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Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age

  1. Aamer Imdad1,
  2. Kurt Herzer2,
  3. Evan Mayo-Wilson3,
  4. Mohammad Yawar Yakoob1,
  5. Zulfiqar A Bhutta1,*

Editorial Group: Cochrane Developmental, Psychosocial and Learning Problems Group

Published Online: 8 DEC 2010

Assessed as up-to-date: 26 OCT 2010

DOI: 10.1002/14651858.CD008524.pub2

How to Cite

Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008524. DOI: 10.1002/14651858.CD008524.pub2.

Author Information

  1. 1

    Aga Khan University Hospital, Division of Women and Child Health, Karachi, Pakistan

  2. 2

    Johns Hopkins School of Medicine, Baltimore, MD, USA

  3. 3

    University of Oxford, The Centre for Evidence-Based Intervention, Oxford, UK

*Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan. zulfiqar.bhutta@aku.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 DEC 2010

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Characteristics of included studies [ordered by study ID]
Agarwal 1995

MethodsCluster randomised trial conducted in Uttar Pradesh, India, Asia.


ParticipantsAll children below 6 years of age were eligible for inclusion in the trial. Children with xerophthalmia were excluded.

A total of 16 clusters (subcentres) were randomly selected. Four subdivisions (4 subcentres in each) were made and drugs A (vitamin A) and B (placebo) distributed in two each randomly. It was found at the end of the study that by mistake vitamin ‘A’ was distributed in 3 subdivisions (12 subcentres) and placebo in 1 only (4 subcentres). A total of 17,778 children were approached but only 15,247 children were included in the final analysis based on the fact that they received at least 1 dose of vitamin A.


InterventionsChildren in experimental group received vitamin A along with small amounts of vitamin E. The dosages were 50,000 IU of vitamin A and 10 IU of vitamin E for children 1-6 months and 100,000 IU of vitamin A and 20 IU of vitamin E for children 7-72 months. The intervention was delivered every 4 months and continued for 12 months.


OutcomesAll-cause and cause specific mortality of diarrhoea, pneumonia, measles and meningitis .


NotesThe trial was conducted in two phases. First phase consisted of 15 months i.e. 3 months for registration and 12 months for intervention and measurement of relevant outcomes. In second phase, mortality was measured in a sub-sample of initially included children exactly after 12 months of termination of first phase. The cause of death was assigned by using a verbal autopsy tool. Baseline mortality rates for children below 6 years of age were 27.7 and 23.3 per 1000 for intervention and control group respectively and was significantly different in two groups (P < 0.01). According to WHO, India is a country with a high child mortality rate (i.e. > 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Out of the total 43 subcentres, 16 were randomly selected, four subdivisions (4 subcentres in each) were made and drugs A and B distributed in two each randomly"

Authors do not specify the method of sequence generation.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
UnclearInsufficent information to permit judgment.

Blinding?
Blinding of provider
UnclearInsufficent information to permit judgment.

Blinding?
Blinding of outcome assessor
UnclearInsufficent information to permit judgment.

Incomplete outcome data addressed?UnclearInsufficent information to permit judgment.

Free of selective reporting?UnclearInsufficent information to permit judgment.

Free of other bias?UnclearInsufficent information to permit judgment.

Arya 2000

MethodsIndividually randomised trial conducted in New Delhi, India, Asia.


ParticipantsInfants age 9-12 months attending immunisation clinic of Safdurjung hospital in New Delhi were eligible for inclusion in the trial. Sick infants requiring hospitalisation were excluded.

A total of 256 infants were enrolled in the study with equal numbers (i.e. 128) in vitamin A and placebo group. Mean age of participants was 9 months.


InterventionsThe experimental group received a single dose of 100 000 IU of vitamin A in Archis oil. The control group received placebo in peanut oil. Both vitamin A and placebo were administered at the time of measles vaccination. At the end of study vitamin A group received placebo and placebo group received vitamin A.


OutcomesIncidence of side effects in first 24 hours: vomiting, loose motions, fever, irritability, bulging fontanelle.


NotesStudy participants were not significantly different in sex, age and weight distribution and nutritional status at the baseline.The baseline prevalence of vomiting, loose stools, fever and irritability during 24 hours prior to dosing was similar in both groups. 97.3% of the included infants had normal serum retinol level before the study.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?No"The infants were randomised ... according to the order of arrival at hospital. Randomisation was done by the nurse who gave measles vaccine to these children."

Probably not done.

Allocation concealment?UnclearChildren were randomised according to their entry into hospital.

Blinding?
Blinding of Participants
Yes"This double-blind, randomised, ... supplied in small dark bottles marked '1' and '2'."

Blinding?
Blinding of provider
Yes"This double-blind, randomised, ... supplied in small dark bottles marked '1' and '2'."

Blinding?
Blinding of outcome assessor
Yes"This double-blind, randomised, ... supplied in small dark bottles marked '1' and '2' ... Two clinicians examined each of the infants at both first and second visits. Neither clinician knew the bottle code."

Incomplete outcome data addressed?NoA total of 39 (15.2%) infants were lost to follow-up with similar distribution in both the groups. Reasons for loss to follow-up not given.

Free of selective reporting?NoMethods describe that the clinicians did physical examinations and recorded weight, nutritional status, any signs of vitamin A deficiency, heart rate, respiratory rate, temperature and systemic examination especially neurological examination including the state of the fontanelle, reflexes, motor and sensory functions, etc. But bulging fontanelle not reported as an outcome, neither other variables mentioned in the results.

Free of other bias?YesNo other apparent bias was noted in the study.

Bahl 1999

MethodsThis individually randomised study was conducted in an urban slum of Delhi, India, Asia.


ParticipantsInfants aged 6-9 months were identified and enrolled into study when they became 9 months old. Those infants were excluded who had a previous history of measles, contact with a case of measles or measles immunisation, or if they had received a dose of vitamin A in the previous 4 months. Participants with serious illness requiring hospitalisation or having clinical signs of vitamin A deficiency (i.e. xerophthalmia, Bitot's spots etc.) were also excluded.

A total of 618 infants were enrolled and randomised either to vitamin A (309) or placebo group (309). 50% of study population consisted of male infants.


InterventionsParticipants in intervention group were given a single dose of 30 mg (100 000 IU) of vitamin A in the form of retinol palmitate and control group received soybean oil as placebo. Children were followed for four months.


OutcomesAntibody response to measles vaccine. Incidence of measles during study period and side effects like vomiting, drowsiness etc in first 48 hours were also reported.


NotesThe primary objective of the study was to determine the response to measles vaccine when administered along with vitamin A at 9 months of age. The study found no significant difference in antibody titers between the two groups at three months after the administration of intervention.The baseline prevalence of clinical vitamin A deficiency in children 1-5 years in study area was 3.5% and that of biochemical vitamin A deficiency of 37%.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Infants were randomly assigned to receive vitamin A or a placebo by using a simple randomisation scheme with random permuted blocks of size eight, i.e., four infants each out of every eight infants enrolled were randomised to receive vitamin A or a placebo."

Probably done.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
Yes"This scheme ensured that all infants received 30 mg vitamin A by 12 mo of age without interfering with the double-blind design of the study."

Probably done.

Blinding?
Blinding of provider
YesAdequate masking of vitamin A and placebo should have meant that providers were adequately blinded.

Blinding?
Blinding of outcome assessor
YesAdequate masking of vitamin A and placebo should have meant that outcome assessors were adequately blinded.

Incomplete outcome data addressed?NoLosses to follow-up and exclusions described. Missing data excluded from the analysis. It is not possible to ascertain whether the exclusion of data from 17% of participants (equally distributed between treatment groups) would have impacted on the results. The investigators state that the reason for their exclusion is that a follow-up serum sample could not be ascertained.

Free of selective reporting?NoData on harms are incompletely disclosed in the study report.

Free of other bias?YesThis study appears to be free of other bias.

Barreto 1994

MethodsIndividually randomised trial conducted in Serrinha, Brazil, Latin America.


ParticipantsChildren aged 6 to 48 months were eligible for inclusion in the trial. Exclusion criteria was presence of xerophthalmia or measles infection within the previous 30 days. Children who received a high dose of vitamin A supplementation in the previous 6 months or had weight-for-age less than 60% of the statistical median were also excluded.

A total of 1240 children were included, 620 in vitamin A group and 620 in placebo. Mean age of participants was 28 months and the proportion of males was 52%.


InterventionsThe experimental group received vitamin A in a dose of 100,000 IU for children younger than 12 months and 200,000 IU for the older. The control group received placebo only. The intervention was delivered every 4 months for 1 year.


OutcomesAll-cause mortality, incidence and prevalence of diarrhoea and respiratory tract disease. Incidence of measles and xerophthalmia.


NotesThe study area had inadequate pubic health services. A previous survey in the area showed biochemical deficiency (serum vitamin A concentration < 0.35 mmol/L) rate of 7.4% in children of this age group. According to WHO criteria, vitamin A deficiency should be considered a pubic health problem in this area. The surveillance for morbidity outcome was done 3 times per week for 1 year, so the recall period was 48 to 72 hours. We took data for incidence of measles and xerophthalmia from account of attrition in results section. According to WHO, Brazil does not have a high child mortality rate (i.e. < 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Children were randomly assigned to receive vitamin A or placebo four times-at the start of the trial and every 4 months thereafter."

Authors do not specify the method of sequence generation.

Allocation concealment?Yes"...only an external investigator had the codes for the individually wrapped and numbered capsules."

Although specific details were not disclosed, the available information suggests that allocation was adequately concealed.

Blinding?
Blinding of Participants
Yes"The gelatinous capsules of vitamin A and placebo (supplied by Hoffman La Roche) were identical in appearance and were unwrapped just before administration."

The study was double-blind, with identical presentation and dosing of vitamin A and placebo.

Blinding?
Blinding of provider
Yes"The gelatinous capsules of vitamin A and placebo (supplied by Hoffman La Roche) were identical in appearance and were unwrapped just before administration."

Probably done.

Blinding?
Blinding of outcome assessor
Yes"The study was kept double-blind and only an external investigator had the codes for the individually wrapped and numbered capsules."

If the assessors were not involved in the allocation process as suggested by the available information, outcome assessors were likely to have been blinded to treatment group assignment.

Incomplete outcome data addressed?Yes"The total loss in follow-up time was 10.3%, equally distributed between the study groups."

The rate of attrition was balanced between the two treatment groups, and was primarily attributable to migration. On that basis, attrition bias is not likely to have impacted on the results of the review.

Free of selective reporting?UnclearThe protocol for the study was not available and as such, this aspect of the reporting of the study could not be assessed.

Free of other bias?YesThis study appears to be free of other potential bias.

Benn 1997

MethodsIndividualy randomised trial conducted in Belem and Mindra, two districts in Bissau, the capital of Guinea-Bissau, Africa.


ParticipantsInfants aged 6-9 months were eligible for inclusion in the trial. Those with signs of xerophthalmia, history of previous vitamin A supplementation, history of measles infection before age 9 months or who had a positive haemagglutinin-inhibition assay (HIA) titre at age 9 months, were excluded. All infants reported to have had measles between 9 to 18 months of age were also excluded.

A total of 462 infants were randomised to either intervention or control group. The mean age of participants was 8.7 months and proportion of males was 51%.


InterventionsThere were three study groups:

Group 1: included "infants aged 6 months and were randomly allocated to receive either a dose of measles vaccine at 6 months and a dose of measles vaccine at 9 months together with vitamin A supplement or the same dosing of measles vaccine with placebo as the supplement".

Group 2: consisted of "infants who were randomly allocated either poliomyelitis vaccine at 6 months and a single dose of measles vaccine at 9 months with vitamin A supplement or the same vaccine doings with a placebo as the supplement".

Group 3: included "Infants who were older than 7·5 months at the beginning of the study or who were not found at home until they reached the age of 7·5 months. They were included in the study at age 9 months and received a measles vaccine plus vitamin A or placebo supplement at that age.

Vitamin A was supplemented in a single dose of 100 000 IU dissolved in 1 ml of vegetable oil along with 40 IU of vitamin E. The placebo group received 40 IU of vitamin E dissolved in vegetable oil.


OutcomesAntibody response to measles vaccine, all-cause mortality, incidence of measles.


NotesThe primary objective of the study was to calculate the antibody response to measles vaccine when given with vitamin A. The results for antibody response to measles vaccine showed no significant difference between the groups. It was concluded from the study that simultaneous administration of measles vaccine and vitamin A has no negative effect on measles immunity. Similarly vitamin A supplementation was shown to have no significant effect on immune response of CD4 and CD8 T-cell in children without clinical vitamin A deficiency. Please note that vitamin A or placebo was given only at 9 months of age in all three study groups. The only difference among the groups was the frequency and type of vaccine administered. We therefore added all the numbers for all three intervention and placebo groups to report the outcomes of interest to our review. We primarily took data from trial flow diagram and calculated the effect sizes accordingly.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"The allocation sequence was computer generated."

Allocation concealment?Yes"The allocation sequence was kept in sealed envelopes and only released when all clinical laboratory analyses were completed."

Blinding?
Blinding of Participants
YesIdentical presentation: "...because of the young age of the participants, any difference in taste was irrelevant..."

Probably adequate.

Blinding?
Blinding of provider
Yes"None of the staff involved knew whether the bottles contained vitamin A or placebo..."

Blinding?
Blinding of outcome assessor
Yes"None of the staff involved knew whether the bottles contained vitamin A or placebo..."

Masking of treatment group assignment and treatment to study personnel likely to have been maintained throughout.

