Jul 22, 2015 - diseases in children, the effects of daily multivitamin (MV) and/or ... Keywords: multivitamins, zinc, child morbidity, diarrhea, respiratory infection.
The Journal of Nutrition Community and International Nutrition
Daily Zinc but Not Multivitamin Supplementation Reduces Diarrhea and Upper Respiratory Infections in Tanzanian Infants: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial1,2 Christine M McDonald,3 Karim P Manji,4 Rodrick Kisenge,4 Said Aboud,5 Donna Spiegelman,6,7 Wafaie W Fawzi,6,8,9 and Christopher P Duggan3,8,9* 3 Division of Gastroenterology, Hepatology and Nutrition, Boston ChildrenÕs Hospital, Boston, MA; Departments of 4Pediatrics and Child Health and 5Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; and Departments of 6Epidemiology, 7Biostatistics, 8Nutrition, and 9Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA
Abstract Background: Although various micronutrient regimens have been shown to prevent and treat common infectious diseases in children, the effects of daily multivitamin (MV) and/or zinc supplementation have not been widely evaluated in young African infants. Objective: The objective was to determine whether daily supplementation of HIV-unexposed Tanzanian infants with MVs or zinc reduces the risk of infectious morbidity compared with placebo. Methods: In a 2 3 2 factorial, double-blind, randomized controlled trial, 2400 infants who were 6 wk of age and born to HIV-negative mothers in a low-malaria setting were randomly assigned to receive daily oral supplementation of MVs (vitamin B complex and vitamins C and E), zinc, zinc + MVs, or placebo for 18 mo. Morbidity was assessed by study nurses at monthly visits and by physicians every 3 mo and/or when the child was acutely ill. Results: No significant differences were found in the percentage of nurse visits during which diarrhea, cough, or any other symptom were reported throughout the previous month when receiving either zinc or MVs. However, physician diagnoses of all types of diarrhea (RR = 0.88; 95% CI: 0.81, 0.96; P = 0.003), dysentery (RR = 0.84; 95% CI: 0.74, 0.95; P = 0.006), and acute upper respiratory infection (RR = 0.92; 95% CI: 0.88, 0.97; P = 0.0005) were significantly lower for infants supplemented with zinc than for those who did not receive zinc. Among the 2360 infants for whom vital status was obtained, there was a nonsignificant increase in all-cause mortality among infants who received zinc (HR = 1.80; 95% CI: 0.98, 3.31; P = 0.06) compared with those who did not receive zinc. MVs did not alter the rates of any recorded physician diagnoses or mortality. Neither zinc nor MVs reduced hospitalizations or unscheduled outpatient visits. Conclusions: Daily zinc supplementation of Tanzanian infants beginning at the age of 6 wk may lower the burden of diarrhea and acute upper respiratory infections, but provision of MVs using the regimen in this trial did not confer additional benefit. This trial was registered at clinicaltrials.gov as NCT00421668. J Nutr 2015;145:2153–60.
Keywords:
multivitamins, zinc, child morbidity, diarrhea, respiratory infection
Introduction Diarrheal diseases and respiratory infections are among the leading causes of child mortality globally and were responsible 1 Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD R01 HD048969-01 and K24HD058795). 2 Author disclosures: CM McDonald, KP Manji, R Kisenge, S Aboud, D Spiegelman, WW Fawzi, and CP Duggan, no conflicts of interest. * To whom correspondence should be addressed. E-mail: christopher.duggan@childrens. harvard.edu.
