Daily zinc but not multivitamin supplementation reduces diarrhea and upper respiratory infections in tanzanian infants: A randomized, double-blind, placebo-controlled clinical trial

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Study Justification:
– The effects of daily multivitamin (MV) and/or zinc supplementation on infectious morbidity in young African infants have not been widely evaluated.
– Previous research has shown deficiencies in micronutrients among breastfeeding women in sub-Saharan Africa, suggesting low infant micronutrient status in the region.
– Previous clinical trials have demonstrated improved birth outcomes and lower rates of fever and vomiting with MV supplementation in pregnant Tanzanian women and HIV-exposed children.
Study Highlights:
– The study was a randomized, double-blind, placebo-controlled clinical trial conducted in Tanzania.
– 2400 infants born to HIV-negative mothers were randomly assigned to receive daily oral supplementation of MVs, zinc, zinc + MVs, or placebo for 18 months.
– Morbidity was assessed by study nurses at monthly visits and by physicians every 3 months and/or when the child was acutely ill.
– Zinc supplementation significantly reduced the risk of physician-diagnosed diarrhea, dysentery, and acute upper respiratory infection compared to placebo.
– MV supplementation did not confer additional benefit in terms of reducing morbidity.
– Neither zinc nor MVs reduced hospitalizations or unscheduled outpatient visits.
– There was a nonsignificant increase in all-cause mortality among infants who received zinc compared to those who did not.
Study Recommendations:
– Daily zinc supplementation starting at 6 weeks of age may be beneficial in reducing the burden of diarrhea and acute upper respiratory infections in Tanzanian infants.
– Further research is needed to investigate the potential adverse effects of zinc supplementation on mortality.
– MV supplementation did not show any additional benefit in this study, but further research may be warranted to explore its potential effects in different populations or settings.
Key Role Players:
– Study nurses: Responsible for assessing morbidity at monthly visits.
– Study physicians: Conducted physical examinations, diagnosed illnesses, and provided medical treatment.
– Data Safety and Monitoring Board: Met twice annually to review study progress and ensure participant safety.
– Harvard T.H. Chan School of Public Health Human Subjects Committee: Granted institutional approval for the study.
– Muhimbili University of Health and Allied Science Committee of Research and Publications: Granted institutional approval for the study.
– Tanzanian National Institute of Medical Research: Granted institutional approval for the study.
– Tanzanian Food and Drugs Authority: Granted institutional approval for the study.
Cost Items for Planning Recommendations:
– Study personnel salaries and benefits
– Study clinic operation and maintenance costs
– Supplies and equipment for data collection and analysis
– Medications and medical treatments for participants
– Training and capacity building for study personnel
– Data management and analysis software and services
– Institutional review board fees and administrative costs
– Travel and transportation expenses for study personnel and participants
– Communication and dissemination of study findings

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is strong because it is based on a randomized, double-blind, placebo-controlled clinical trial with a large sample size. The study design and methodology are clearly described. However, there are some limitations that could be addressed to improve the evidence. Firstly, the study was conducted in a specific population (HIV-unexposed Tanzanian infants), so the results may not be generalizable to other populations. Secondly, there was a nonsignificant increase in all-cause mortality among infants who received zinc, which should be further investigated. Lastly, the study did not assess the long-term effects of supplementation. To improve the evidence, future studies could include a more diverse population, investigate the potential adverse effects of zinc supplementation, and assess the long-term effects of supplementation.

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 × 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.