Incomplete outcome data addressed?YesNumber lost to follow-up and those excluded were explicitly described and was equal in both the groups. Loss to follow-up exceeded the number of deaths and children with measles. Reasons for missing data (migration) probably unrelated to treatment.

Free of selective reporting?YesSome evidence of selective outcome reporting around malaria; however, deaths and prevalence of measles reported.

Free of other bias?UnclearAuthors report imbalance in self-reported disease in the children aged 6 months at baseline. It is unclear how big an impact this will have had as the variable is not specific.

Biswas 1994

MethodsThis study was an individual randomised, placebo-controlled trial conducted in Gobinda-Khatick slum area of eastern Calcutta, India, Asia.


ParticipantsChildren aged 12-71 months were eligible for inclusion in the study. Participants with signs of vitamin A deficiency (for example, xeropthalmia) were excluded.

A total of 180 children were randomised either to vitamin A or placebo group. Mean age of children and proportion of males were not specified in the study.


InterventionsThe experimental group received 200 000 IU of vitamin A in the form of retinyl palmitate. The control group received placebo. Only a single dose of intervention was administered and children were followed for 6 months.


OutcomesIncidence of diarrhoea and acute respiratory tract infection.


NotesThe baseline age and nutritional characteristics were similar in both the groups. The surveillance for morbidity outcomes was done fortnightly. For respiratory disease morbidity, we took data for lower respiratory tract infection only.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesBlock randomisation by age and weight: "For each strata, a restricted randomisation list was prepared (...) a random permutated block of block length 6 was used."

Probably done.

Allocation concealment?Yes"...randomisation was done by a pharmacist of the drug manufacturing company."

Assuming that the pharmacist was independent of the study team this was probably adequate.

Blinding?
Blinding of Participants
Yes"...identical (colour and taste) placebo. Both drug and placebo were prepared and dispensed in a single dose amber coloured glass ampoule by a local pharmaceutical company."

Blinding?
Blinding of provider
Yes"For keeping the trial totally blinded to all participants (for example, patients, investigators, surveyor), randomisation was done by a pharmacist of the drug manufacturing company. Samples of drug (or placebo) were identified by the code number of the respective child."

Blinding?
Blinding of outcome assessor
Yes"For keeping the trial totally blinded to all participants (for example, patients, investigators, surveyor), randomisation was done by a pharmacist of the drug manufacturing company. Samples of drug (or placebo) were identified by the code number of the respective child."

Incomplete outcome data addressed?Yes"....data was analysed for 174 children due to attrition of 6 children for various reasons (for example, 5 children were hospitalised due to illnesses unrelated to the study objectives and the death of 1 child due post-measles bronchopneumonia)."

Attrition was low and reported not to relate to treatment.

Free of selective reporting?UnclearStudy protocol was not available to permit a clear judgement. Study aims were to measure diarrhoea and respiratory infection; both outcomes were reported in full in the study report. One child died and the treatment group assignment was not disclosed.

Free of other bias?YesThis study appears to be free of other bias.

Cheng 1993

MethodsThis randomised trial was conducted in a rural area of China, Asia.


ParticipantsChildren aged 6 months to 3 years were eligible for inclusion in the trial.

A total of 198 children were randomised either to vitamin A or placebo group. There were 105 children in vitamin A and 81 in placebo group. Mean age of children and proportion of males were not specified in the study.


InterventionsVitamin A was supplemented in a dose of 200 000 IU for children > 12 months and 100 000 IU for < 12 months of age. Control group received placebo in the form of vegetable oil. Interventions were given every 4 months for 12 months.


OutcomesIncidence of diarrhoea and respiratory disease, all-cause hospitalisations, diarrhoea specific hospitalisations, pneumonia specific hospitalisations, mean vitamin A serum levels.


NotesBaseline serum levels of retinol were similar in both the groups. Measurement of biochemical vitamin A levels in the study area fulfilled the WHO criteria for an action to be triggered at a pubic health level. The morbidity surveillance was done twice a month.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"198 children who were randomly assigned on a 3:2 allocation to treatment (105) and control (81) groups."

No more information was provided about sequence generation.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
Yes"Administration was double blind: neither parents nor doctors knew whether the child was in a treatment or control group."

Placebo capsules contained vegetable oil and were likely to have been indistinguishable from intervention.

Blinding?
Blinding of provider
Yes"Placebo capsules contained vegetable oil and were likely to have been indistinguishable from intervention."

In view of the adequate blinding procedures, performance bias was unlikely to have influenced the results.

Blinding?
Blinding of outcome assessor
Yes"Data collected by doctors who were already blind to treatment group assignment."

Incomplete outcome data addressed?NoReasons for loss to follow- up were not provided. The number randomised and those reported after loss to follow- up do not match.

Free of selective reporting?UnclearProtocol of study was not available to permit a clear judgement.

Free of other bias?YesThis study appears to be free of other bias.

Cherian 2003

MethodsIndividually randomised trial conducted in Vellor, India, Asia.


ParticipantsInfants aged 9-12 months were eligible for inclusion in the study. Participants with previous history of measles vaccination or an exanthematous illness, with moderate or severe malnutrition, clinical signs of vitamin A deficiency, known immune deficiency or on immunosuppressive therapy and those who had received blood or blood products in the previous 6 months were excluded.

A total of 395 infants were randomised to either vitamin A or placebo group. There were 198 infants in vitamin A group and 197 in placebo. Mean age of participants was 9.8 months and proportion of males was 52%.


InterventionsInfants in experimental group received a single dose of vitamin A in a dose of 100 000 IU. The control group received placebo only. Interventions were given out at the time of measles vaccination.


OutcomesAntibody response to measles vaccine.


NotesThe primary objective of the study was to measure the antibody response to measles vaccine when given with and without vitamin A. This study found no significant inhibitory or enhancing influence on antibody response to measles vaccine when administered concomitantly with vitamin A.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The infants who were immunized with monovalent measles vaccine were randomly assigned, in blocks of eight, to concomitantly receive 100,000 IU of Vitamin A in arachis oil or a placebo containing carboxymethylcellulose prepared in the hospital pharmacy."

Authors do not specify the method of sequence generation.

Allocation concealment?Yes"...arachis oil or a placebo containing carboxymethylcellulose prepared in the hospital pharmacy."

Probably done since hospital pharmacy was responsible for preparing the order of vitamin A and placebo and not likely to have been internal to the study team.

Blinding?
Blinding of Participants
Unclear"...Vitamin A in arachis oil or a placebo containing carboxymethylcellulose..."

Insufficent information to permit judgment.

Blinding?
Blinding of provider
UnclearInsufficent information to permit judgment.

Blinding?
Blinding of outcome assessor
UnclearInsufficent information to permit judgment.

Incomplete outcome data addressed?NoThe proportion of children providing adequate samples is low at 6 months, and there is insufficient detail about the reasons for missing data.

Free of selective reporting?NoThere is no mention of mortality or any morbidity of measles or diarrhoea.

Free of other bias?UnclearInsufficent information to permit judgment.

Chowdhury 2002

MethodsIndividually randomised trial conducted in urban slums of Chandigarh, India, Asia.


ParticipantsChildren aged less than 10 years were eligible for inclusion in the study. Children with xerophthalmia and previous history of vitamin A supplementation were excluded.

A total of 1520 children were randomised either to vitamin A or placebo group. There were 756 children in vitamin A group and 759 in placebo group. Mean age of participants was 51 months and proportion of males in study sample was 50%.


InterventionsThe experimental group received vitamin A in a of 50 000 IU for children aged < 6 months, 100 000 IU for 6-12 months and 200 000 for > 1 year. The control group received placebo. The intervention was given every 4 months for 15 months.


OutcomesAll-cause mortality, cause specific mortality of diarrhoea, pneumonia and meningitis. Incidence of diarrhoea, pneumonia and measles. Measuerement of sub-clinical vitamin A deficiency status by conjunctival impression cytology.


NotesBaseline socio-demographic and anthropometric characteristics were similar in both the groups. Study population had high prevalence of vitamin A deficiency. Children were contacted every 15 days by home visits to obtain information on morbidity and mortality. The study included children less than ten of years of age; however, the mean age of children was 51 months. Study methods were not explicitly described. According to WHO, India is a country with a high child mortality rate (i.e. > 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"From three slums of Chandigarh, 1520 non-xerophthalmic children of less than 10 years of age were individually randomised in equal number to receive vitamin A or placebo."

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
Unclear"An equivalent volume of arachis oil was given as placebo."

Insufficent information to permit judgment.

Blinding?
Blinding of provider
UnclearInsufficent information to permit judgment.

Blinding?
Blinding of outcome assessor
UnclearInsufficent information to permit judgment.

Incomplete outcome data addressed?NoAlthough attrition rates were balanced the rates of mortality were lower than the rate of withdrawal. This could impact on the reliability of the results.

Free of selective reporting?UnclearInsufficent information to permit judgment.

Free of other bias?UnclearStudy not sufficiently reported in order to assess this item fully.

Daulaire 1992

MethodsA cluster randomised, non-placebo controlled trial conducted in Jumla district, Nepal, Asia.


ParticipantsChildren 1-59 months were eligible for inclusion in the trial.

A total of 16 clusters were randomly assigned either to vitamin A or control group. These include a total of 7197 children in which 3786 children were in vitamin A group and 3411 in control group. Proportion of male participants was 51%.


InterventionsChildren in experimental group received vitamin A in a dose of 200 000 IU for children aged 12-59 months, 100 000 IU for those of 6-12 months and 50 000 IU for < 6 months old. Vitamin A was supplemented once only and children were followed for 5 months.


OutcomesAll-cause mortality and cause specific mortality for diarrhoea, pneumonia and measles.


NotesThe study site was a remote mountainous region of northwestern Nepal with a total population of about 80,000, with 12,000 children under 5 years of age. This area was considered as one of the poorest and most medically underserved areas of the country. Infant mortality rate was 189 deaths per 1000 live births and child (1-4 years) mortality rate was 52 per 1000 per year. Malnutrition was prevalent in the study area, and 26% of children aged 1-4 years were suffering from substantial malnutrition. A survey of 3651 children in children under 5 years showed active xerophthalmia in 1.3-2% of population and 1-5% among infants, which is high for this age group. Disaggregated data on mortality was available according to different age groups. We have used data for children 6-59 months according to the objectives of our review. According to WHO, Nepal is a country with a high child mortality rate (i.e. > 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"We randomly selected by card eight of the 16 sub-districts for vitamin A supplementation."

Probably done.

Allocation concealment?NoAuthor contacted and replied, "No effort was made to conceal the allocation sequence."

Blinding?
Blinding of Participants
No"There was no placebo or blinding."

Blinding?
Blinding of provider
No"There was no placebo or blinding."

Blinding?
Blinding of outcome assessor
No"There was no placebo or blinding."

Incomplete outcome data addressed?YesThere was no loss to follow- up. Coverage of intervention was described in detail.

Free of selective reporting?UnclearInsufficent information to permit judgment.

Free of other bias?YesThis study appears to be free of other bias.

DEVTA 2007

Methods


Participants


Interventions


Outcomes


NotesThis study was not included, but some available data was used in a sensitivity analysis. See Characteristics of studies awaiting classification

Dibley 1994

MethodsIndividually randomised trial conducted in 34 rural villages located on the southern coast of Central Java in Indonesia, Asia.


ParticipantsChildren aged 6 to 47 months were eligible for inclusion in the review. Children with cerebral palsy, epilepsy, flaccid paralysis, mental retardation, congenital or rheumatic heart disease were permanently excluded. Those with weight-for-height more than 3.00 SD below the WHO growth reference mean or acute xerophthalmia were excluded for one cycle and treated with high dose vitamin A and then included.

A total of 1405 children were randomised to either vitamin A or placebo group. Proportion of male participants was 50.9%.


InterventionsIntervention group received 206,000 IU of vitamin A in the form of retinyl ester plus 37 IU vitamin E for children > 12 months or 103,000 IU retinyl ester plus 17 IU vitamin E if less than 12 months of age. The control group received placebo that contained 17 or 37 IU vitamin E according to the age of the subject. The intervention was given every 4 months for 24 months. An average of 89% of the children received a treatment (vitamin A or placebo).


OutcomesAll-cause mortality, incidence of diarrhoea and respiratory disease, mean vitamin A serum level, proportion of vitamin A deficient, growth.


NotesBaseline demographic, clinical and nutritional characteristics of the participants were the same, and the groups remained balance at the start of each of the other 5 cycles. Children were visited every other day for 6 cycles. The longest recall period allowed was 4 days. Observed child-days of ALRI of vitamin A group and control group were 280,186 and 273,630. According to WHO, Indonesia is a country with a high child mortality rate (i.e. > 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Randomization of the treatments was done with a 1:1 allocation ratio in blocks of eight, based on a table of random permutations of integers (Cochrane and Cox 1950)."

Likely to be adequate.

Allocation concealment?Yes"All investigators, field and laboratory staff, and participants were masked to the treatment code."

"The capsules were packaged in opaque blister packs with a unique treatment code."

Blinding?
Blinding of Participants
Yes"The oily contents of the vitamin A and placebo capsules were of similar taste and colour."

Blinding?
Blinding of provider
Yes"All investigators, field and laboratory staff, and participants were masked to the treatment code."

Adequate allocation concealment and the identical presentation of placebo and vitamin A should have prevented providers becoming unblinded to treatment group assignment. Low risk of performance bias.

Blinding?
Blinding of outcome assessor
Yes"All investigators, field and laboratory staff, and participants were masked to the treatment code."