for the deaths of 1.9 million children 38.3°C or chest retractions. ‘‘Any form of respiratory infection’’ included acute upper respiratory infection, acute lower respiratory infection, pulmonary tuberculosis, or other causes of pneumonia. Children who missed their scheduled monthly follow-up appointment were visited at home and their vital status was confirmed through contact with immediate family members. In cases of child death, a verbal autopsy was performed to determine the cause of death. The cause of death forms were then coded by 2 independent pediatricians (KPM and CPD), and any differences were resolved by a third pediatrician. Data management and analysis. The primary outcomes of the study were the incidence of clinical symptoms of diarrhea and lower respiratory infection. Power was calculated for 1 factor in the factorial design, which represented either the zinc or MV arm. Based on findings from our previous trial, we estimated that the mean (SD) number of diarrheal and lower respiratory illnesses per child per year in the placebo group would be 3.4 (4.2) and 2.1 (1.0), respectively (16). After applying a 2-sided a-value of 0.025 to yield an overall type I error rate of 0.05 for each primary outcome and allowing for a 15% loss to follow-up and minimum power of 80%, we calculated that we would require 2400 subjects to detect a reduction of 18% in the mean number of diarrheal episodes per year. We then calculated that with this sample size we would have 90% power to detect an 8% reduction in the mean number of episodes of lower respiratory illness per year. Data were double entered using Microsoft Access software (Microsoft Corp.) at the central study site and then converted to SAS data sets and uploaded to a secured UNIX-based server for analysis. Intent-totreat analyses were conducted according to a pre-established data
analysis plan. Descriptive statistics were used to summarize baseline characteristics of the study population. Frequencies were reported for categorical variables and the mean 6 SD for continuous variables. The x2-test and ANOVA were used to detect any differences among treatment groups. We used generalized estimating equations with the log link, binomial variance, and exchangeable correlation matrix to compare the proportion of follow-up visits in which the illness symptom had occurred in the previous 4 wk between factors. For physician diagnoses that were made during routine visits every 3 mo or during unscheduled visits during acute illness episodes, the mean number of diagnoses over the follow-up period was compared between factors using Poisson regression. In both sets of analyses we introduced interaction terms to test for joint effects between the zinc and MV factors. We also tested for effect modification by each factor and sex and low birth weight. When the P-interaction term was 0.05).
Discussion In this randomized, double-blind trial in 2400 HIV-unexposed Tanzanian infants, we found that zinc supplementation significantly lowered rates of physician diagnoses of diarrhea and acute upper respiratory infections. Zinc specifically reduced the rates of dysentery, particularly among boys. The occurrence of diarrhea, as reported at monthly clinic visits with study nurses, was also significantly reduced among children who received only zinc in comparison with placebo. MVs did not alter the occurrence of any recorded morbidities, and neither zinc nor
TABLE 1
Baseline characteristics of enrolled Tanzanian infants and their mothers by supplementation group1