The study was a randomized, double-blind, 2 × 2 factorial design trial that took place in periurban Dar es Salaam, Tanzania (clinicaltrials.gov {“type”:”clinical-trial”,”attrs”:{“text”:”NCT 00421668″,”term_id”:”NCT00421668″}}NCT 00421668). Mothers of potentially eligible infants were recruited into the study in 1 of 2 ways: 1) pregnant women ≤34 wk gestation presenting at 1 of 3 prenatal clinics in Dar es Salaam were informed about the study and consented prenatally or 2) women were recruited from the labor ward of Muhimbili National Hospital within 12 h of delivering a healthy singleton baby. In both cases, written informed consent was obtained and mothers were asked to present at a study clinic within 1–2 wk of delivery for HIV testing. Maternal HIV status was determined using 2 sequential ELISAs that used the Murex HIV antigen/antibody (Abbott Murex) followed by the Enzygnost anti-HIV-1/2 Plus (Dade Behring) or the Enzygnost HIV Integral II Antibody/Antigen (Siemens). Any discrepancy between the first and second ELISA was resolved by a Western blot assay. Consenting mothers who were confirmed to be HIV-negative were enrolled into the study and their infants were randomly assigned to 1 of 4 regimens between 5 and 7 wk of age. Infants of multiple births and infants with congenital anomalies or other conditions that would interfere with the study procedures were excluded. Birth characteristics were obtained immediately after delivery whenever possible. We used reference data from Oken et al. (11) to calculate the percentile of birth weight for each completed week of gestation and defined small-for-gestational age as ≤10th percentile. At the time of randomization, clinical examination was performed by a study physician, history of morbidity and infant feeding practices was conducted by a study nurse, infant blood was drawn for a complete blood count, and anthropometric measurements were performed. Institutional approval was granted by the Harvard T.H. Chan School of Public Health Human Subjects Committee, the Muhimbili University of Health and Allied Science Committee of Research and Publications, the Tanzanian National Institute of Medical Research, and the Tanzanian Food and Drugs Authority. Over the course of the study, a Data Safety and Monitoring Board met twice annually. Infants were randomly assigned in a factorial design to receive a daily oral dose of 1 of the following 4 regimens for 18 mo from the time of randomization: 1) zinc, 2) MVs, 3) zinc + MVs, or 4) placebo. The biostatistician in Boston prepared a randomization list from 1 to 2400 that used blocks of 20 and was stratified by study clinic. Capsules were packaged in a blister pack of 15 each and numbered boxes containing 6 blister packs were prepared containing the corresponding treatments. Each eligible infant was assigned the next numbered box of capsules at his/her respective site. The supplement used was an orange-flavored powder encapsulated in an opaque gelatinous capsule and was manufactured by Nutriset. All 4 regimens were field tested and the taste, smell, and appearance were found to be indistinguishable between groups. All study personnel and participants were blinded to treatment assignment for the duration of the study. From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow-up, 2 capsules were provided daily. For infants in the zinc group, the capsule contained 5 mg of zinc. For infants in the MV group, the capsule contained 60 mg of vitamin C, 8 mg of vitamin E, 0.5 mg of thiamine, 0.6 mg of riboflavin, 4 mg of niacin, 0.6 mg of vitamin B-6, 130 mg of folate, and 1 mg of vitamin B-12. Infants in the MV + zinc group received 1 capsule containing the micronutrients listed in both the MV and the zinc groups. For children 0–6 mo of age, these doses represented between 150% and 600% of the RDA or Adequate Intake, and for children 7–12 mo of age, the doses were equivalent to 200–400% of the RDA or Adequate Intake. Mothers were shown how to push the capsule through the back of the blister pack, open the capsule, decant the powder into a small plastic cup, mix the powder with 5 mL of sterile water, and administer the solution to the child orally. Our choice of supplement composition was based on several considerations including: 1) previous research that found deficiencies in vitamin B-12, folate, zinc, vitamin A, and vitamin