Adequate allocation concealment and the identical presentation of placebo and vitamin A should have prevented outcome assessors becoming unblinded to treatment group assignment.

Incomplete outcome data addressed?YesComplete details of those excluded and lost to follow-up with reason were described. There were a low and balanced number of withdrawals between the treatment groups. The analytical method took account of the time on treatment (i.e. follow-up time for each cycle) and this may have been adequate.

Free of selective reporting?YesLack of trial protocol hinders full assessment of this item. However, data on outcomes of relevance to the review were reported.

Free of other bias?YesThis study appears to be free of other bias.

Donnen 1998

MethodsIndividually randomised, non-placebo controlled trial conducted in South Kivu province of Congo, Africa.


ParticipantsChildren 0-72 months were eligible for inclusion in the trial. Children were recruited as soon they were discharged from children hospital Kotive. No exclusion criteria was described.

A total of 358 children were randomly assigned to vitamin A, mebendazole, or control group. Vitamin A had 118 children and control group had 117.


InterventionsThere were three study groups. The first group was supplemented with vitamin A, second group received mebendazole for deworming and third group was simply observed as control. Children in vitamin A group received retinol palmitate in a dose of 100 000 IU for children aged < 1 year and 200 000 IU for those > 1 year. Supplementation was repeated after 6 months and continued for 12 months.


OutcomesAll-cause mortality, growth and incidence of diarrhoea and respiratory disease morbidity.


NotesMorbidity surveillance was done every 2 weeks during 3 months, then every 3 months until 12 months. Data on morbidity outcomes were presented in the form of odds ratios based on generalised estimating equation models. As we were using the data in the form of relative risk and no nominators were given in this study, we could not pool the data for diarrhoea and respiratory morbidity of this study.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"As soon as the children were discharged from the hospital, they were randomly assigned to one of the three groups."

Probably not done

Allocation concealment?UnclearInsufficient details available to make a judgment.

Blinding?
Blinding of Participants
UnclearInsufficient details available to make a judgment.

Blinding?
Blinding of provider
UnclearInsufficient details available to make a judgment.

Blinding?
Blinding of outcome assessor
UnclearInsufficient details available to make a judgment.

Incomplete outcome data addressed?YesAuthors indicate that 6% were lost to follow- up, not discussed in detail. Number died but not indicated how or by group data. Overall, 6% of the children were lost to follow-up, with approximately equal proportions in each group.

Free of selective reporting?UnclearInsufficient details available to make a judgment.

Free of other bias?YesThis study appears to be free of other bias.

Florentino 1990

MethodsIndividually randomised trial conducted in the municipalities of Pililla and Binangonan in the province of Rizal, Philippines, Asia.


ParticipantsChildren 1-6 years of age were eligible for inclusion in the study. Any child with clinical signs of vitamin A deficiency was excluded from the trial.

A total of 2471 children were randomised to three intervention groups. Mean age of children was 3.4 years and proportion of males in study population was 49.5%.


InterventionsThere were 3 study groups, 2 were supplemented with vitamin A and 1 with placebo. The first group in the experimental group received a high dose of vitamin A i.e. 200 000 IU and the second group received a medium dose of vitamin A i.e. 100 000 IU. The control group received placebo only. Children were supplemented only once and were followed for 1 week.


OutcomesIncidence of side effects within 1 week: nausea and/or vomiting, headache, diarrhoea and fever.


NotesThe study area had a high prevalence of malnutrition, and therefore vitamin A deficiency was likely to be prevalent. Study reported outcome for first 48 hours and within a week. We have pooled the data for first week.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"By use of a double-blind study design, children were randomly assigned to three treatment groups."

No qualifying information on what 'randomly assigned' means is provided. Difficult to assess sequence generation.

Allocation concealment?UnclearInsufficient details available to make a judgment.

Blinding?
Blinding of Participants
Yes"Neither the researchers and field workers nor the subjects knew the contents of the preparations; the code was kept confidential by Hoffman La Roche until after the analysis of the results was completed."

Blinding?
Blinding of provider
Yes"Neither the researchers and field workers nor the subjects knew the contents of the preparations; the code was kept confidential by Hoffman La Roche until after the analysis of the results was completed."

Blinding adequate and performance bias unlikely to have influenced results.

Blinding?
Blinding of outcome assessor
Yes"Neither the researchers and field workers nor the subjects knew the contents of the preparations; the code was kept confidential by Hoffman La Roche until after the analysis of the results was completed."

Incomplete outcome data addressed?YesComplete details of those excluded and lost to follow-up were provided. Only 76 children lost, differences slight between groups.

Free of selective reporting?YesThough not explicitly stated all reported measured outcomes have data reported in results with sufficient clarity and explanation.

Free of other bias?YesNo other apparent bias was noted.

Herrera 1992

MethodsCluster randomised trial was conducted in five rural councils in northern Sudan, Africa.


ParticipantsEligibily criteria was age 9-72 months. Children with xerophthalmia were excluded.

Randomisation was done by households. Study included a total of 28,753 children of whom 14,343 were in vitamin A group and 14,149 were in placebo group. Proportion of male children in the study was 50.7%.


InterventionsChildren in vitamin A group received 200 000 IU of retinol palmitate along with 40 IU of vitamin E. The comparison group received 40 IU of vitamin E only. The intervention was given every six months for 18 months.


OutcomesAll-cause mortality and cause specific mortality of diarrhoea, measles, respiratory disease. Incidence of diarrhoea, respiratory disease and measles. Incidence of xeropthalmia, Bitot's spots and night blindness.


NotesAuthors used non- specific terms for describing cause of death (in table 4) like "shortness of breath" "convulsions" and "fever" etc. We have pooled data for "shortness of breath" under heading of lower respiratory tract infection mortality. This is because it is highly unlikely that a child will die of an upper respiratory tract infection and lower respiratory tract infection is a more general term than pneumonia to cover this as it includes pneumonia as well. According to WHO, Sudan is a country with a high child mortality rate (i.e. > 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?No"Randomisation was done by household... Assignment to treatment group was achieved by the two interviewers visiting alternate households throughout the village.

All eligible children in alternate households were assigned to receive, every 6 months, either a capsule of 60 mg (200 000 IU) of vitamin A and 40 mg (40 IU) of vitamin E or a capsule of 40 mg of vitamin E without vitamin A."

Does not appear to be randomised.

Allocation concealment?UnclearInsufficient details available to make a judgment.

Blinding?
Blinding of Participants
Yes"The capsules were colour-coded to avoid the possibility of mix ups, but none of the study team members was aware which was the experimental capsule and which was the placebo until the end of data collection. All eligible children in a household received capsules of the same colour."

Blinding?
Blinding of provider
Yes"The capsules were colour-coded to avoid the possibility of mix ups, but none of the study team members was aware which was the experimental capsule and which was the placebo until the end of data collection. All eligible children in a household received capsules of the same colour."

Performance bias unlikely given that trialists and staff were blinded during the intervention.

Blinding?
Blinding of outcome assessor
Yes"Only the manufacturer knew the contents of the capsules until after data collection and preliminary analysis of the results."

Probably done.

Incomplete outcome data addressed?Yes3320 children did not receive 1 or 2 of the 3 vitamin A or placebo capsules. Most of this non-compliant group consisted of children absent from the household at the time of follow-up, whereas others had moved away or refused to take part further. As a group, the non-compliant children tended to be from poorer households than those who continued in the study. However, there were no significant differences between vitamin A and placebo groups in the number of non-compliant subjects or in their ages, sex, or nutritional status.

With respect to the variables relevant to the intervention, the losses to follow- up were not significantly different from those that remained in the study.

Free of selective reporting?UnclearDoes not reference a protocol or trial registration and does not state that all measured outcomes are reported.

Free of other bias?UnclearInsufficient details available to make a judgment.

Kartasasmita 1995

MethodsIndividually randomised trial conducted in a suburban community of city Bandung, Indonesia, Asia.


ParticipantsChildren aged 12-54 months were included in the study. No exclusion criteria was specified.

A total of 269 children were randomised either to vitamin A or placebo group. Vitamin A supplemented group had 126 children while placebo group had 141 children. Mean age of study participants was 33 months and proportion of males was 51%.


InterventionsThe experimental group received 200 000 IU of vitamin A once every 6 months for 12 months. The comparison group received placebo only.


OutcomesIncidence of respiratory disease. Mean serum retinol levels.


NotesAuthors presented data on respiratory outcomes according to severity of disease. We have included data for "severe respiratory disease" only.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The children were selected by randomised stratified sampling from the almost 2000 under-fives residing in Cikutra."

Insufficient details available to make a judgment.

Allocation concealment?UnclearInsufficient detail provided to make judgement.

Blinding?
Blinding of Participants
Unclear"All children participated in an age- and sex-matched randomised, double blind vitamin A supplementation programme by receiving vitamin A 200,000 IU or placebo capsules orally, at the start and at the 6th month of the study."

Blinding?
Blinding of provider
UnclearInsufficient detail provided to make judgement.

Blinding?
Blinding of outcome assessor
UnclearInsufficient detail provided to make judgement.

Incomplete outcome data addressed?NoInsufficient reporting of attrition/exclusions to permit judgement.

Free of selective reporting?UnclearInsufficient detail provided to make judgement.

Free of other bias?UnclearThe methods of the study are not described very clearly.

Lima 2010

MethodsIndividually randomised trial conducted in Fortaleza, the capital of the Ceara state in northeastern Brazil, Latin America.


ParticipantsChildren aged 2 months to 9 years were eligible for inclusion in the study. Those participants who had fever > 38 C or exclusively breastfed were excluded.

A total of 79 children were randomised either to vitamin A or placebo group. There were 39 participants in vitamin A group and 40 in placebo. Mean age of participants was 43.3 months and proportion of males was 57%.


InterventionsRetinol palmitate was supplemented in a dose of 100 000 IU for children aged < 12 months and 200 000 IU > 12 months in experimental group. The comparison group received Tocopherol (vitamin E) as placebo. Supplements were given at enrolment, 4 and 8 months.


OutcomesMean serum retinol levels, growth and adverse reactions to vitamin A.


NotesThe infant mortality rate in study are was 35/1000 live births. The primary objective of the study was to measure the effect of vitamin A on barrier function of gastrointestinal tract. The study concluded that the prevalence of new parasitic infection, especially with Giardia species, was significantly decreased with vitamin A intervention, suggesting an immune regulatory modulation of this nutrient on parasitic intestinal infections.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes79 children were randomly selected (using computer-generated random numbers).

Allocation concealment?UnclearInsufficient detail provided to make judgement.

Blinding?
Blinding of Participants
YesThe parent or guardian of the children, field study team, and investigators were blinded to treatment agent.

Blinding?
Blinding of provider
YesThe parent or guardian of the children, field study team, and investigators were blinded to treatment agent.

Blinding?
Blinding of outcome assessor
YesThe parent or guardian of the children, field study team, and investigators were blinded to treatment agent.

Indication that field study teams assessed outcomes. They were blinded.

Incomplete outcome data addressed?YesAfter 12-month follow-up, a total of 22 children were withdrawn from the study for the following reasons: change of address (16), parents or guardians did not co-operate with the study (5), and 1 had above the median z score for length or height at the time of the study initiation. The percentage of participants completing the study at 12 months was 72.2%.

Free of selective reporting?NoThe objective of study also included reporting of diarrhoea. Authors had reported the overall incidence of diarrhoea in the whole population but the figures had been presented in a way that they can not be used in the meta-analysis.

Free of other bias?YesNo other apparent bias was observed.

Lin 2008

MethodsThis study was described as randomised, placebo-controlled trial conducted in Wuhan, an industrial centre in central region of China, Asia.


ParticipantsInlcusion criteria was age 2 to 7 years. children were recruited from kindergarten in the area. Those who had fever, diarrhoea or a recent preventive injection were excluded from the study. Underweight children with BMI age- and sex- specific 5th percentile of the first US National Health and Nutrition Examination Survey data were excluded. Children whose protein or energy intake of Chinese RDA were also excluded.

A total of 105 children were randomised to three intervention groups (described below). Mean age of study participants was 55 months and proportion of male participants was 61%.


InterventionsThere were 3 study groups. Two of these consisted of children who were vitamin A deficient and 1 with children who were vitamin A sufficient. Vitamin A was given only to 1 of the group of vitamin A deficient children in a dose of 100 000 IU every month for three months. The rest of two groups received placebo.


OutcomesAll-cause mortality, mean serum vitamin A levels.


NotesIn this review we have included data for vitamin A deficient children who were either supplemented with vitamin A or placebo. According to WHO, China does not have a high child mortality rate (i.e. < 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The remaining 70 vitamin A-deficient children were randomly and equally divided into vitamin A deficient-supplemented group and vitamin A-deficient placebo group."

The term 'randomised' is also used to describe a 3rd group that is clearly matched. This may not be a RCT.

Allocation concealment?UnclearInsufficient detail provided to make judgement.

Blinding?
Blinding of Participants
Yes"Children of vitamin A-deficient-supplemented group were given 100 000 IU (retinol equivalent) vitamin A capsules every 2 weeks for 3 months (Grubesic, 2004). Children of vitamin A-sufficient placebo group and vitamin A-deficient placebo group received placebo capsules in the same way."

Blinding?
Blinding of provider
UnclearAlthough study was double randomised trial but no details of how blinding was achieved was described in the district.

Blinding?
Blinding of outcome assessor
UnclearInsufficient detail provided to make judgement.

Incomplete outcome data addressed?YesNo attrition reported.

Free of selective reporting?NoMain outcome data are not reported in a manner that can be analysed.