Maternal characteristics Age, y Formal education, n (%) None 1–7 y $8 y Employment, n (%) Housewife without income Housewife with income Other Married or cohabitating with partner, n (%) Prior pregnancies, n (%) None 1–4 $5 Midupper arm circumference, cm Recruited prenatally, n (%) Socioeconomic characteristics Daily food expenditure per person in household is ,1000 TSh, n (%) Household possessions,2 n (%) None 1–3 .3 Child characteristics Age at randomization, wk Male, n (%) Low birth weight (,2500 g), n (%) Born ,37 wk gestational age, n (%) Born ,34 wk gestational age, n (%) Born small for gestational age (,10th percentile), n (%) Apgar score #7 at 5 min after birth, n (%) Hemoglobin, g/dL Length-for-age z score3 Weight-for-length z score Weight-for-age z score
Placebo (n = 604)
Zinc only (n = 596)
MVs only (n = 598)
Zinc + MVs (n = 602)
26.5 6 5.0
26.8 6 5.1
26.2 6 5.0
26.1 6 5.0
9 (1.5) 453 (75.3) 140 (23.3)
8 (1.4) 421 (71.1) 163 (27.5)
10 (1.7) 416 (70.2) 167 (28.2)
9 (1.5) 441 (73.4) 151 (25.1)
386 (64.4) 176 (29.4) 37 (6.2) 537 (90.0)
365 175 46 534
337 212 45 542
357 201 39 542
(62.3) (29.9) (7.9) (90.5)
(56.7) (35.7) (7.6) (91.4)
(59.8) (33.7) (6.5) (90.5)
184 (30.6) 398 (66.2) 19 (3.2) 27.0 6 3.1 86 (14.2)
169 (28.6) 410 (69.3) 13 (2.2) 27.1 6 3.1 76 (12.8)
205 (34.5) 375 (63.1) 14 (2.4) 27.1 6 3.1 90 (15.1)
187 (31.2) 396 (66.1) 16 (2.7) 26.7 6 3.2 92 (15.3)
158 (27.6)
162 (28.6)
164 (28.8)
170 (29.4)
171 (28.4) 358 (59.5) 73 (12.1)
192 (32.7) 308 (52.4) 88 (15.0)
173 (29.2) 330 (55.7) 90 (15.2)
180 (30.0) 339 (56.5) 81 (13.5)
5.9 6 0.4 293 (48.5) 18 (3.0) 77 (14.0) 15 (2.7) 45 (8.4) 9 (1.6) 10.7 6 1.6 20.17 6 1.28a 0.05 6 1.32 20.16 6 1.05
5.9 6 0.4 296 (49.7) 21 (3.6) 80 (14.6) 14 (2.6) 47 (8.7) 17 (3.1) 10.6 6 1.6 20.33 6 1.92a,b 0.16 6 1.33 20.23 6 0.97
5.9 6 0.4 282 (47.2) 21 (3.6) 66 (12.0) 12 (2.2) 52 (9.7) 5 (0.9) 10.7 6 1.4 20.26 6 1.20a,b 0.14 6 1.29 20.17 6 0.99
5.9 6 0.4 313 (52.0) 22 (3.7) 67 (12.1) 22 (4.0) 47 (8.7) 10 (1.8) 10.6 6 1.4 20.37 6 1.23b 0.15 6 1.31 20.26 6 1.03
According to the x2-test or ANOVA, there were no significant differences in baseline characteristics among treatment groups (P . 0.05) with the exception of length-for-age z score (P = 0.03). Values are means 6 SDs or percentages. MV, multivitamin; TSh, Tanzanian shilling. 2 From a list that includes sofa, television, radio, refrigerator, and fan. 3 Labeled means in a row without a common letter differ, P , 0.05. 1
MVs reduced hospitalizations or unscheduled outpatient visits. Although our study was not powered to detect differences in mortality, we observed a nonsignificant increase in mortality among infants who received zinc. Furthermore, in a subset of children with immunologic measures available at 12 mo of age, mean CD4 T cell percent was slightly but significantly higher among children who received zinc and MVs in comparison with placebo. To our knowledge, this is the first study of preventive zinc and MV supplementation to be conducted among young infants in sub-Saharan Africa. Given the large global burden of diarrhea and acute respiratory infections in young children, we believe that the 12% reduction in diarrhea, 16% reduction in dysentery, and 8% reduction in acute upper respiratory infections among children who received zinc are clinically significant and potentially of major public health importance. Although, to our knowledge, no other studies have assessed the effects of daily zinc supplementation in tandem with MVs from such a young age, our findings can be compared with trials of zinc vs. placebo on infant morbidity. Osendarp et al. (17) reported that daily zinc supplementation from 4 to 24 wk