E among breastfeeding women in South Africa (10) and, therefore, suggests that infant micronutrient status may be low in sub-Saharan Africa; 2) a previous clinical trial involving pregnant Tanzanian women that confirmed improved birth outcomes with supplementation of vitamin B complex, vitamin E, and vitamin C (12); and 3) findings from our previous trial of MV supplementation involving HIV-exposed children, which revealed lower rates of fever and vomiting among supplemented children (13). Dar es Salaam has been described as a malaria-endemic area, although studies have suggested that rates of malaria are declining (14). Nonetheless, owing to the potential that iron supplementation of nonanemic children may have adverse consequences in malaria-endemic regions (15), the MV supplement did not include iron. Mothers and children were followed from the time of randomization for 18 mo, until the child’s death, or until loss to follow-up. Mothers who were enrolled during pregnancy received standard prenatal care including anthropometric assessment, intermittent prophylaxis for malaria, tetanus toxoid immunization, deworming using mebendazole, anemia assessment, and iron-folic acid supplementation. During this follow-up period, mothers and children were asked to return to the study clinic every 4 wk for data collection and standard clinical care, including growth monitoring, immunizations, routine medical treatment for illnesses, and periodic vitamin A supplementation (100,000 IU at 9 mo and 200,000 IU at 15 mo). Children who were diagnosed with anemia were treated with iron supplementation. At ~12 mo of age, CD4 and CD8 T cell counts and percentages were measured from a subset of 428 children using FACSCalibur system (Becton Dickinson) in order to determine any potential immune effect of micronutrient supplementation. At each of the monthly follow-up visits study nurses assessed compliance by counting the number of unconsumed capsules, assessed infant feeding practices, and conducted a morbidity history with the aid of pictorial diaries that mothers were instructed to complete daily in order to document the occurrence of any of the following symptoms: diarrhea; common cold; cough; difficulty breathing; fever; refusal to eat, drink, or breastfeed; pus draining from ears; and vomiting. They also assessed symptoms that were present on the day of the visit, recorded vital signs (including measurement of the child’s temperature and respiratory rate and detection of chest indrawing), and inquired about the occurrence of any unscheduled clinic visits or hospitalizations in the past month. Diarrhea was defined as ≥3 loose or watery stools within a 24-h period. Rapid respiratory rate was defined as >50 breaths/min in infants 2–11 mo of age and >40 breaths/min among infants ≥12 mo of age. At baseline, every 3 mo, and/or when acute illnesses were noted by the study nurse a study physician conducted a physical examination, diagnosed illnesses, and provided necessary medical treatment. Physicians underwent regular training so that they used standardized diagnostic criteria and treatment guidelines consistent with the WHO and Tanzanian Ministry of Health and Social Welfare policies. For the purposes of the analysis of physician diagnosis, “any form of diarrhea” included persistent diarrhea, acute diarrhea, dysentery, and/or intestinal parasites. Acute upper respiratory infection was defined as pharyngitis or rhinitis (both without fast breathing or chest indrawing). Acute lower respiratory infection was defined as cough or difficulty breathing, rapid respiratory rate (based on the same definition described previously), and either a fever of >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. 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 α-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-to-treat 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 ± SD for continuous variables. The χ2-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 <0.10, stratified analyses were performed. Although the study was not powered to detect differences in mortality, we used Cox proportional hazards modeling to explore differences in all-cause and cause-specific mortality by factor. Values in the text are means ± SDs unless otherwise indicated. All analyses were performed using SAS software (version 9.2; SAS Institute).