Free of other bias?UnclearAs blinding is not described, potential performance bias and other sources of bias cannot be assessed.

Lin 2009

MethodsIndividual randomised trial conducted in rural China, Asia.


ParticipantsChildren age 6 months to 7 years were included in the study. Those without informed consent or with acute
and chronic diseases were excluded.

A total of 132 children were randomly allocated to three intervention groups. Mean age of children was 36.5 months and proportion of males was 50%.


InterventionsThe three intervention groups included vitamin A, beta-carotene and placebo. The experimental group received 100 000 IU of vitamin A every month for 3 months. Placebo group received biscuits.


OutcomesMean vitamin A serum levels


NotesWe have included the results for vitamin A group versus placebo only.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"The 50 severe vitamin A deficient children and 82 marginal vitamin A deficient children were randomly divided into three groups respectively by using a table with randomly assorted digits."

Probably done.

Allocation concealment?UnclearNo methods of allocation concealment are described in the text.

Blinding?
Blinding of Participants
No"Vitamin A intervening group were administered 100,000 IU vitamin A capsules...the beta-carotene intervening group...was administered 4 mg purified beta-carotene...dissolved in vegetable oil and dropped into a general little biscuit...the placebo group were just administered a general little biscuit."

Vitamin A and placebo were administered in two different forms. Vitamin A was administered in capsule form while placebo was given in the form of biscuits.

Blinding?
Blinding of provider
NoVitamin A and placebo were administered in two different forms. Vitamin A was administered in capsule form while placebo was given in the form of biscuits.

Blinding?
Blinding of outcome assessor
NoVitamin A and placebo were administered in two different forms. Vitamin A was administered in capsule form while placebo was given in the form of biscuits.

Incomplete outcome data addressed?YesNo dropouts reported, and numbers at baseline and follow-up appear to be the same.

Free of selective reporting?NoUse of clinic services, hospitalisation, cause specific morbidity not reported.

Free of other bias?YesThis study appears to be free of other bias.

Long 2006

MethodsFactorial design, individually randomised trial conducted in La Magdalena Atlicpac, Mexico, North America.


ParticipantsChildren aged 6 to 15 months were eligible for inclusion in the review. Children who were suffering from diseases causing immunosuppression and any congenital or acquired alteration of the digestive tract that could alter the absorption of micronutrients, were excluded. Children who were taking vitamin supplements were also excluded
from the study.

A total of 786 children were randomised to four intervention groups. Mean age of participants was 9.8 months. The proportion of males in study population was 51.7%.


InterventionsThe four intervention groups were as follows:
1) Vitamin A group that received 20,000 IU retinol every 2 months for children aged < 1 year or 45,000 IU for children aged > 1 year.
2) Zn group that received a daily dose equivalent to 20 mg elemental Zn as zinc methionine
3) A group that received both the zinc supplement and the vitamin A as above
4) A placebo group

Interventions were delivered every 2 months for 12 months.


OutcomesDiarrhoea and respiratory disease morbidity.


NotesWe have included data of this factorial design trial in two sets. First data set give comparisons for vitamin A vs. placebo and the second set includes data for vitamin A + Zinc vs. zinc only. Data on respiratory morbidity was given with three definitions. We have pooled the data for "cough + difficulty breathing" under the heading of lower respiratory tract infection.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"The randomisation sequence was generated by using a random-number table by project personnel from CENSIA, a division of the Mexican Ministry of Health."

Allocation concealment?Yes"These solutions were packaged in consecutively numbered, colour-coded, opaque plastic droplet bottles to ensure that field personnel and the principal investigator were blinded."

Blinding?
Blinding of Participants
Yes"The vitamin A, zinc, and vitamin A + zinc supplements were prepared by personnel at the National Institute of Nutrition in 5-mL solutions that were similar in taste and appearance."

Blinding?
Blinding of provider
Yes"This double-blind randomised trial ... These solutions were packaged in consecutively numbered, color-coded, opaque plastic droplet bottles to ensure that field personnel and the principal investigator were blinded."

Blinding?
Blinding of outcome assessor
Yes"This double-blind randomised trial ... These solutions were packaged in consecutively numbered, color-coded, opaque plastic droplet bottles to ensure that field personnel and the principal investigator were blinded."

Probably done.

Incomplete outcome data addressed?YesLost to follow-up data given along with reasons for lost to follow-up. Ninety- three children were lost to follow-up or were excluded.

Free of selective reporting?UnclearStudy protocol not available so can not assess or make any judgement.

Free of other bias?YesThis study appears to be free of other bias.

Long 2006 (2)

Methods


Participants


Interventions


Outcomes


NotesAs Long 2006 above.

Long 2007

MethodsIndividually randomised trial conducted in Mexico, North America.


ParticipantsChildren 5-15 months were eligible for inclusion in the trial. Those who were immunosuppressed, had any congenital abnormality or chronic diarrhoea were excluded. Those who had a history of vitamin A supplementation were also excluded.

A total of 195 children were randomised in which 97 were in vitamin A group and 98 in placebo group. The proportion of males study population was 49.7%.


InterventionsThe experimental group received vitamin A in a dose of 20,000 IU for those aged < 12 months and 45,000 IU for those > 12 months. Intervention was repeated every 2 months for 12 months.


OutcomesIncidence of diarrhoea and respiratory disease.


NotesThe baseline socio-demographic characteristics of study children and households were similar between children who received vitamin A and those who were given the placebo. Children received monthly visits and referrals to the doctor, which appeared to exceed normal treatment.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"The randomisation sequence was generated by project personnel based at the National Institute of Public Health."

Probably done.

Allocation concealment?YesPersonnel at the National Institute of Nutrition carried out the preparation of the supplements to assure that field personnel and the principal investigator were unaware of treatment regimen. Children in the vitamin A and placebo groups received a 5ml solution, from identical opaque plastic droplet bottles numbered consecutively, administered by the field team.

Blinding?
Blinding of Participants
Yes"Testing had been carried out at the National Institute of Nutrition to assure that the placebo and vitamin A water miscible solution were similar in taste, viscosity and colour."

Blinding?
Blinding of provider
Yes"Personnel at the National Institute of Nutrition carried out the preparation of the supplements to assure that field personnel and the principal investigator were unaware of treatment regimen."

Blinding?
Blinding of outcome assessor
Yes"Personnel at the National Institute of Nutrition carried out the preparation of the supplements to assure that field personnel and the principal investigator were unaware of treatment regimen."

Incomplete outcome data addressed?YesUnclear what was done with data for 7 missing children, but dropout was small and similar between groups (4 intervention, 3 control).

Free of selective reporting?UnclearProtocol not referenced, though the grant applications may be available.

Free of other bias?YesThis study appears to be free of other bias.

Pant 1996

MethodsCluster randomised trial in rural Nepal, Asia.


ParticipantsChildren aged between 6 months and 10 years were eligible to participate in the study.

From 100 potentially eligible cluster sites, 75 were randomised (approximately 25,301 children). Baseline data on the number in each treatment group, proportion of male participants and mean age were not provided.


InterventionsThe intervention groups were:

1. Vitamin A given as a single dose via a capsule (100,000 IU for children aged 6 to 12 months and 200,000 IU for children aged 1 to 10 years).

2. Control (not adequately described)

3. Nutritional education

Study duration: 24 months.


OutcomesAll- cause mortality and Bitot's spots.


NotesNo details on loss to follow- up were given. Inclusion/exclusion criteria were inadequately described. No nominators/denominators were available for Bitot's spots.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Using random number tables and the reference number for each block ..."

Allocation concealment?UnclearInsufficient detail provided to make judgment.

Blinding?
Blinding of Participants
UnclearInsufficient detail provided to make judgment.

Blinding?
Blinding of provider
UnclearInsufficient detail provided to make judgment.

Blinding?
Blinding of outcome assessor
UnclearInsufficient detail provided to make judgment.

Incomplete outcome data addressed?NoNo information regarding incomplete outcome data addressed given.

Free of selective reporting?NoVery specific outcomes reported. Five types of examinations were administered to the study children: ophthalmic, physical, anthropometric, blood, and faecal; while data in results is given only for prevalence of Bitot's spots and all-cause mortality.

Free of other bias?UnclearInsufficient detail provided to make judgment.

Pinnock 1986

MethodsIndividually randomised study in urban area of Australia.


ParticipantsChildren aged between 1 and 4 years of age in three general practices from Adelaide. Children with more than 15 days of cough or three separate episodes of respiratory illness during the preceding 3 months were eligible.

147 children were randomised to the treatment groups. Mean age was 39.3 months. 50% of the sample was male.


InterventionsVitamin A administered orally as retinyl palmitate (1160mcg) three times per week for 20 weeks versus placebo.


OutcomesAcute respiratory infections, pneumonia, mean serum vitamin A.


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Randomization of treatment was achieved by combining active and placebo bottles in a sequence, which was determined by consulting a table of random numbers, and numbering the bottles accordingly."

Probably done.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
Yes"The placebo was a similarly constituted syrup omitting retinyl palmitate and labelled and bottled identically."

Blinding?
Blinding of provider
Yes"All staff connected with the study remained blind to the identity of the child's medication."

Blinding?
Blinding of outcome assessor
Yes"All staff connected with the study remained blind to the identity of the child's medication."

Incomplete outcome data addressed?YesA high rate of attrition, but reasons for withdrawal given and that there were no significant changes in the distribution of major potential confounding factors between the two groups.

Free of selective reporting?UnclearThe protocol of the study not available.

Free of other bias?YesNo other apparent bias was observed.

Pinnock 1988

MethodsIndividually randomised study in urban area of Australia.


ParticipantsChildren aged between 0 and 2 years with previous history of bronchiolitis and nasal culture positive for HSV were included.

Children taking vitamin A, and those with cystic fibrosis, cardiopulmonary difficulties, major brain dysfunctions were excluded.

206 children were randomised to the treatment groups. Mean age was 58 months. 60% sample was male.


InterventionsVitamin A administered as retinyl palmitate 4.2mg per week for 12 months versus placebo.


OutcomesDiarrhoea, diarrhoea-related hospitalisation, acute respiratory infections, pneumonia, pneumonia-related hospitalisation, mean serum vitamin A.


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Randomization was achieved by randomly allocating four of eight batch numbers to Vitamin A supplement and the remaining four to placebo. The batch number code was retained by the manufacturer."

Allocation concealment?Yes"The batch number code was retained by the manufacturer. The bottles were then distributed sequentially according to batch number as children presented..."

Probably done.

Blinding?
Blinding of Participants
Yes"The placebo had an identical appearance and formulation except for the active ingredient."

Probably done.

Blinding?
Blinding of provider
Yes"Both investigators and parents were blind as to the treatment status of the child."

Blinding?
Blinding of outcome assessor
Yes"Both investigators and parents were blind as to the treatment status of the child ... The batch number code was retained by the manufacturer."

Incomplete outcome data addressed?YesComplete details of those excluded and lost to follow-up were provided.

Free of selective reporting?NoOutcomes mentioned in methods not reported in results.

Free of other bias?YesThis study appears to be free of other bias.

Rahman 2001

MethodsIndividually randomised study conducted in an urban area of Bangladesh, Asia.


ParticipantsChildren aged between 12 and 35 months were eligible for inclusion in the study.

Children who had received Vitamin A within the previous 4 months, had severe malnutrition, with signs or symptoms of vitamin A or zinc deficiency, or with any systemic illness such as diarrhoea, respiratory infection, fever, or any other illness that warranted medical intervention at the time of enrolment were excluded.

800 children were enrolled (200 in each of the four treatment groups). Mean age of participants was between 23.5 and 24.2 months across the treatment groups. 56% of the participants were male.


InterventionsThere were four treatment groups:

1. Vitamin A 200,000 IU (60 mg) given as a single capsule at day 14, with placebo syrup daily for 14 days.

2. Placebo capsule at day 14 and placebo syrup for 14 days.

3. Vitamin A 200,000 IU (60 mg) given as a single capsule at day 14, with zinc syrup daily for 14 days.

4. Zinc syrup daily for 14 days, placebo capsule at day 14.

Duration of study: 6 months.


OutcomesDiarrhoea, acute respiratory infections, serum vitamin A levels and vitamin deficiency.


NotesData on treatment analysis was not presented. We have written to authors for data on each treatment arm.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"The children were randomly assigned by a person not involved in the study who used permuted blocks of random numbers."

Probably done.

Allocation concealment?Yes"Sets of 2 bottles and 1 capsule for each child were serially numbered ... A local pharmaceutical company prepared the study syrups (zinc and placebo) which were supplied in identical 50-mL bottles ... The vitamin A and placebo capsules looked identical."

Probably done.

Blinding?
Blinding of Participants
Yes"The zinc and placebo syrups were supplied in bottles that looked identical, and the appearance and consistency of the syrups were similar. Vitamin A and placebo capsules were identical in appearance."

Probably done.

Blinding?
Blinding of provider
YesIdentical presentation and: 'The randomisation code was kept sealed until the completion of the study.'

Probably done.

Blinding?
Blinding of outcome assessor
Yes"The treatment allocations were disclosed after the final analysis."

Incomplete outcome data addressed?YesData on lost to follow-up given and also stated that the baseline characteristics of children who were excluded or lost to follow-up were comparable to those of the children who continued in the study.

Free of selective reporting?UnclearProtocol not available.

Free of other bias?YesNo other bias was noticed.

Rahmathullah 1990

MethodsCluster-randomised trial conducted in Trichy district of Tamil Nadu in southern India, Asia.


ParticipantsChildren aged 6 to 60 months were included in the study.

