EAL

H/A: Diarrhea/Malabsorption (2009)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine the effect of vitamin A supplementation on the risk of diarrhea and of acute respiratory infection.

Inclusion Criteria:

Children hospitalized with pneumonia.

Exclusion Criteria:

Treatment with vitamin A in the preceding four months
Weight for age less than 60% of the median
Measles
Pulmonary tuberculosis
Diphtheria
Whooping cough
Xerophthalmia.

Description of Study Protocol:

Recruitment

Study was conducted between April 1993 and March 1997 among children aged six to 60 months who were admitted to the hospital with pneumonia.

Design

Randomized placebo-controlled trial. Children were randomly assigned in blocks of 20.

Blinding Used

Double-blind.

Intervention

Children received vitamin A or placebo at baseline, another dose on day two and at four and eight months after discharge from the hospital
Children older than one year received 1.0ml of the solution, and infants were given 0.5ml
1.0ml solution contained 200,000 IU (60mg) of retinol
Of 687 children enrolled, 75% of those still alive received the third dose, and 74% were given the fourth dose.

Statistical Analysis

Intent to treat analysis completed
Mean number and duration of episodes of diarrheal and respiratory tract infections were compared using Wilcoxon rank sum tests
Proportions of children who had one or more episodes were compared by using logistic regression
Cox proportional hazards models were used to examine the effect of the supplements on the time to the first episode during the follow-up period
Multivariate models were used to adjust for age, sex, weight-for-age Z-score, mother's education and the number of possessions as a socioeconomic score
Effect of supplements was also examined within groups of children categorized by age, nutritional status and HIV status.

Data Collection Summary:

Timing of Measurements

Blood specimens taken at baseline and from a subset of children at four months and eight months.

Dependent Variables

Weight
Height or length
Blood specimen tested for HIV antibodies using ELISA
Incidence and duration of episodes of diarrhea and respiratory tract infections during the year after discharge from the hospital measured through biweekly visits alternately at the study clinic or at home and pictorial diaries.

Independent Variables

Vitamin A or placebo at baseline, day two and at four and eight months after discharge from hospital.

Control Variables

Age
Sex
Weight-for-age Z-score
Mother's education
Number of possessions as a socioeconomic score.

Description of Actual Data Sample:

Initial N: 687 children enrolled
Attrition (final N): 574 children, 289 in vitamin A group, 285 in placebo group
Age: Aged six to 60 months old
Other relevant demographics: 95% of the children were fully immunized against poliomyelitis and almost 85% of mothers had elementary education or higher
Anthropometrics: There were no differences between who did and those who did not receive the third and fourth doses in terms of vitamin A or placebo. However, baseline differences between groups was not discussed.
Location: Dar es Salaam, Tanzania.

Summary of Results:

	HIV Status: Negative	HIV Status: Positive
Acute diarrhea, N (%)	363 (74.8%)	37 (77.1%)
Acute diarrhea, RR (95% CI)	1.21 (0.98 to 1.49)	1.55 (0.75 to 3.17)
Acute diarrhea, P-value	0.08	0.23
Acute diarrhea, Chi-square, df, P-value	0.13, 1,	0.71
Cough and rapid respiratory rate, N (%)	284 (58.3%)	29 (60.4%)
Cough and rapid respiratory rate, RR (95% CI)	1.47 (1.16 to 1.86)	0.54 (0.24 to 1.20)
Cough and rapid respiratory rate, P-value	0.001	0.13
Cough and rapid respiratory rate, Chi-square, df, P-value	3.29, 1	0.07

Other Findings

9% of children were HIV infected.

Relative to those receiving placebo, children receiving vitamin A had a significantly smaller risk of severe watery diarrhea (multivariate odds ratio = 0.56, 95% CI = 0.32 to 0.99, P=0.04) but a higher risk of cough and rapid respiratory rate (multivariate odds ratio = 1.67, 95% CI = 1.17 to 2.36, P=0.004).

Vitamin A supplementation was also associated with increased risk of acute diarrhea among normally nourished children or children with stunted growth but was relatively protective among children with wasting disease (P=0.01).

The apparently increased risk of respiratory tract infection was limited to children who were seronegative for HIV (P=0.07).

The effects of vitamin A supplements on risk of acute diarrhea did not differ by HIV infection status.

Author Conclusion:

We found that vitamin A supplements resulted in a significant reduction of risk of severe watery diarrhea and a non-significant reduction in the risk of hospitalization. Vitamin A was also associated with increased risks of respiratory tract infection defined as cough alone, cough and fever or cough, rapid respiratory rate and with an increased risk of health center visits. Vitamin A supplements provide a low-cost intervention against morbidity in HIV-infected and undernourished children. Supplements may also have serious non-lethal adverse outcomes in well-nourished individuals. Whether these apparent detrimental effects of vitamin A are transient or long-term needs to be examined.

Funding Source:

University/Hospital:

Harvard School of Public Health/Mubimbili University College of Health Sciences

Reviewer Comments:

Not all subjects received third and fourth doses. Baseline differences between groups not discussed. Subjects measured over a four-year period.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	???
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	No
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		???
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		???
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes