ARS)	Rice-based ORS	Difference in time to attain 80% of median WLZ, days (95% CI)	Difference between glucose and rice ORS	− 0.06 (− 1.19, 1.07)
				Difference between glucose with amylase resistant starch and rice ORS	− 0.08 (− 1.20, 1.04)
			Proportion with diarrhea at or after day 7 (RR [95% CI])	Risk in glucose ORS group compared to rice ORS group (RR, [95% CI])	1.00 (0.15, 6.86)
			Proportion with diarrhea at or after day 7 (RR [95% CI])	Risk in glucose with ARS group compared to rice ORS groups (RR, [95% CI])	0.49 (0.05, 5.27)
Probiotics
Boudraa 2001 [47]	Milk-based formula fermented with L. bulgaricus S. andthermophilus	Milk-based formula only	Difference in weight gain at day 7, g (95% CI)	43 (− 109.18, 195.18)
Boudraa 2001 [47]		Milk-based formula only	Difference in weight gain at day 7, g/kg (95% CI)	4.4 (−5.50, 14.30)
Villarruel 2007 [41]	S. boulardii capsules	Placebo	Proportion with diarrhea on day 7 (Prevalence Ratio [95% CI])	0.39 (0.20, 0.74)
Villarruel 2007 [41]	S. boulardii capsules	Placebo	Proportion with diarrhea after day 7 (Prevalence Ratio [95% CI])	0.25 (0.07, 0.82)
Misra 2009 [19]	L. rhamnosus GG 10⁹ CFU	Placebo	Difference in change in WHZ at 6 weeks	No difference between groups (p = 0.06)
Sindhu 2014 [20]	L. rhamnosus GG 10¹⁰ CFU	Placebo	Proportion with diarrhea at 4 weeks follow up (Prevalence Ratio [95% CI])	0.65 (0.40, 1.07)
			Proportion with severe diarrhea during follow-up (Prevalence Ratio [95% CI])	1.15 (0.65, 2.05)
			Proportion with diarrhea requiring hospitalization during follow-up (Prevalence Ratio [95% CI])	1.03 (0.54, 1.98)
			Proportion stunted (HAZ < −2 SD) at week 4 (Prevalence Ratio [95% CI])	1.77 (1.00, 3.13)
			Proportion wasted (WHZ < − 2 SD) at week 4 (Prevalence Ratio [95% CI])	0.53 (0.16, 1.71)
			Proportion underweight (WAZ < − 2 SD) at week 4 (Prevalence Ratio [95% CI])	1.66 (0.83, 3.30)
Dinleyici 2014 [52]	ORS with L. reuteri 17,938 10⁸ CFU	ORS only	Proportion with diarrhea at day 12 (Prevalence Difference [95% CI])^xvii	0.17 (0.08, 0.26)
Therapeutic Micronutrients (Vitamin A and Zinc)
Faruque 1999 [34]	Vitamin A (4500 μg retinol equivalent daily for 15 days), zinc acetate (14.2 mg daily for 15 days),^xviiior both^xix	Placebo	Proportion with diarrhea on day 7 (Prevalence Ratio [95% CI])	Zinc-supplemented vs. non-supplemented	0.64 (0.43, 0.96)
				Vitamin A –supplemented vs. non-supplemented	0.78 (0.52, 1.49)
			Proportion with diarrhea on day 16 (Prevalence Ratio [95% CI])	Zinc-supplemented vs. non-supplemented	0.67 (0.24, 1.85)
				Vitamin A –supplemented group vs. non-supplemented	0.67 (0.24, 1.85)
Khatun 2001 [22]	Multivitamin syrup with 20 mg elemental zinc (twice daily for 7 days), or multivitamin syrup with Vitamin A^xx or both	Multivitamin syrup only	Difference in change in weight at day 7 compared to day 1, g^xxi	Zinc group vs control	0.11 kg (p = 0.045)
				Vitamin A group vs control	0.07 kg (p = 0.21)
				Zinc+Vitamin A vs. control	0.06 kg (p = 0.074)
			Proportion with diarrhea at day 7, (Prevalence Ratio [95% CI])	Zinc group vs. control	0.23 (0.08, 0.71)
				Vitamin A group vs. control	0.92 (0.54, 1.59)
				Zinc+Vitamin A vs. control	0.62 (0.31, 1.21)
Therapeutic Micronutrients (Zinc alone)
Sazawal 1995 [23]	Multivitamin syrup with 20 mg elemental zinc^xxii	Multivitamin syrup only	Proportion of episodes lasting longer than 7 days (Prevalence Ratio [95% CI])	0.87 (0.65, 1.16)
Sazawal 1995 [23]	Multivitamin syrup with 20 mg elemental zinc^xxii	Multivitamin syrup only	Proportion of diarrhea episodes taken to a physician during follow up (Prevalence Ratio [95% CI])	0.78 (0.57, 1.07)
Roy 1998 [24]	Multivitamin syrup with 20 mg elemental zinc, 14 days	Multivitamin syrup only	Mortality	Relative Risk (95% CI)	0.18 (0.02, 1.49)