Clustering unit was "panchyat" (local-government areas). A total of 206 clusters were formed, and the majority of them consisted of 50 to 100 children.The included clusters had a total of 15,419 children of whom 7764 were in vitamin A group and 7655 in placebo group.


InterventionsChildren in experimental group received weekly doses of 8333 IU vitamin A and 20 mg vitamin E. The control group received 20 IU of vitamin E only in peanut oil. Any children diagnosed with xerophthalmia at baseline, midterm, or final examination was given a high-dose (200 000 IU) supplement of vitamin A and continued in the study. Supplementations were given for 52 weeks. Children who missed 7 consecutive dosages were excluded from the analysis.


OutcomesAll-cause mortality, cause specific mortality of diarrhoea, measles and respiratory disease. Incidence of diarrhoea and respiratory disease morbidity.


NotesThe baseline characteristics of the two groups were similar in terms of age and sex, one-month history of diarrhoea and respiratory disease, anthropometric indexes of nutritional status, xerophthalmia status, five-year retrospective history of mortality of children under five, household economic, household hygienic status, and serum retinol levels. On average > 90% of the children were contacted each week, and the lowest coverage in any single week was 88%. 11% had clinical evidence of xerophthalmia while about 38% had serum retinol concentrations < 0.35 mmol/L at baseline.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The clusters were arranged according to population size; after a random start, they were assigned alternately to the treated or control groups."

Exact method of sequence generation was not provided.

Allocation concealment?Yes"...no one associated with the study was aware of the colour code, which was held by the Hoffmann-LaRoche until the study ended."

Blinding?
Blinding of Participants
Yes"The appearance and taste of the solutions were identical ... no one associated with the study was aware of the colour code, which was held by the Hoffmann-LaRoche until the study ended."

Probably done.

Blinding?
Blinding of provider
Yes"The appearance and taste of the solutions were identical ... no one associated with the study was aware of the colour code, which was held by the Hoffmann-LaRoche until the study ended ... masked controlled..."

Probably done.

Blinding?
Blinding of outcome assessor
Yes"The appearance and taste of the solutions were identical ... no one associated with the study was aware of the colour code, which was held by the Hoffmann-LaRoche until the study ended ... masked controlled..."

Incomplete outcome data addressed?Yes"There was no difference in rates of contact between the treated and control groups. The reasons for lack of contact included moving from the study area ..."

Reasons for lost to follow-up given with a note that there was no difference in contact rates between the two groups.

Free of selective reporting?YesAll important outcomes given in results as mentioned in the methods section.

Free of other bias?YesNo other apparent bias was noticed.

Ramakrishnan 1995

MethodsIndividually randomised trial conducted in rural India, Asia.


ParticipantsChildren aged 6-36 months were eligible for inclusion in the trial. Those with ophthalmic signs of xerophthalmia, serious diseases, or severe malnutrition (< 60% of weight-for-age or < 85% of height-for-age of the National Center for Health Statistics median) were excluded and received appropriate treatment including vitamin A.

A total of 538 children were included, 309 in vitamin A group and 274 in placebo group. Mean age of children was 18.6 months and proportion males was 49.9%.


InterventionsChildren in experimental group received vitamin A in a dose of 100,000 IU for children aged < 1 year and 200,000 IU for children aged > 1 year. The comparison group received only placebo. The interventions were given every 4 months for 12 months.


OutcomesIncidence of diarrhoea and respiratory disease.


NotesDefinition used for respiratory disease was too generalised to be included under lower respiratory tract infection. It mainly covered upper respiratory tract infections.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The study design was a randomised, double-blind, placebo controlled intervention trial in which every 4 mo the treatment group received a high-dose vitamin A supplement and the control group received a placebo."

Insufficient detail provided.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
Yes"The study design was a randomised, double-blind, placebo controlled intervention trial in which every 4 mo the treatment group received a high-dose vitamin A supplement and the control group received a placebo."

Statement that blinding occurred, no further details provided.

Blinding?
Blinding of provider
Yes"The study design was a randomised, double-blind, placebo controlled intervention trial in which every 4 mo the treatment group received a high-dose vitamin A supplement and the control group received a placebo."

Statement that blinding occurred, no further details provided.

Blinding?
Blinding of outcome assessor
Yes"The study design was a randomised, double-blind, placebo controlled intervention trial in which every 4 mo the treatment group received a high-dose vitamin A supplement and the control group received a placebo."

Statement that blinding occurred, no further details provided.

Incomplete outcome data addressed?Yes"Out of the 660 children who were eligible, a final group of 592 children who had both pre- and post-anthropometric measurements were used in this analysis. The losses at follow-up due to migration (n = 50), death (n = 10) and incomplete measurements (n = 8) were similar for both groups."

Losses were not large and balanced between groups; unlikely to introduce substantial bias here. Clinically relevant impact unlikely.

Free of selective reporting?No"The examination for ophthalmic signs of vitamin A deficiency, using WHO criteria (27), was conducted by trained ophthalmologists from the Department of Ophthalmology, CMCH, at baseline and at the end of the 1-y follow-up period. Blood samples were also taken (from finger pricks) at the beginning and the end of the study by using 250-pt capillary tubes. Serum retinol concentrations were estimated by using reversed-phase HPLC at the Wellcome Research Laboratory, CMCH, Vellore, using retinyl acetate and all trans-retinol (Sigma Chemical Co, St Louis) as standards."

Though measured, serum retinol results are never reported.

Free of other bias?YesThis study appears to be free of other bias.

Ranjini 2001

MethodsIndividually randomised trial conducted in India, Asia.


ParticipantsChildren aged 12-60 months and having recurrent respiratory tract infections were eligible for inclusion in the trial. Those with mild or moderate asthma; children who were on vitamin supplements or who had received a massive dose of vitamin A in the previous 6 months, those with pre-existing congenital heart disease, chronic lung disease, pulmonary tuberculosis or immunodeficiency disorders, those on immunosuppressive drugs and those with clinically apparent vitamin A deficiency were excluded.

A total of 61 children were randomised in which 30 were in vitamin A group and 31 in placebo group. The mean age of children was 35.7 months and proportion of males was 60.7%.


InterventionsChildren in experimental group received a single dose of vitamin A in a dose of 200 000 IU. The comparison group was given placebo in archis oil. Follow- up period was 6 months.


OutcomesIncidence of respiratory disease. Mean vitamin A serum levels.


NotesDefinition of respiratory illness used was not specific enough.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Eligible children were randomly allocated to receive either 200,000 IU of vitamin A in arachis oil or a placebo containing arachis oil without vitamin A."

Details of sequence generation not specified.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
Unclear"Eligible children were randomly allocated to receive either 200,000 IU of vitamin A in arachis oil or a placebo containing arachis oil without vitamin A."

Blinding?
Blinding of provider
UnclearNot mentioned.

Blinding?
Blinding of outcome assessor
UnclearNot mentioned.

Incomplete outcome data addressed?Unclear"Of the 61 included children, seven (three in the placebo group and four in vitamin A group) did not return for follow-up." (second page)

Authors do not address the reasons for losses to follow- up, and given the small size of this trial, bias may or may not be introduced depending on why the losses occurred by group. given this lack of discussion, it is difficult to judge weather or not there is a low or high risk of bias, but it is likely to be high.

Free of selective reporting?Unclear"Details of doctor or outpatient visits and hospital cough, wheezy breathing, shortness of breath and fever. Details of doctor or outpatient visits and hospital admissions during the study period were also recorded. During each monthly follow-up visit, the entries in the monthly calendar were reviewed with the parent." (1st, 2nd page)

Hospitalisation was not reported though it was collected.

Free of other bias?UnclearVery little information provided in the paper; difficult to assess.

Reddy 1986

MethodsFactorial design individually randomised trial conducted in India, Asia.


ParticipantsChildren aged 1-5 years were included in the study. Those without parental consent were excluded.

A total of 487 children were randomised to four intervention groups. Mean age and proportion of males were not described.


InterventionsThe four intervention groups were as follows:

Group A: oral administration of L-tetramisole (50 mg) followed 3 days later by a dose of 200 000 IU of vitamin A.
Group B: massive dose of vitamin A of 200 000 IU
Group C L-tetramisole (50 mg) orally.
Group D placebo.


OutcomesMean vitamin A serum levels.


NotesData have been included in two sets.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"After the baseline survey, the children were assigned, randomly, into four groups, matched for age, anthropometry, serum vitamin A, and worm infestation and the following treatment was given."

Insufficient details provided to make judgement.

Allocation concealment?UnclearInsufficent information to permit judgment.

Blinding?
Blinding of Participants
UnclearInsufficent information to permit judgment

Blinding?
Blinding of provider
UnclearInsufficent information to permit judgment

Blinding?
Blinding of outcome assessor
UnclearInsufficent information to permit judgment

Incomplete outcome data addressed?UnclearInsufficent information to permit judgment

Free of selective reporting?Unclear"After 6 months and 12 months, heights and weights were measured, clinical status was assessed and morbidity for the preceding one month was recorded. Finger-prick blood samples were collected and serum vitamin A levels were estimated, stool samples were examined for the presence of ascaris ova and other parasites."

Authors do not report height or weights, or detailed data on clinical status or morbidity.

Free of other bias?UnclearInsufficent information to permit judgment.

Reddy 1986 (2)

Methods


Participants


Interventions


Outcomes


NotesAs Reddy 1986 above.

Ross 1993 HEALTH

MethodsRandomised double-blind controlled trial conducted in guinea savannah area of Ghana, Africa.


ParticipantsChildren aged 6 to 59 months were included. Those with active xerophthalmia or measles were excluded from the trial the moment them were confirmed.

A total of 1455 children were included. The proportion of male children was 49.5%.


InterventionsChildren in vitamin A group received either 200,000 IU retinol equivalent for participants aged > 12 months or 100,000 IU for aged 6-12 months. The control group received placebo. Interventions were given every 4 months for 12 months.


OutcomesAll-cause mortality. Mean daily prevalence of respiratory tract disease, diarrhoea, measles, malaria. Mean vitamin A serum levels, all-cause hospitalisations.


NotesThe study populations were rural and their main staple foods are deficient in carotenoids and vitamin A. Vitamin A deficiency and xerophthalmia were recognised as problems locally. Children were visited weekly for 1 year. Children in the Health Study were followed up 596 child-years for vitamin A group and 589 for control group. According to WHO, Ghana is a country with a high child mortality rate (i.e. > 40/1000).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Randomisation was blocked in both studies to ensure similar numbers of children in each group in each part of the study area."

Explicit methods for generating allocation sequence not available.

Allocation concealment?Yes"Randomisation was carried out in London by an independent statistician, who held the randomisation code and who also did an interim analysis of the mortality results from the Survival Study for the trial's data-monitoring committee after a year of follow-up."

Code was protected for the duration of the trial.

Blinding?
Blinding of Participants
Yes"Vitamin A and placebo were supplied by Hoffmann-La-Roche's Sight and Life Programme, and were similar in taste and colour. In the Survival Study, liquid vitamin A or placebo was supplied in opaque 150 mL bottles containing 20 IU/mL vitamin E alone (placebo) or plus 100 000 IU/mL retinol equivalent as retinyl palmitate (vitamin A) in purified peanut oil. Each bottle had a unique number, and was labelled with a cluster code before despatch to Ghana."

Blinding?
Blinding of provider
YesAs above; probably done.

Blinding?
Blinding of outcome assessor
YesIn view of the blinding procedures in place elsewhere in the study this was probably adequate.

Incomplete outcome data addressed?UnclearMorbidity information was missing for 5-7% of the weekly follow-up visits owing to temporary absences of the study children or their mothers, but the missing data were equally distributed between the treatment groups.

Free of selective reporting?NoThere was an indication that xerophthalmia data were measured, but none are reported. No protocol is available.

Free of other bias?YesNo other apparent bias was noted.

Ross 1993 SURVIVAL

MethodsCluster randomised trial conducted Ghana, Africa.


ParticipantsChildren aged 6-90 months were eligible for inclusion in the trial. Xeropthalmic children were excluded.

Study involved 185 cluster that included 21906 children. Proprtion of male children was 51.5%.


InterventionsThe experimental group received vitamin A supplementation in a dose of 100 000 IU for children aged 6-11 months and 200,000 IU for older children. The comparison group received placebo. Vitamin E in a dose of 20 IU was given to both the groups. Intervention were delivered every 4 months for 24 months.


OutcomesAll-cause mortality and cause specific mortality of diarrhoea, respiratory disease, measles and meningitis. Mean vitamin A serum levels. Malaria prevalence.


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Randomisation was blocked in both studies to ensure similar numbers of children in each group in each part of the study area."

Explicit methods for generating allocation sequence not available.

Allocation concealment?Yes"Randomisation was carried out in London by an independent statistician, who held the randomisation code and who also did an interim analysis of the mortality results from the Survival Study for the trial's data-monitoring committee after a year of follow-up."

Code was protected for the duration of the trial.

Blinding?
Blinding of Participants
Yes"Vitamin A and placebo were supplied by Hoffmann-La-Roche's Sight and Life Programme, and were similar in taste and colour. In the Survival Study, liquid vitamin A or placebo was supplied in opaque 150 mL bottles containing 20 IU/mL vitamin E alone (placebo) or plus 100 000 IU/mL retinol equivalent as retinyl palmitate (vitamin A) in purified peanut oil. Each bottle had a unique number, and was labelled with a cluster code before despatch to Ghana."

Probably done.

Blinding?
Blinding of provider
YesAs above; probably done.

Blinding?
Blinding of outcome assessor
YesIn view of the blinding procedures in place elsewhere in the study this was probably adequate.