The study mentioned in the description is titled “Daily zinc but not multivitamin supplementation reduces diarrhea and upper respiratory infections in Tanzanian infants: A randomized, double-blind, placebo-controlled clinical trial.” The objective of the study was to determine whether daily supplementation of HIV-unexposed Tanzanian infants with multivitamins (MVs) or zinc reduces the risk of infectious morbidity compared with placebo.

The study found that daily zinc supplementation of Tanzanian infants starting at 6 weeks of age may lower the burden of diarrhea and acute upper respiratory infections. However, the provision of multivitamins using the regimen in this trial did not confer additional benefit. The study also found a nonsignificant increase in all-cause mortality among infants who received zinc compared to those who did not receive zinc.

The study was a randomized, double-blind, 2 × 2 factorial design trial conducted in periurban Dar es Salaam, Tanzania. The trial included 2400 infants who were 6 weeks of age and born to HIV-negative mothers in a low-malaria setting. Infants were randomly assigned to receive daily oral supplementation of multivitamins (vitamin B complex and vitamins C and E), zinc, zinc + multivitamins, or placebo for 18 months.

The study assessed morbidity by study nurses at monthly visits and by physicians every 3 months and/or when the child was acutely ill. Physician diagnoses of all types of diarrhea, dysentery, and acute upper respiratory infection were significantly lower for infants supplemented with zinc compared to those who did not receive zinc. However, neither zinc nor multivitamins reduced hospitalizations or unscheduled outpatient visits.

In conclusion, daily zinc supplementation of Tanzanian infants starting at 6 weeks of age may help reduce the burden of diarrhea and acute upper respiratory infections. However, multivitamin supplementation did not provide additional benefits in this trial.
AI Innovations Description
The study mentioned in the description evaluated the effects of daily multivitamin (MV) and/or zinc supplementation on infectious morbidity in Tanzanian infants. The findings showed that daily zinc supplementation reduced the risk of diarrhea, dysentery, and acute upper respiratory infections compared to placebo. However, MV supplementation did not provide additional benefits.

Based on these findings, a recommendation to improve access to maternal health could be to incorporate daily zinc supplementation for pregnant women and lactating mothers. This could help improve the health outcomes of both mothers and infants, reducing the burden of diarrhea and respiratory infections. It is important to note that this recommendation should be implemented in conjunction with existing prenatal care and nutritional interventions to ensure comprehensive support for maternal and infant health.
AI Innovations Methodology
The study you provided focuses on the impact of daily zinc supplementation on reducing the risk of infectious morbidity in Tanzanian infants. To improve access to maternal health, here are some potential recommendations based on the findings of the study:

1. Implement routine zinc supplementation for pregnant women: Based on the positive impact of zinc supplementation on reducing diarrhea and upper respiratory infections in infants, it may be beneficial to provide zinc supplementation to pregnant women. This can help improve the health of both the mother and the developing fetus.

2. Strengthen antenatal care services: Enhancing antenatal care services can ensure that pregnant women receive appropriate nutritional counseling and supplementation. This can include providing information on the importance of a balanced diet, including foods rich in zinc and other essential nutrients.

3. Promote breastfeeding and nutrition education: Educating mothers about the benefits of exclusive breastfeeding and proper nutrition during pregnancy and lactation can contribute to improved maternal and infant health outcomes. This can be done through community-based programs, health campaigns, and support groups.

4. Integrate maternal health services with existing programs: To improve access to maternal health, it is important to integrate maternal health services with existing programs, such as immunization campaigns or family planning services. This can help reach a larger population and ensure that women receive comprehensive care.

Methodology to simulate the impact of these recommendations on improving access to maternal health:

1. Define the target population: Identify the specific population that will be the focus of the simulation, such as pregnant women in a particular region or community.

2. Collect baseline data: Gather data on the current status of maternal health in the target population, including indicators such as maternal mortality rates, access to antenatal care, and nutritional status.

3. Develop a simulation model: Create a mathematical model that simulates the impact of the recommendations on improving access to maternal health. This model should take into account factors such as population size, coverage of interventions, and potential barriers to access.

4. Input data and parameters: Input the baseline data and parameters into the simulation model. This includes information on the current coverage of interventions, the effectiveness of the recommendations, and any potential constraints or limitations.

5. Run simulations: Run the simulation model using different scenarios to assess the potential impact of the recommendations. This can involve varying parameters such as coverage rates, implementation strategies, and timeframes.

6. Analyze results: Analyze the results of the simulations to determine the potential impact of the recommendations on improving access to maternal health. This can include assessing changes in maternal mortality rates, antenatal care utilization, and nutritional status.

7. Validate and refine the model: Validate the simulation model by comparing the simulated results with real-world data. Refine the model based on feedback and additional data to improve its accuracy and reliability.

8. Communicate findings: Communicate the findings of the simulation study to relevant stakeholders, such as policymakers, healthcare providers, and community members. This can help inform decision-making and guide the implementation of interventions to improve access to maternal health.

It is important to note that simulation studies provide estimates and projections based on assumptions and available data. The actual impact of implementing these recommendations may vary depending on various contextual factors.

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