			Mortality	Risk Difference (95% CI)	−0.05 (− 0.11, 0.01)
			Change in weight at discharge, g^xxiii	Mean body weight in intervention group was maintained while body weight decreased in control group
			Proportion with diarrhea after day 15 (RR [95% CI])^xxiv	0.99 (0.53, 1.88)
Bhutta 1999 [49]	Multivitamin with 3 mg of elemental zinc per kg of body weight, 28 days	Multivitamin only	Difference in weight at day 7 and 14, kg^xxv (95% CI)	Day 7: −0.57 (−1.14, − 0.002)
			Difference in weight at day 7 and 14, kg^xxv (95% CI)	Day 14: −0.46 (− 1.06, 0.14)
			Difference in overall weight increment at day 14, g/kg/day	1.60 (− 1.48, 4.68)
			Difference in MUAC at day 7 and 14, cm (95% CI)	Day 7: −0.30 (− 0.98, 0.38)
			Difference in MUAC at day 7 and 14, cm (95% CI)	Day 14: −0.40 (−1.08, 0.28)
			Difference in overall MUAC increment, cm (95% CI)	0.00 (−0.13, 0.13)
Roy 1999 [25]	Multivitamin with 20 mg of elemental zinc, 14 days	Multivitamin only	Difference in weight gain at each week of 8 week follow up, g (95% CI)	Week 1: 30 (−204.70, 264.73)
				Week 2: −4 (− 202.60, 194.60)
				Week 3: −45 (−303.70, 213.70)
				Week 4: −60 (− 347.70, 227.70)
				Week 5: −79 (−361.40, 203.40)
				Week 6: −57 (− 354.38, 240.40)
				Week 7: −53 (− 352.70, 246.70)
				Week 8: −19.00 (− 394.15, 356.15)
			Difference in gain in length at week 8, mm	4.40 mm, 30% greater gain (p < 0.03)^xxvi
Baqui 2002 [27]	ORS with 20 mg zinc per day, 14 days	ORS only	Incidence of diarrhea during 2 year follow up	RR (95% CI)	0.85 (0.76, 0.96)
			Incidence of diarrhea during 2 year follow up	RD (95% CI)^xxvii	2.9 (0.80, 5.10)^xxviii
			Mortality during 2 year follow up	RR (95% CI)	0.49 (0.25, 0.94)
			Mortality during 2 year follow up	RD (95% CI)	2.2 (0.60, 3.70)^xxix
Walker 2007 [53]	ORS with 10 mg zinc, 14 days	ORS with placebo	Difference in weight at week 4 and 8, kg (95% CI)	Week 4: 0.06 (−0.08, 0.20)
			Difference in weight at week 4 and 8, kg (95% CI)	Week 8: 0.06 (− 0.08, 0.20)
			Difference in length at week 4 and 8, cm (95% CI)	Week 4: −0.09 (− 0.61, 0.43)
			Difference in length at week 4 and 8, cm (95% CI)	Week 8: −0.12 (− 0.63, 0.39)
			Proportion of infants with ≥1 episode of any diarrhea (RR [95% CI])^xxx	1.01 (0.92, 1.12)
			Proportion of infants with ≥2 episode of any diarrhea (RR [95% CI])	0.79 (0.67, 0.95)^xxxi
			Proportion of infants with ≥1 episode of dysentery (any day with blood in the stool) (RR [95% CI])	2.10 (0.96, 4.61)
			Incidence of diarrhea (episodes/month)	Intervention group (mean ± SD)	0.62 ± 0.68
			Incidence of diarrhea (episodes/month)	Control group (mean ± SD)	0.61 ± 0.70
			Prevalence of diarrhea (days/mo)	Intervention group (mean ± SD)	2.68 ± 4.11
			Prevalence of diarrhea (days/mo)	Control group (mean ± SD)	2.20 ± 3.19
			Mortality	RR (95% CI)	0.99 (0.01, 77.9)
			Mortality	RD (95% CI)^xxxii	−0.18 (−66.42, 66.06)
Roy 2007 [28]	Multivitamin with 10 mg zinc per 5 ml, 14 days	Multivitamin only	Difference in mean number of diarrhea episodes during 6 mo follow up (95% CI)^xxxiii	− 0.33 (− 0.39, − 0.27)
			Percent gain in length at 12 weeks, mm^xxxiv	Comparable between groups when all patient were compared (p = 0.6)
			Percent gain in length at 12 weeks, mm^xxxiv	24% greater among underweight (WAZ ≤ 70% NCHS median) (p < 0.03)
			Mortality	RR (95% CI)	0.84 (0.29,2.37)
			Mortality	RD (95% CI)	−0.01 (−0.10, 0.07)
Roy 2008 [29]	Multivitamin with 20 mg zinc, 14 days	Multivitamin only	Geometric mean diarrhea incidence	Statistically significantly higher in control group (p = 0.03)
Fajolu 2008 [48]	20 mg zinc for patients > 1 y; 10 mg zinc for patients < 1 y	Placebo	Number of subsequent diarrhea episodes during 2 month follow up	Difference not significant (p = 0.53)