Incomplete outcome data addressed?Unclear8.4% (1847) children lost to follow-up and similar between treatment groups.

The reasons for losses to follow-up are not provided.

Free of selective reporting?NoAuthors collected data on night blindness, Bitot's spots, and xerophthalmia but do not report it.

Free of other bias?UnclearThe method for inflating the CIs is not well-described. No ICC reported.

Semba 1992

MethodsIndividually randomised trial conducted in Indonesia, Asia.


ParticipantsChildren aged 3-6 years were eligible for inclusion in the study. Those who had median weight for age <80% of the National Center for Health Statistics were excluded from the study. Children with serious illness were also excluded from the study and treated appropriately.

A total of 236 children were randomised to four intervention groups. Mean age of participants was 58.9 months and proportion of males was 71.6%.


InterventionsThere were 4 intervention groups. Two groups (vitamin A and placebo) had clinical signs of vitamin A deficiency while two groups were clinically normal.

Participants in vitamin A groups received a single dose of 60 000 microgram of retinol equivalent. Children were followed for one month.


OutcomesMean vitamin A serum levels.


NotesThe 2 vitamin A and 2 placebo groups were combined, respectively, for meta- analysis.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"A double-masked, randomised, placebo-controlled, clinical trial involving 236 preschool children, age 3-6 years, was carried out at the outpatient clinic of the Cicendo Eye Hospital in Bandung, West Java, Indonesia."

Details of sequence generation not provided.

Allocation concealment?Yes"The treatment code was broken after the conclusion of the study."

Allocation sequence appears to have been protected.

Blinding?
Blinding of Participants
Yes"A double-masked, randomised, placebo-controlled, clinical trial involving 236 preschool children."

"The vitamin A and placebo solutions were supplied in coded containers, and the identity of the solutions was known only to the manufacturer... The solutions were identical in colour, taste, smell and consistency."

Blinding?
Blinding of provider
YesAs above; providers likely to have been adequately blinded.

Blinding?
Blinding of outcome assessor
UnclearThe provider administering vitamin A and the outcome assessor appear to be different individuals and it is not clearly stated if the outcome assessors were also blinded to group assignment.

Incomplete outcome data addressed?Yes232/236 children enrolled at baseline completed the study protocol. (page 102)

Free of selective reporting?UnclearDoes not reference a protocol or trial registration and does not state that all measured outcomes are reported.

Free of other bias?UnclearInsufficient information to permit judgment.

Semba 1995

MethodsIndividually randomised study in rural Indonesia, Asia.


ParticipantsChildren aged 6 months at vaccination against measles were included.

Children who had measles previously were excluded.

336 children were randomised to the two treatment groups. Baseline details on age and gender were not provided.


InterventionsVitamin A given as a single dose (100,000 IU) versus placebo.

Vitamin A or placebo given with measles vaccine.

Study duration: 6 months.


OutcomesMeasles.


NotesThe primary objective of the study was to measure the antibody response to measles vaccine when given along with vitamin A or placebo. Trialists found a significant decrease in seroconversion of measles vaccine in the intervention group compared to placebo.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Treatment was assigned by random number table in blocks of ten."

Probably done.

Allocation concealment?Yes"Infants received identification numbers as they were enrolled in the study, and each identification number had an envelope with an identical capsule containing either vitamin A or placebo."

Probably done.

Blinding?
Blinding of Participants
Yes"Vitamin A, 100 000 IU, or placebo in identical capsules."

Probably done.

Blinding?
Blinding of provider
Yes"Infants received identification numbers as they were enrolled in the study, and each identification number had an envelope with an identical capsule containing either vitamin A or placebo."

Probably done.

Blinding?
Blinding of outcome assessor
YesAs above; probably done.

Incomplete outcome data addressed?No"Follow-up rates were 93% and 90% at one and six months post immunisation, respectively."

The reasons for lost to follow-up not given; only available case data given.

Free of selective reporting?UnclearStudy protocol was not available.

Free of other bias?UnclearInadequate information presented to assess this formally.

Sempertegui 1999

MethodsIndivdualy randomised trial conducted in the northwestern region of the Quito, Ecuador, South America.


ParticipantsChildren aged 6 to 36 months were eligible for inclusion in the review. Those children who had clinical vitamin A deficiency, who did not reliably stayed at home or at day care centres during weekdays or who had been given multivitamins in the last 3 months, were excluded.

A total of 400 children were randomised either to vitamin A or placebo group with equal (200 each) in both the groups. Mean age of participants was 21.1 months and half of the study population was male.


InterventionsChildren in the supplement-treated group received a weekly dose of 10,000 IU of vitamin A for 40 weeks, and children in the non-supplement group received a weekly placebo for the same period.


OutcomesIncidence of diarrhoea and respiratory disease morbidity. Mean vitamin A serum levels.


NotesThe baseline study characteristics were comparable in both the groups. Study was conducted in a slum with substantial rates of malnutrition and subclinical vitamin A deficiency. Morbidity surveillance was done weekly.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"For random allocation of each child to treatment or placebo group the following procedure was performed. Identical flasks containing vitamin A or placebo were numbered from 1 to 400 by members of the study team in Boston, Massachusetts. The local Ethical Committee of the Ecuadorian Biotechnology Corporation in Quito did not know the identity of the active or placebo flasks, because they did not have the code. Then, this committee assigned each flask to a specific child from a random list by using a table of random numbers. After randomisation, the ethical committee received the confidential code from Boston."

Allocation concealment?Yes"After randomisation, the ethical committee received the confidential code from Boston and kept it for the remainder of the study, when it was revealed."

Blinding?
Blinding of Participants
Yes"Identical flasks containing vitamin A or placebo were numbered from 1 to 400 by members of the study team in Boston, Massachusetts."

Trial described as double blind; given procedures used for ensuring that intervention and placebo were identical, it is very likely that blinding of children was maintained.

Blinding?
Blinding of provider
Yes"The syrups were administered at home and at day care centres by study researchers who were blinded to the presence or absence of active drug."

Blinding?
Blinding of outcome assessor
YesOutcome assessors were the same as the providers, therefore blinded.

Incomplete outcome data addressed?Yes"A total of 306 children finished the study, because 50 children from the supplement-treated group and 44 from the non- supplemented group were lost to follow-up when their families moved to other neighbourhoods. Of all children, 70%, including those lost to follow-up, accumulated >30 weeks of observation... Children with incomplete follow-up were distributed evenly in relation to the baseline variables (Table 2)."

Loss to follow-up similar in magnitude in both groups and for similar reasons. Some lost still contributed data.

Free of selective reporting?UnclearProtocol referred to but not referenced. Not explicitly stated if all measured outcomes were reported.

Free of other bias?YesNo other apparent bias was noted

Shankar 1999

MethodsThis study was an individually randomised trial conducted in Guinea Bissau, Africa.


ParticipantsChildren aged 6-60 months and those who plan to reside within the study area for at least 1 year were eligible for inclusion in the trial. Those with ocular signs of vitamin A deficiency or history of night blindness were excluded.

A total of 480 children were randomised either to vitamin A or placebo group. The vitamin A group had 239 participants whole placebo group 241. Proportion of males in the study population was 51%.


InterventionsThe experimental group received vitamin A supplementation in a dose of 100 000 IU for children aged < 1 year and 200,000 IU for older children. The comparison group received placebo. Both the groups received 20 IU of vitamin E. Intervention was given every 4 months for 13 months.


OutcomesIncidence of diarrhoea and malaria morbidity. Mean vitamin A serum levels.


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Within these strata, children were individually allocated vitamin A or placebo in blocks of four (two vitamin A, two placebo) by computer generated randomly permutated codes."

Allocation concealment?Yes"Capsules were encoded into four groups; two placebo and two vitamin A, and the code was kept offsite by personnel who were not involved in the study."

Blinding?
Blinding of Participants
YesIdentical capsules, and allocation was concealed and code kept off site. Described as double-blind.

Blinding?
Blinding of provider
YesAs above; probably done.

Blinding?
Blinding of outcome assessor
YesUnlikely that the trained village-based morbidity worker knew the assignments, however this is never stated explicitly.

Probably done.

Incomplete outcome data addressed?Yes"Cross sectional follow-up rates for mid-study and end of study were 428 of 480 (89%) and 410 of 480 (85%), respectively, and similar for vitamin A and placebo groups. During the trial two children dropped out, 66 moved out of the study area, and two died."

Intention-to-treat used. Missing outcome data balanced in numbers across groups.

Free of selective reporting?UnclearProtocol not referenced and not stated that all measured outcomes were reported. Data at 7 months not completely reported.

Free of other bias?YesNo other apparent bias was noted.

Sinha 1976

MethodsIndividually randomised trial conducted in India, Asia.


ParticipantsChildren aged 2 months to 4.5 years were eligible for inclusion in the trial. No exclusion criteria was described.

A total of 306 children were randomised either to vitamin A or placebo group in equal numbers (153 in each group).


InterventionsChildren in experimental group received vitamin A in a dose of 200 000 IU every 4 months for 12 months. The comparison group received placebo only.


OutcomesBitot spots. Side effects; vomiting.


NotesThe people in the study population were extremely poor.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The children were divided in two groups of 153 each (two of the children died in the 1st year and two left the village) and were matched for age, sex, socioeconomic status, and playmate contacts. One of the children of each matched pair was selected randomly for receiving vitamin A and the other child received a placebo."

No detail about randomisation method provided.

Allocation concealment?Unclear"In a separate laboratory, the designated 2-ml dose of vitamin A or placebo for each child was put into a vial labelled with the child's number and the vials were then shipped to the field station for distribution. Neither the clinician nor the paramedical workers, who personally fed vitamin A and placebo or examined the children for the signs and symptoms of vitamin A deficiency, knew which children received vitamin A."

Insufficient details provided.

Blinding?
Blinding of Participants
Yes"Neither the clinician nor the paramedical workers, who personally fed vitamin A and placebo or examined the children for the signs and symptoms of vitamin A deficiency, knew which children received vitamin A."

Probably done.

Blinding?
Blinding of provider
Yes"Neither the clinician nor the paramedical workers, who personally fed vitamin A and placebo or examined the children for the signs and symptoms of vitamin A deficiency, knew which children received vitamin A." "The placebo consisted of deodorized arachis oil which was coloured and favoured with orange to match exactly the vitamin A preparation."

Provider blinded.

Blinding?
Blinding of outcome assessor
Yes"Neither the clinician nor the paramedical workers, who personally fed vitamin A and placebo or examined the children for the signs and symptoms of vitamin A deficiency, knew which children received vitamin A."

Incomplete outcome data addressed?UnclearBased on the outcome data reported it does not seem that any children dropped out (i.e., there were no losses); however, this could be because the authors are conducting an intent-to-treat analysis but never say so. They are not explicit in this regard, as such the risk of bias due to incomplete outcome data is unclear.

Free of selective reporting?UnclearDoes not reference a protocol or trial registration and does not state that all measured outcomes are reported.

Free of other bias?YesNo other apparent bias was noted.

Smith 1999

MethodsFactorial design, individually randomised trial conducted in Belize, Central America.


ParticipantsChildren aged 2.2 to 5.5 years were eligible for inclusion in the trial. Those with fever or serious respiratory illness were excluded.

A total of 51 children were randomised to four intervention groups. Mean age of children were 46.3 months.


InterventionsThe four intervention groups were as follow:

Vitamin A only; received 10 000 IU vitamin A

Zinc only; received 70 mg zinc

Vitamin A + Zinc; received vitamin A and zinc in above mentioned dosage

Placebo

Duration of study was for 6 months.


OutcomesVitamin A serum level.


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The children selected were randomly assigned to receive one of the following supplements once per week: placebo; Zn, 70 mg as Zn gluconate; vitamin A, 3030 RE as retinyl palmitate; or a combination of vitamin A and Zn."

Stated to be randomised, but no further data reported.

Allocation concealment?UnclearInsufficient details provided.

Blinding?
Blinding of Participants
Unclear"Supplements were ingested orally in an orange flavoured powder (10 g), Tangt (Kraft General Foods Inc, White Plains, NY 10625) prepared as a beverage dissolved in approximately 120 mL of water."

Stated to be "double-blind" in the article keywords, but there appear to be no details about blinding methods in the text. The intervention (or no intervention in the placebo group) were diluted in the same solution, so presumably all groups were identical.

Blinding?
Blinding of provider
UnclearNot adequately reported.

Blinding?
Blinding of outcome assessor
UnclearNot adequately reported.

Incomplete outcome data addressed?UnclearInsufficient details provided; losses not accounted for by group and small sample size makes this especially relevant.

Free of selective reporting?UnclearDoes not reference a protocol or trial registration and does not state that all measured outcomes are reported.

Free of other bias?UnclearInsufficient details provided.

Sommer 1986

MethodsCluster randomised trial conducted in a rural area of Indonesia, Asia.


ParticipantsChildren aged between 0 and 5 years were included. Children with active xerophthalmia were excluded from the study.

29,236 children from 450 villages (cluster sites) in Java. 50% of the sample were male.


InterventionsVitamin A (capsules administered twice over the course of the study: 200,000 IU of Vitamin A) was compared with a no treatment control group that served as a waiting list control.

40 IU of vitamin E was also administered with vitamin A.

Duration of study: 9-13 months.


OutcomesMortality, diarrhoea, Bitot's spots, night blindness, xerophthalmia.


NotesICC not reported (confidence intervals from analyses reported to have been adjusted for design effect). TJL back-calculated an ICC of 0.008307 from effect estimate provided in paper.