of age did not reduce morbidity from diarrhea or respiratory infections in Bangladeshi infants. Likewise, a large trial of preventive zinc and/or folic acid supplementation involving Nepalese children 1–35 mo of age saw no differences in the frequency or duration of diarrhea or acute lower respiratory infection between treatment groups (18). However, weekly zinc supplementation for 12 mo was found effective in reducing the incidence of diarrhea and pneumonia among urban Bangladeshi infants aged 2–12 mo (19). Similarly, a study in Delhi, India, involving infants 6–11 mo of age, reported that a short course of daily zinc supplementation for 2 wk effectively reduced the subsequent number and duration of diarrhea episodes (20). In contrast, a multicenter study involving infants 1–5 mo of age with acute diarrhea found that infants who received therapeutic zinc supplementation for 14 d had more days of diarrhea and similar prevalence of pneumonia and respiratory infection compared with the placebo group (21). Differences in the age of study participants, dose and duration of supplementation, and length of follow-up make it difficult to identify the reasons behind these contrasting results. However, it Effects of multivitamins and zinc on child health
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TABLE 2
Effect of daily MVs and zinc on the occurrence of common infectious morbidities in Tanzanian infants by nurse evaluation1 Received zinc2 Yes (n = 1198)
Morbidity reported in the past 4 wk
% (n event/visit)
Received MV3
No (n = 1202) 4
Diarrhea 3.7 (547/14,703) Cough 22.1 (3266/14,782) Difficulty breathing 1.1 (159/14,777) Cough + fever 4.9 (723/14,782) Cough plus7 1.7 (247/14,782) 0.1 (16/14,782) Cough with rapid respiratory rate8 Fever 10.0 (1471/14,780) Cold 21.3 (3153/14,782) Vomiting 1.8 (261/14,779) Refusal to eat, drink, or breastfeed 2.3 (336/14,780) Pus draining from ears 0.5 (74/14,778) Hospitalizations 0.2 (34/14,620) Unscheduled outpatient visits 2.0 (282/14,286)
% (n event/visit)
Yes (n = 1200) 4
4.0 (584/14,725) 23.4 (3474/14,823) 1.0 (141/14,818) 5.3 (789/14,823) 1.8 (261/14,823) 0.1 (14/14,823) 10.4 (1539/14,821) 22.5 (3329/14,822) 1.7 (249/14,819) 2.5 (368/14,817) 0.5 (73/14,817) 0.1 (21/14,669) 1.7 (237/14,358)
RR (95% CI) 0.93 0.95 1.15 0.90 0.95 0.98 0.95 0.95 1.05 0.90 1.06 1.50 1.18
(0.82, (0.90, (0.89, (0.81, (0.78, (0.40, (0.88, (0.90, (0.87, (0.77, (0.74, (0.83, (0.98,
5
1.05) 1.01) 1.47) 1.01) 1.15) 2.43) 1.03) 1.01) 1.26) 1.06) 1.52) 2.70) 1.43)
P
5
0.26 0.10 0.29 0.08 0.57 0.97 0.18 0.09 0.60 0.22 0.75 0.18 0.08
No (n = 1200) 4
% (n event/visit)4
3.9 (566/14,611) 22.8 (3,350/14,697) 1.1 (161/14,692) 5.2 (760/14,697) 1.8 (268/14,697) 0.1 (15/14,697) 10.3 (1,514/14,694) 22.0 (3,226/14,697) 1.9 (272/14,691) 2.5 (363/14,691) 0.4 (59/14,691) 0.2 (29/14,528) 1.90 (270/14,194)
3.8 (565/14,817) 22.7 (3,390/14,908) 0.9 (139/14,903) 5.0 (752/14,908) 1.6 (240/14,908) 0.1 (15/14,908) 10.0 (1,496/14,907) 21.8 (3,256/14,907) 1.6 (238/14,907) 2.3 (341/14,906) 0.6 (88/14,904) 0.1 (26/14,761) 1.72 (249/14,450)
% (n event/visit)
P5
Pint6
0.74 0.73 0.25 0.78 0.17 0.72 0.78 0.82 0.11 0.38 0.02 0.56 0.28
0.06 0.78 0.51 0.53 0.80 0.99 0.80 0.82 0.79 0.75 0.91 0.63 0.46
RR (95% CI)5 1.02 1.01 1.16 1.02 1.14 0.85 1.01 1.01 1.16 1.07 0.65 1.18 1.11
(0.90, (0.95, (0.90, (0.91, (0.94, (0.34, (0.94, (0.95, (0.97, (0.91, (0.45, (0.67, (0.92,
1.16) 1.07) 1.49) 1.13) 1.39) 2.10) 1.09) 1.07) 1.39) 1.26) 0.93) 2.11) 1.34)
1
MV, multivitamin. Received zinc ‘‘yes’’ refers to children who received zinc alone as well as those who received zinc and MVs. Received zinc ‘‘no’’ refers to all children who received MVs alone and those who received the placebo. 3 Received MVs ‘‘yes’’ refers to children who received MVs alone as well as those who received zinc and MVs. Received MVs ‘‘no’’ refers to all children who received zinc alone and those who received the placebo. 4 Total number of events occurring during follow-up, defined as being reported in the 28 d (4 wk) before visit or being present on the day of the evaluation. 5 RR, 95% CI, and corresponding P values were obtained from generalized estimating equations with the binomial variance, log link, and exchangeable working covariance structure. 6 P-interaction effect. 7 Cough plus defined as cough with one or more of the following events: difficult breathing, chest retractions, and refusal to eat, drink, or breastfeed. 8 Cough with rapid breathing on the day of the evaluation (respiratory rate: .60/min in infants ,2 mo old, .50/min in infants 2–11 mo old, .40/min in infants 12–59 mo old). 2