Fajolu 2008 [48]		Placebo	Weight gain at 2 months, g	Higher in intervention group (p < 0.001)
Larson 2010 [30]	10 days therapeutic zinc (20 mg) followed by 3 mo supplementary zinc (10 mg)	10 days therapeutic zinc (20 mg) followed by 3 mo supplementary zinc placebo	Diarrhea episodes during follow up,^xxxv months 1–3 Risk Difference, [95% CI])	−1.02 (0.26, 1.79)
			Diarrhea episodes during follow up, months 4–6 (Risk Difference, [95% CI])	−0.37 (− 0.35, 1.07)
			Diarrhea episodes during follow up, months 7–9 (Risk Difference, [95% CI])	−0.18 (− 0.41, 0.75)
			Diarrhea episodes during entire 9 month follow up (Risk Difference, [95% CI])	−0.54 (0.07, 1.01)
Alam 2011 [31]	Short course zinc – 20 mg zinc, 5 days	Standard course zinc – 20 mg zinc, 10 days	Difference in mean number of diarrhea episodes during 3 month follow up (95% CI)	0.06 (− 0.07, 0.19)
			Difference in mean number of days of diarrhea during 3 month follow up (95% CI)	0.2 (−0.35, 0.75)
			Proportion of children with at least 1 episode of diarrhea during 3 month follow up (RR [95% CI])	1.03 (0.95, 1.14)
			Proportion of children with prolonged diarrhea (≥ 7 days) (Prevalence Ratio [95% CI])^xxxvi	0.63 (0.50, 0.79)
			Proportion of children with persistent diarrhea (≥ 14 days) (Prevalence Ratio [95% CI])	0.63 (0.48, 0.81)
			Day of onset of first subsequent diarrhea episode during follow up	No difference between groups^xxxvii
Patel 2013 [32]	Zinc (2 mg/kg/day) or zinc + copper (Zn 2 mg/kg/day + Cu 0.2 mg/kg/day), 14 days	Placebo	Proportion with at least 1 diarrhea episode during 3 month follow up (Prevalence Ratio [95% CI])	Zinc group vs placebo	1.01 (0.76, 1.33)
				Zinc + Copper group vs placebo	0.96 (0.72, 1.27)
			Proportion with at least 2 episodes of diarrhea during 3 month follow up^xxxviii (Prevalence Ratio [95% CI])	Zinc group vs placebo	2.25 (1.10, 4.63)
				Zinc group vs Zinc + Copper group	1.12 (0.64, 1.97)
			Proportion with at least 1 dysentery episode during 3 month follow up (Prevalence Ratio[95% CI])	Zinc group vs placebo	1.31 (0.30, 5.77)
				Zinc group vs Zinc + Copper group	1.37 (0.31, 6.04)
			Difference in mean number of subsequent diarrhea episodes per child during 3 month follow up (95% CI)	Zinc group vs placebo	0.08 (−0.05, 0.21)
				Zinc + copper group vs placebo	0.05 (−0.07, 0.17)
			Difference in change in WAZ at month 3 (95% CI)	Zinc group vs placebo	−0.1 (− 0.12, 0.10)
			Difference in change in WAZ at month 3 (95% CI)	Zinc + copper group vs placebo	0.06 (−0.04, 0.16)
			Difference in change in WHZ at month 3 (95% CI)	Zinc group vs placebo	−0.01 (− 0.18, 0.16)
			Difference in change in WHZ at month 3 (95% CI)	Zinc + copper group vs placebo	0.09 (−0.07, 0.25)
			Difference in change in HAZ at month 3 (95% CI)	Zinc group vs placebo	0.02 (−0.09, 0.13)
			Difference in change in HAZ at month 3 (95% CI)	Zinc + copper group vs placebo	0.03 (−0.08, 0.14)
Negi 2015 [33]	Zinc (20 mg/day) for 14 days	Placebo	Risk of having at least 1 episode of diarrhea during 3 mo follow up (Relative risk [95%])	Among all subjects	0.65 (0.37, 1.23)
Negi 2015 [33]	Zinc (20 mg/day) for 14 days	Placebo		Among zinc-deficient subjects (n = 60)	0.65 (0.31, 1.38)

ⁱEstimate may be interpreted as 11 fewer deaths per 100 children in the intervention group compared to the control group
ⁱⁱQuantitative estimates not presented and reported p-values not specific to time-points of interest
ⁱⁱⁱData presented were assumed to be mean ± SD
^ivDuration of diets was variable. Diets were started at low concentrations and were advanced every 48 hours if no sign of intolerance. If there were signs of intolerance, diets were maintained or decreased as necessary. When full concentrations were reached, the diet was given for an additional 7 days.