Vitamin A was not intended to have been distributed to children under the age of 12 months, but it would appear that some 0 to 12 month old children received the vitamin A capsule. Outcome data were reported on a cohort of 0 to 12 month old children.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"From a random start, 450 villages were systematically selected for the study; these were then randomised for capsule distribution after the baseline examination..."

Inadequate information provided.

Allocation concealment?UnclearInadequate information was presented in order to assess this item in relation to timing of recruitment into the study.

Blinding?
Blinding of Participants
Unclear"The Government of Indonesia would not condone the use of placebos but field-workers collecting demographic data were unaware that mortality was a research issue."

Described as a controlled study, without adequate description of what control group received.

Blinding?
Blinding of provider
Unclear"The Government of Indonesia would not condone the use of placebos but field-workers collecting demographic data were unaware that mortality was a research issue."

Described as a controlled study, without adequate description of what control group received.

Blinding?
Blinding of outcome assessor
Unclear"The Government of Indonesia would not condone the use of placebos but field-workers collecting demographic data were unaware that mortality was a research issue."

Described as a controlled study, without adequate description of what control group received.

Incomplete outcome data addressed?Unclear"Follow-up information was available on 89% of the programme children and 88.4% of the controls."

Authors indicate percent remaining per group at follow- up, but nothing more detailed.

Free of selective reporting?UnclearTrial protocol not available.

Free of other bias?UnclearInsufficent information to permit judgement.

Stabell 1995

MethodsIndividually randomised trial conducted in Guinea Bissau, Africa.


ParticipantsChildren aged 6 months of age years were eligible for inclusion in the trial.

A total of 68 children were included in which 32 were in vitamin A group and 36 in placebo.


InterventionsChildren in the intervention group received vitamin A in a dose of 100 000 IU at the time of measles vaccination at age of 6 and 9 months. The comparison group received placebo only.


OutcomesSide effects: Bulging fontanelle.


NotesDenominator data not entirely clear in Table 1 of the study.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Carrying out a double-blinded, randomised, placebo-controlled trial."

Sequence generation not mentioned in the paper.

Allocation concealment?UnclearNothing mentioned regarding allocation concealment.

Blinding?
Blinding of Participants
UnclearClaimed it was blinded but no detail provided.

Blinding?
Blinding of provider
UnclearClaimed it was blinded but no detail provided.

Blinding?
Blinding of outcome assessor
UnclearChildren were examined by one of us (C.S.) to see if their fontanelle was normal, sunken or bulging.

Appears outcome assessors were the same individuals as the investigators.

Incomplete outcome data addressed?UnclearLosses to follow-up by group indicated but no detail provided. Unclear what losses actually occurred in Table 1.

Free of selective reporting?UnclearNo protocol referenced, nor statement that all measured outcomes were reported.

Free of other bias?UnclearShort communication, insufficient detail to make an informed judgment.

Stansfield 1993

MethodsThis randomised, placebo-controlled was conducted north west of Haiti, Latin America.


ParticipantsChildren aged 6 to 83 months were included in the study. Those with corneal changes consistent with vitamin A deficiency, with measles and those had received vitamin A within the past 4 months were excluded.

A total of 13651 children were found to be eligible for inclusion in the trial. The proportion of males in the study population was 49%.


InterventionsThe vitamin A group received 100,000 IU supplements every 4 months for 3 distribution cycle for those 6 to 11 months and 200,000 IU for the older, while the other group only received placebo.


Outcomes2 week prevalence of signs of respiratory tract infections: cold, cough and rapid breathing and diarrhoea.


NotesA slightly larger number of children (55%) were assigned to vitamin A group. There was a significant difference between 2 study groups with respect to age. Study area had a high prevalence of malnutrition and xerophthalmia in the study population. Children were visited every 2 weeks for 12 months. The respiratory disease morbidity was reported with respect to cold, cough and rapid breathing which were too non- specific for inclusion under umbrella of pneumonia or lower respiratory tract infection morbidity in our review.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?NoQuote from the author: "A random number generator was used to number the first household and the households were numbered sequentially thereafter. Every other household was given a green capsule, while the rest were given red capsules."

Alternate allocation.

Allocation concealment?YesQuote from the author: "The manufacturer (Roche) held the code until the study was completed."

Blinding?
Blinding of Participants
Yes"The colour code was held only by the manufacturer until the study was completed."

Probably done.

Blinding?
Blinding of provider
Yes"Before the study inquiries among health workers and community members had indicated no symbolism associated with or preference for either green or red."

Highly unlikely that providers would be biased about a single intervention.

Blinding?
Blinding of outcome assessor
Yes"The colour code was held only by the manufacturer until the study was completed."

Probably done.

Incomplete outcome data addressed?Yes"The frequency of non-participation was essentially identical among children from even and odd-numbered households."

Probably done.

Free of selective reporting?No"We did not collect data on the impact of supplementation on vitamin A status, or on the incidence, duration, or severity of symptoms of infection."

Only mortality and morbidity outcomes given. Protocol not available.

Free of other bias?YesThis study appears to be free of other bias.

van Agtmaal 1988

MethodsIndividually randomised, non-placebo trial conducted in Thailand, Asia.


ParticipantsParticipants had a mean age of 3.1 years. No exclusion criteria was described.

Study included 30 children in which 14 were in vitamin A group and 21 in control group.


InterventionsChildren in experimental group received a single dose vitamin A in a dose of 200 000 IU. Study participants were followed for 4 months.


OutcomesMean vitamin A serum levels.


NotesChildren were recruited from three rural day care centres.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"After selection, 14 children were randomly supplemented with a single, oral dose of vitamin A (110 mg retinylpalmitate, 200,000 IU),according to WHO recommendations (9). and 21 children served as a control group."

Inadequate information provided.

Allocation concealment?UnclearInadequate information provided.

Blinding?
Blinding of Participants
UnclearInadequate information provided.

Blinding?
Blinding of provider
UnclearInadequate information provided.

Blinding?
Blinding of outcome assessor
UnclearInadequate information provided.

Incomplete outcome data addressed?No"Due to the absence of some children at the different time points the number of data available for statistical analysis was less than the total number of children involved in this study ... the number of children from whom complete data sets could be collected was rather low."

No comprehensive data given on lost to follow-up nor reasons for loss.

Free of selective reporting?NoDoes not report data on serum retinol levels, which were collected/measured.

Free of other bias?UnclearInadequate information provided.

Venkatarao 1996

MethodsIndividual randomised trial conducted in India, Asia.


ParticipantsInfants aged 6 months were included. Proportion of males in the study was 50%.

A total of 909 infants were randomised to three intervention groups.


InterventionsThe three intervention groups were as follows:

Group AA: Mother received and infants both received vitamin A

Group AP: Mother received vitamin A while infant received placebo

Group PP: Both mother and infant received placebo.

Dose of vitamin A for infant was 200 000 IU.


OutcomesAll-cause mortality and cause specific mortality of diarrhoea and respiratory disease. Incidence of diarrhoea and respiratory disease morbidity.


NotesWe have included the data for groups AA vs. AP.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"Each pair of subjects enrolled for the study was randomly allocated to one of the following three groups: (i) AA-Both mother and infant received Vitamin A, the former soon after delivery and the latter at 6 months; (ii) AP: Mother received Vitamin A but her infant received a placebo (Sesame oil); and (iii) PP: Both mother and infant received placebo, the former Vitamin E and the latter Sesame oil."

Insufficient detail to form judgment.

Allocation concealment?UnclearInsufficient detail to form judgment.

Blinding?
Blinding of Participants
Yes"At the age of 6 to 6Vi months, the infant was weighed again and given the appropriate syrup by the Medical Officer from coded bottles, supplied again by the Statistical Section at the Camp Office."

Probably done.

Blinding?
Blinding of provider
YesAs above; probably done.

Blinding?
Blinding of outcome assessor
YesAs above; probably done.

Incomplete outcome data addressed?Unclear"4 each in the AA and AP groups and 5 in the PP group were withdrawn from the trial on medical grounds such as congenital abnormalities, epileptic fits or jaundice. Migration accounted for the loss of 34 infants in the AA group, 25 in the AP group and 20 in the PP group while 7, 9 and 7 were excluded due to other miscellaneous reasons. Of the remaining 263, 255 and 256 infants in the three group, 233 in the AA and 228 each in the AP and PP groups were followed-up very regularly and form the basis for analyses in this report."

They provided specific information about losses by group. However, it is unclear why 263, 255 and 256 infants that remain in the three group after attrition is described results in only 233 in the AA and 228 each in the AP and PP groups being used as the basis for analysis.

Free of selective reporting?YesDoes not reference a protocol or trial registration and do not state that all measured outcomes are reported.

Free of other bias?Yes"Quality control of the morbidity data collected by the field investigators was undertaken throughout. As long recall periods pose problems, the collection of morbidity data was intensified from once a fortnight to once a week when the study had been in progress for 9 months."

Authors attempted to minimise other biases such as recall bias, though specific details of "quality control" are not provided.

Vijayaraghavan 1990

MethodsCluster randomised study in rural India, Asia.


ParticipantsChildren aged 1-5 years were eligible for entry in the study. Children with corneal involvement were excluded from the review.

15,775 children in 84 clusters were randomised to the treatment groups. 50.4% participants were male.


InterventionsVitamin A given twice (200,000 IU) versus placebo (archis oil).

Study duration: not clear.


OutcomesMortality, diarrhoea, acute respiratory infections, measles.


NotesRespiratory infection has non-specific definition of "clinically significant cough".


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"The villages were allocated randomly into two groups-treatment and control."

Insufficient detail to form judgment.

Allocation concealment?UnclearInsufficient detail provided.

Blinding?
Blinding of Participants
Yes"The trial was double blind: the investigators and medical officers did not know which were the treatment and which were the control areas. They were not aware whether the dose they were distributing was vitamin A or placebo. Decoding was done only after data had been collected."

Blinding?
Blinding of provider
YesAs above; probably done.

Blinding?
Blinding of outcome assessor
YesAs above probably done.

Incomplete outcome data addressed?UnclearInsufficient detail provided.

Free of selective reporting?NoIncidence of infections outcome not given with respect to vitamin A and control groups. Given according to the clinical vitamin A status of all the study children.

Free of other bias?YesThis study appears to be free of other bias.

West 1991

MethodsCluster randomised study in rural Nepal, Asia.


ParticipantsChildren aged between 0 and 5 years were eligible for the study. Children with xerophthalmia were included. Children who had recently participated in a Vitamin A programme were excluded from the study.

28,630 children in 261 clusters were recruited. 51.3% sample was male.


InterventionsVitamin A (100,000 IU for 6-11 months and 200,000 IU for children 12 months and older) administered 1 to 3 times was compared with a very low dose of vitamin A (1000 IU). Both supplements contained 40 IU vitamin E.

Study duration:16 months.


OutcomesMortality, cause-specific mortality, Bitot's spots, night blindness, xerophthalmia.


NotesICC not disclosed, although study estimates reported to have been adjusted for the unit of allocation.

Study had additional recruitment phases in second and third treatment cycles. 1807 and 2018 children entered at 4 and 8 months.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"After blocking on the local development area, the 261 wards were randomly assigned to receive vitamin A supplementation or placebos at 4-month intervals."

Inadequately described to permit judgment.

Allocation concealment?Unclear"Both the investigators and communities were masked to the random assignment."

The study was a cluster-designed trial and there was insufficient information to determine whether allocation took place before or after treatment group assignment was known.

Blinding?
Blinding of Participants
Yes"The supplements were given as single-dose gelatin capsules of identical taste and appearance."

Blinding?
Blinding of provider
YesAs above; probably done.

Blinding?
Blinding of outcome assessor
YesAs above; probably done.

Incomplete outcome data addressed?Unclear"All analyses were carried out on an intention-to-treat basis. Computed mortality rates were based on child-years of observation."

"...all children living in wards which received high dose vitamin A every 4 months were considered to have been treated with vitamin A, and all children living in wards which received placebo were considered 'untreated.'"

The rates of withdrawal were balanced between the treatment groups and the data were analysed based on patient years of observation. The unclear reasons for withdrawals, variable duration of follow-up due to more than recruitment cycle and the low rate of mortality in relation to the withdrawal rates mean that it is uncertain whether the study is at risk of attrition bias.

Free of selective reporting?YesComplete data for all time points were available for the review. The last available observation reported in a follow-up article gave a RR for mortality slightly higher than that for the 12 month data given in the primary study report (0.74 versus 0.7).

Free of other bias?YesA method for estimating the ICCs was reported in Katz 1988 (Journal of international epidemiology).

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bahl 1997The study included children currently having diarrhoea.

Bhaskaram 1997The study was not a randomised controlled trial.

Bloem 1990The study was not a randomised controlled trial. The mean age of children was 6.6 years (range 3-9 years).

Kothari 1991The study was not a randomised controlled trial.

Semba 1990Vitamin A was given as a therapeutic intervention for Bitot's spots.

Semba 2005The study population consisted of children infected with HIV.

Wu 2007The study was not a randomised controlled trial.

Yang 2002Other micronutrients were supplemented with vitamin A and these supplements were not balanced out in the control group. It was difficult to disaggregate the effect of vitamin A.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Aklamati 2006

MethodsIndividually randomised, placebo-controlled trial conducted in Zambia, Africa.

ParticipantsBoys 3-4 years old were eligible for inclusion in the trial. A total of 36 children were included in the trial in which 19 were in vitamin A and 17 in placebo group.

InterventionsThe intervention group received a single dose of 60 mg vitamin A and control group received the same amount of placebo.