is important to note that, to our knowledge, our study provided supplementation for the longest period of time and followed infants well into their second year of life, capturing the period during which the incidence of infectious morbidities typically rises. TABLE 3
Our findings build on previous investigations into the possible effects associated with the addition of multiple micronutrients to zinc supplementation regimens among older infants and children. We previously reported that the same MV regimen did not affect the risk of mortality among HIV-exposed
Effect of daily MVs and zinc on the incidence of common infectious morbidities in Tanzanian infants by physician diagnosis1 Received zinc2 Yes
Physician diagnosis Acute upper respiratory infection Acute lower respiratory infection Pulmonary tuberculosis or other causes of pneumonia Diagnosis of any form of respiratory infection Acute diarrhea Dysentery Persistent diarrhea Intestinal parasites Diagnosis of any form of diarrhea Uncomplicated malaria Severe malaria Pallor/anemia 1
n
Diagnosis, n
Received MV3
No 4
n
Diagnosis, n
Yes 4
RR (95% CI)
5
P
5
n
Diagnosis, n
No 4
n
Diagnosis, n4
RR (95% CI)5
P 5 Pint6
1094 3.39 6 2.60 1072 3.70 6 2.80 0.92 (0.88, 0.97) 0.0005 1082 3.52 6 2.68 1084 3.57 6 2.73 0.98 (0.94, 1.03) 0.43 0.35 1040 0.63 6 0.95 1034 0.63 6 0.95 1.01 (0.91, 1.13) 0.86 1039 0.64 6 0.96 1035 0.62 6 0.94 1.02 (0.92, 1.14) 0.69 0.56 1027 0.003 6 0.07 1022 0.001 6 0.03 3.01 (0.31, 28.86) 0.34 1027 0.002 6 0.06 1023 0.002 6 0.04 0.99 (0.14, 7.05) 0.99 — 1096
3.94 6 2.91 1074
1033 0.46 6 0.77 1048 0.43 6 0.79 1028 0.003 6 0.05 1030 0.14 6 0.38 1054 1.00 6 1.18 1052 1032 1029
4.26 6 3.06 0.93 (0.89, 0.97)
1028 0.50 6 0.85 1040 0.52 6 0.87 1022 0.009 6 0.10 1023 0.15 6 0.40 1043 1.14 6 1.33
0.87 6 1.08 1037 0.06 6 0.24 1023 0.16 6 0.45 1026
0.91 0.84 0.33 0.94 0.88
(0.81, (0.74, (0.09, (0.74, (0.81,
1.03) 0.95) 1.23) 1.17) 0.96)
0.91 6 1.08 0.96 (0.87, 1.05) 0.06 6 0.24 1.05 (0.73, 1.52) 0.15 6 0.42 1.10 (0.88, 1.37)
0.0006 1083
4.09 6 2.97 1087
0.15 0.006 0.10 0.56 0.003
1032 0.48 6 0.79 1045 0.49 6 0.85 1027 0.009 6 0.10 1029 0.14 6 0.39 1049 1.09 6 1.29
0.33 0.79 0.41
1048 1028 1030
4.11 6 3.01 0.99 (0.95, 1.03) 0.62 0.26
1029 0.47 6 0.83 1043 0.46 6 0.80 1023 0.003 6 0.05 1024 0.14 6 0.39 1048 1.05 6 1.23
0.88 6 1.07 1041 0.05 6 0.22 1027 0.15 6 0.42 1025
1.02 1.05 1.99 0.97 1.03
(0.90, 1.16) (0.93, 1.19) (0.81,11.01) (0.77, 1.21) (0.95, 1.12)
0.75 0.42 0.10 0.76 0.43
0.29 0.25 0.71 0.33 0.24
0.90 6 1.09 0.98 (0.89, 1.07) 0.63 0.92 0.06 6 0.25 0.79 (0.55, 1.15) 0.22 0.34 0.16 6 0.45 0.88 (0.70, 1.09) 0.25 0.42
MV, multivitamin. Received zinc ‘‘yes’’ refers to children who received zinc alone as well as those who received zinc and MVs. Received zinc ‘‘no’’ refers to all children who received MVs alone and those who received the placebo. 3 Received MVs ‘‘yes’’ refers to children who received MVs alone as well as those who received zinc and MVs. Received MVs ‘‘no’’ refers to all children who received zinc alone and those who received the placebo. 4 Mean 6 SD diagnoses over the course of follow-up. 5 RRs, 95% CIs, and corresponding P values were obtained from generalized estimating equations with the Poisson distribution and log link and by using the log of the follow-up time as the offset variable. 6 P-interaction term. 2
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McDonald et al.