^vAppropriate data for calculation of weight gain or difference in weight gain not presented
^viDefined as when diarrhea had ceased and patient had consistent weight gain for at least 48 hours
^viiAll outcome measurements were compared against measurements at entry, when the child had had diarrhea for 14 days
^viiiUnits were assumed to be cm/y due to description of results in the manuscript (rather than (cm/y)2 as presented in the study’s Four)
^ixDefined as age- and sex-specific weight standard deviation scores, from the National Center for Health Statistics median value
^xNo quantitative estimates given
^xiAll diets were equivalent in caloric and protein content
^xiiNo estimate or statistical significance given
^xiiiNo estimate or statistical significance given
^xivNo estimates or statistical significance is given
^xvConfidence interval states in manuscript is (0.605, 0.090) which does not contain the relative risk estimate of 0.812 therefore have assumed the 0.090 was a typo and replaced with 1.090.
^xviNo estimates or statistical significance given
^xviiRR was undefined due to a “0” cell
^xviiiThe authors changed the dose after 417 children were enrolled (dosages listed, analyzed as "standard strata" of subjects), and the remaining 273 children received a higher dose of zinc (analyzed as "high dose strata"): Vitamin A (4500 ug retinol equivalent daily for 15 days) and/or zinc acetate (40 mg daily for 15 days)
^xixResults from comparison of zinc+vitamin A vs. placebo not reported (reported on zinc effect by combing the zinc alone and zinc+vitamin A group and reported on vitamin A effect by combining vitamin A alone with the zinc+vitamin A group).
^xxVitamin A dosage was 100000 IU for children < 1 yo, and 200000 for children > 1 yo
^xxiNo SDs or CIs given for differences. P-value for the difference between zinc group and control is 0.045; for the difference between vitamin A group and control is 0.207; and for the difference between zinc + vitamin A group is 0.074.
^xxiiDuration of intervention is unclear
^xxiiiData were presented but were not interpretable due to an ambiguous or incorrect title
^xxivAssessed by proportion of patients with delayed recovery, with recovery defined as the passage of formed stool followed by 2 days without diarrhea
^xxvFor this and all outcomes, data were not labeled. Data presented were assumed to be mean and SD based on labeled data on another figure in the paper
^xxviNo SDs or CIs given. P< 0.05.
^xxviiDifference in mean diarrhea incidence rates. Estimate may be interpreted as 2.9 more episodes per 100 child-years of observation were experienced in the control group compared to the intervention group
^xxviiiCalculated values of lower and upper limits of 95% CI differed from what was represented in original publication
^xxixDifference in mean mortality rates. Estimate may be interpreted as 2.2 more deaths per 1000 child years of observation experienced by the control group compared to the intervention group
^xxxAll data presented are unadjusted. The authors’ results are discrepant from this table’s results, as authors adjust for original diarrhea episode lasting > 7 days, exclusive breastfeeding upon enrollment, and WLZ at beginning of follow up
^xxxiCalculated values of lower and upper limits of 95% CI use data presented on unadjusted proportions and differed from what was represented in original publication
^xxxiiEstimate may be interpreted as 0.18 deaths fewer in intervention group per 100,000 child-weeks of observation compared to control group
^xxxiiiData presented was assumed to be mean ± SD
^xxxivQuantitative estimates not presented
^xxxvRisk differences may be interpreted as excess number of acute diarrhea episodes per child-year attributed to lack of zinc supplementation
^xxxviThe authors reported "The proportion of prolonged (>=7 d) and persistent diarrhea episodes (>=14 d) did not vary between the 5-d (19 vs. 16%; P 0.08) and 10-d (12 vs. 10%; P = 0.14) groups" which suggests the p-values correspond to the comparison of persistent and prolonged among children treated with 5-days and among children treated with 10-days. We have instead assumed the appropriate comparisons are proportion of prolonged (19% vs. 12%, p-value=0.0001) and persistent (16% vs. 10%, p-value=0.0004) which would result in statistically significant differences (unlike what was reported).
^xxxviiNo estimates or statistical significance given
^xxxviiiEstimates calculated for relative risk of at least 1, 2, or dysenteric diarrhea episodes are discrepant from published results

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