Tanzanian infants, but it did reduce episodes of vomiting and fever (13). A different study of daily zinc and/or multiple micronutrient supplementation involving rural Tanzanian children 6–60 mo of age showed that zinc supplementation significantly decreased the rate of diarrhea and protected against fever without localizing signs; however, multiple micronutrient supplementation actually increased the rate of diarrhea by approximately one-quarter (9). Similarly, in a trial of micronutrient powders with or without zinc among Pakistani children 6–18 mo of age, Soofi et al. (8) observed an increase in the proportion of days with diarrhea as well as higher rates of bloody diarrhea and chest indrawing among children in the 2 micronutrient groups compared with a nonsupplemented control group. An earlier, relatively small study that provided zinc with or without multiple micronutrients to Peruvian children 6–35 mo of age with persistent diarrhea showed similar results: zinc supplementation tended to reduce morbidity, whereas the addition of MVs increased morbidity (22). However, it is worth noting that iron was included in the multiple micronutrient supplement that was evaluated in these 3 trials (8, 9, 22), whereas our MV regimen did not include iron. When taken as a whole, these findings do not support routine MV supplementation as an effective means of reducing infant and child morbidity, even in resource-limited settings where diets are likely poor. Our findings of increased CD4 T cell percentage with zinc and MV supplementation suggest one possible immune effect of supplementation. Although evidence on the topic is particularly limited in HIV-negative children, we previously reported an increase in CD4 counts among HIV-infected pregnant women in Tanzania who received a similar MV regimen (23). Zinc and multiple micronutrients have also been shown to increase CD4 counts in HIV-infected adults receiving highly active antiretroviral therapy (24, 25). However, in a safety and efficacy study involving 96 HIV-infected children in South Africa, daily supplementation with 10 mg of elemental zinc for 6 mo did not significantly change the percentage of CD4+ T lymphocytes (26). In an HIV-negative elderly population, Fortes et al. (27) reported that zinc increased the number of CD4 cells. Although the compilation of these findings is encouraging, more research is needed to better understand the potential mechanisms by which certain nutrients could be affecting this marker of immunologic function. Although not statistically significant, our finding of a possible increase in the risk of all-cause mortality among children who received zinc is generally inconsistent with the bulk of the published evidence on this topic. Our results were unexpected, especially considering the fact that zinc reduced rates of diarrhea and acute upper respiratory infections, and we saw no differences in rates of hospitalizations or unscheduled clinic visits between treatment groups. Our trial did not have sufficient power to assess cause-specific mortality, which could have helped to elucidate possible causal pathways driving this apparent effect. A metaanalysis concluded that therapeutic zinc supplementation for the treatment of diarrhea significantly reduces child mortality (5). Although the effect of preventive zinc supplementation on mortality appears to be weaker, Brooks et al. (19) reported a 17% reduction in all-cause mortality among children who received weekly zinc supplementation for 12 mo, and most other studies, including a large study from Pemba Island, Tanzania, have reported a nonsignificant reduction in mortality (18, 28, 29). Clearly, more research is needed to better understand the mechanisms through which zinc may affect certain causes of mortality and to resolve differences that could be attributed to variations in study design and subject characteristics.
Several strengths and limitations of our study deserve comment. As previously noted, to our knowledge, our study is the first to examine the effects of preventive zinc and MV supplementation in African infants 6 wk of age. We enrolled a large number of participants and conducted intensive, monthly follow-up activities over an extended period of time. This allowed us to evaluate the effects of supplementation during the period when rates of morbidity typically increase. We also assessed morbidity in a comprehensive manner, using symptom diaries, monthly nurse evaluations, and regular physician examinations. The discordance in results between the nurse evaluations and the physician diagnoses is notable. One possible explanation is that mild illnesses were only detected by study nurses at the monthly follow-up visits, whereas more severe symptoms prompted a visit with study physicians (30). Other possible limitations include lack of vitamin D in the supplement regimen and what might be considered a low dose of zinc given the possibility of impaired zinc absorption in African children (31). In summary, daily zinc supplementation of HIV-unexposed Tanzanian infants at 6 wk of age significantly reduced physiciandiagnosed cases of diarrhea and acute upper respiratory tract infections. Simultaneous provision of MVs did not appear to confer additional benefit. Further investigation into the optimal timing, frequency, and duration of supplementation is needed before policy recommendations can be formulated. Acknowledgments We are grateful to the field and study staff for their tireless efforts: Esther Kibona (deceased), Frank Killa, Michel Alexander, Phares Zawadi, Susie Welty, Rachel Steinfeld, Anne Marie Darling, James Okuma, Angela Jardin, Elizabeth Long, Jenna Golan, and Emily Dantzer. We thank Roland Kupka for expert advice. We thank the members of the Data Safety and Monitoring Board: Paul Jacques, Davidson Hamer, Roger Mbise, and Zul Premji. CMM analyzed the data and wrote the manuscript; KPM designed the study, supervised data collection, and provided input to the manuscript; RK provided input to the study design, oversaw data collection, and reviewed the manuscript; SA oversaw all laboratory aspects of the study and reviewed the manuscript; DS supervised the statistical analysis and reviewed the manuscript; WWF designed the study, provided input to the statistical analysis, and reviewed the manuscript; CPD designed the study, oversaw study implementation, contributed to the statistical analysis, and provided input to the manuscript. All authors read and approved the final manuscript.
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