OutcomesMean plasma retinol levels, prevalence of fever, diarrhoea, rhinorrhoea, cough and malaria.

NotesData were available only in the form of abstract and the numbers do not match given in the results section of abstract. It was decided among the group to wait for publication of this study before we include it in the review.

DEVTA trial 2007

MethodsCluster-randomised trial conducted in Northern India, Asia.

ParticipantsChildren aged 1-6 years were eligible for inclusion in the review. Total clusters were 72 in which 36 clusters received vitamin A supplementation while 36 acted as control. Authors claim to include a total of 1 million children in the trial.

InterventionsChildren in experimental group received 200,000 IU of vitamin A every 6-months for 5 years. Vitamin A was supplemented on mass treatment days by village child care workers.

OutcomesAll-cause mortality, cause specific mortality of diarrhoea, pneumonia, measles and malnutrition. Mean vitamin A serum levels, incidence of Bitot's spots and prevalence of measles and pneumonia morbidity.

NotesThis is the largest randomised controlled trial conducted on vitamin A but has not been published yet. The current data is based on the abstract presented in ILSI Micronutrient Forum, Istanbul, 16-18 April 2007. It does not contain detail information on conduct of trial neither it give details on attrition of the study. We contacted all the authors of the trial multiple times and asked for more details on methods and results but did not receive any positive response. As we did not have sufficient information on methods and outcome we decided to wait for publication of results of this large trial. We aim to include that in the next update of this review.

 
Comparison 1. Vitamin A versus Control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality (all-cause) at Longest Follow-up17Risk Ratio (Fixed, 95% CI)0.76 [0.69, 0.83]

 2 Mortality (all-cause) at Longest Follow-up (by Age)5Risk Ratio (Fixed, 95% CI)Subtotals only

    2.1 6 to 12 months old
4Risk Ratio (Fixed, 95% CI)0.59 [0.43, 0.82]

    2.2 1 to 5 years old
4Risk Ratio (Fixed, 95% CI)0.68 [0.57, 0.81]

 3 Mortality (all-cause) at Longest Follow-up (by Sex)5Risk Ratio (Fixed, 95% CI)Subtotals only

    3.1 Males
5Risk Ratio (Fixed, 95% CI)0.80 [0.66, 0.97]

    3.2 Females
5Risk Ratio (Fixed, 95% CI)0.79 [0.65, 0.95]

 4 Mortality (all-cause) at Longest Follow-up (Sensitivity Analysis including DEVTA trial)18Risk Ratio (Fixed, 95% CI)0.88 [0.84, 0.94]

 5 Mortality due to Diarrhoea at Longest Follow-up7Risk Ratio (Fixed, 95% CI)0.72 [0.57, 0.91]

 6 Mortality due to Measles at Longest Follow-up5Risk Ratio (Fixed, 95% CI)0.80 [0.51, 1.24]

 7 Mortality due to Meningitis at Longest Follow-up3Risk Ratio (Fixed, 95% CI)0.57 [0.17, 1.88]

 8 Mortality due to LRTI at Longest Follow-up7Risk Ratio (Fixed, 95% CI)0.78 [0.54, 1.14]

 9 Diarrhoea Incidence at Longest Follow-up13Risk Ratio (Fixed, 95% CI)0.85 [0.82, 0.87]

 10 Diarrhoea Prevalence at Longest Follow-up3Risk Ratio (Fixed, 95% CI)1.08 [1.05, 1.12]

 11 Measles Incidence at Longest Follow-up6Risk Ratio (Fixed, 95% CI)0.50 [0.37, 0.67]

 12 Malaria Incidence at Longest Follow-up1174132Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.60, 0.88]

 13 Malaria Prevalence at Longest Follow-up2Risk Ratio (Fixed, 95% CI)0.73 [0.41, 1.28]

 14 Lower Respiratory Tract Infection Incidence at Longest Follow-up9Risk Ratio (Fixed, 95% CI)1.14 [0.95, 1.37]

 15 Bitot's Spots Prevalence at Longest Follow-up4Risk Ratio (Fixed, 95% CI)0.45 [0.33, 0.61]

 16 Night Blindness Incidence at Longest Follow-up1Risk Ratio (Fixed, 95% CI)0.53 [0.28, 0.99]

 17 Night Blindness Prevalence at Longest Follow-up2Risk Ratio (Fixed, 95% CI)0.32 [0.21, 0.50]

 18 Xerophthalmia Incidence at Longest Follow-up3Risk Ratio (Fixed, 95% CI)0.85 [0.70, 1.03]

 19 Xerophthalmia Prevalence at Longest Follow-up2Risk Ratio (Fixed, 95% CI)0.31 [0.22, 0.45]

 20 Vitamin A Deficient at Longest Follow-up42262Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.65, 0.78]

 21 Vitamin A Serum Level at Longest Follow-up146623Std. Mean Difference (IV, Fixed, 95% CI)0.31 [0.26, 0.36]

 22 Hospitalisation, Number of Children Hospitalised Once or More at Longest Follow-up11185Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.40, 1.02]

 23 Hospitalisation due to Diarrhoea at Longest Follow-up1172Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.01, 6.11]

 24 Hospitalisation due to Lower Respiratory Tract Infection at Longest Follow-up1172Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 2.06]

 25 Side effect - Bulging Fontanelle3885Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.24, 103.72]

 26 Side effect - Vomiting32994Risk Ratio (M-H, Fixed, 95% CI)2.75 [1.81, 4.19]

 
Summary of findings for the main comparison.

Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age

Patient or population: Children aged between 6 months and five years

Intervention: Vitamin A supplementation

Comparison: Placebo or usual care

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlVitamin A

All-cause mortality

Follow-up: 12-96 weeks
Low risk populationRR 0.76; 95% CI 0.69 to 0.83194,795

(17 studies)
++++
high
The inclusion of the DEVTA trial reduced the effect size from 0.76 to 0.88 ( Analysis 1.4). The impact on the absolute effect was to reduce the risk of mortality by 2 per 1000 in medium risk and 11 per 1000 in high risk populations.

0 per 100010 per 1000
(0 to 0)

Medium risk population

11 per 100018 per 1000
(7 to 9)

High risk population

90 per 1000168 per 1000
(62 to 75)

Diarrhoea-related mortality

Follow-up: 48-104 weeks
Low risk populationRR 0.72; 95% CI 0.57 to 0.9190,951
(7 studies)
+++O
moderate2
Total number of participants reflects number randomised to studies. The analysis combined cumulative risk and risk per/1000 years follow-up.

3 per 100012 per 1000
(2 to 3)

Medium risk population

4 per 100013 per 1000
(2 to 4)

High risk population

9 per 100016 per 1000
(5 to 8)

Measles-related mortality

Follow-up: 52-104 weeks
Low risk populationRR 0.80; 95% CI 0.51 to 1.2488,261
(5 studies)
+++O

moderate2
Total number of participants reflects number randomised to studies. The analysis combined cumulative risk and risk per/1000 years follow-up.

2 per 10,00012 per 10,000
(1 to 3)

Medium risk population

16 per 10,000113 per 10,000
(8 to 20)

High risk population

44 per 10,000135 per 10,000
(22 to 55)

LRTI-related mortality

Follow-up: 48-104 weeks
Low risk populationRR 0.78; 95% CI 0.54 to 1.1490,951
(7 studies)
++OO
low2, 3
Total number of participants reflects number randomised to studies. The analysis combined cumulative risk and risk per/1000 years follow-up.

4 per 10,00013 per 10,000
(2 to 4)

Medium risk population

11 per 10,00019 per 10,000
(6 to 13)

High risk population

219 per 10,0001171 per 10,000
(118 to 250)

Diarrhoea incidence

Mean episodes per child per year
Follow-up: 24-60 weeks
Mean episodes of diarrhoea in control groups: 1.9/child/year in controls.VAS led to 0.29 episodes fewer per child per year (95% CI 0.34 episodes to 0.25 episodes fewer).Rate ratio 0.85; 95% CI 0.82 to 0.8769,972
(13 studies)
++OO
low4, 5

Measles-morbidity incidence

Mean episodes of measles per child per year
Follow-up: mean 52 weeks
Mean episodes in control groups: 0.028 event per child per year.VAS led to 0.015 fewer episodes per child per year (95% CI 0.019 events fewer per child to 0.01 events fewer per child).Rate ratio 0.50; 95% CI 0.37 to 0.6719,566
(6 studies)
++++
high

LRTI-morbidity incidence

Mean episodes per child per year
Follow-up: mean 52 weeks
Mean episodes in control groups: 0.7 episodes.VAS led to 0.1 more episodes/child/year (95% CI 0.04 episodes fewer to 0.3 episodes more episodes per child per year.Rate ratio 1.14; 95% CI 0.95 to 1.3719,566
(9 studies)
+OOO

very low6,7,8

Bitot's spots

Follow-up: mean 80.72 weeks
Low risk populationRR 0.45; 95% CI 0.33 to 0.6163,278
(4 studies)
+++O
moderate9

4 per 100012 per 1000
(1 to 2)

Medium risk population

14 per 100016 per 1000
(5 to 9)

High risk population

203 per 1000191 per 1000
(67 to 124)

Night blindness

Follow-up: 52 to 68 weeks
Low risk populationRR 0.32; 95% CI 0.21 to 0.5022,972

(2 studies)
+++O

moderate11

4 per 1000101 per 1000
(1 to 2)

High risk population

7 per 1000102 per 1000
(2 to 4)

Vitamin A deficiency

Follow-up: mean 54.5 weeks
Low risk populationRR 0.71; 95% CI 0.65 to 0.782262
(4 studies)
++++
high

93 per 10001066 per 1000
(60 to 72)

Medium risk population

286 per 100010203 per 1000
(186 to 223)

High risk population

588 per 100010417 per 1000
(382 to 458)

Vomiting

Follow-up: 0.14 to 52 weeks
Low risk populationRR 2.75; 95% CI 1.81 to 4.192994
(3 studies)
++OO
low 12, 13

0 per 1000100 per 1000
(0 to 0)

Medium risk population

22 per 10001062 per 1000
(41 to 94)

High risk population

73 per 100010200 per 1000
(132 to 305)

*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk Ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. CERs identified from the studies for this outcome which report cumulative risk.
2. The wide confidence intervals around the pooled effect estimate included both a reduction and an increase in the risk of mortality with vitamin A.
3. The risk of bias assessments determined that Daulaire 1992 and Herrera 1992 were at high risk of selection bias. Inadequate blinding put the results of Daulaire 1992 at a high risk of detection bias. Incomplete data was considered to put the results of Chowdhury 2002 at a high risk of attrition bias. Baseline imbalance was noted for Agarwal 1995.
4. The risk of bias assessment determined that four studies contributing just over 25% weight of the estimated effect were at risk of selection or attrition bias.
5. The I square was 95%, and the results of Herrera 1992; Cheng 1993 and Chowdhury 2002 demonstrated clear evidence of benefit and were discordant with the results of the other studies.
6. The risk of bias assessment determined that Cheng 1993; Kartasasmita 1995 and Chowdhury 2002 were at high risk of attrition bias.
7. Diagnostic procedures were not consistent across the studies.
8. The CIs around the pooled effect included small benefit and a meaningful increase in the risk of RTIs.
9. The risk of bias assessment determined that there was a risk of attrition bias in Pant 1996, which was assigned 47% weight.
10. Risk based on CERs from the included studies.
11. The larger study was not well described and was of uncertain quality; this puts the results at a high risk of selection bias.
12. The follow-up was spread between 1 day and 52 weeks.
13. There was some evidence of under-reporting of adverse events in some of the studies, and the low number of trials giving data in relation to the large of studies included overall means that this selective reporting of adverse events cannot be excluded.
 
Table 1. Sensitivity and subgroup analyses

Outcome or SubgroupStudiesHeterogeneityStatistical MethodEffect EstimateTest for Subgroup difference

(p-value)

Mortality (all-cause) at Longest Follow-up (Sensitivity analysis using random effects model)17Heterogeneity: Tau² = 0.04; Chi² = 29.10, df = 15 (P = 0.02); I² = 48%

 
Risk Ratio (IV, Random, 95% CI)0.71 [0.61, 0.84]NA

Mortality (all-cause) at Longest Follow-up (Sensitivity Analysis assumes NO impact of clustering for studies with unknown ICC)17Heterogeneity: Chi² = 48.83, df = 15 (P < 0.0001); I² = 69%

 
Risk Ratio (IV, Fixed, 95% CI)0.81 [0.75, 0.89]NA

Mortality (all-cause) at Longest Follow-up (Sensitivity Analysis assumes HIGH impact of clustering for studies with unknown ICC)17Heterogeneity: Chi² = 25.67, df = 15 (P = 0.04); I² = 42%

 
Risk Ratio (IV, Fixed, 95% CI)0.75 [0.68, 0.83])NA

Mortality (all-cause) at Longest Follow-up (by National Child Mortality Rate): High (> 40/1000)15Heterogeneity: Chi² = 29.02, df = 14 (P = 0.01); I² = 52% Risk Ratio (IV, Fixed, 95% CI)0.76 [0.69, 0.83]0.78 

 

 Mortality (all-cause) at Longest Follow-up (by National Child Mortality Rate): Low (<40/1000)2Heterogeneity: Not applicable Risk Ratio (IV, Fixed, 95% CI)1.00 [0.14, 7.08]

Mortality (all-cause) at Longest Follow-up (by Region): Asia11 Heterogeneity: Chi² = 15.00, df = 9 (P = 0.09); I² = 40%Risk Ratio (IV, Fixed, 95% CI)0.69 [0.61, 0.79]0.12 

 

 

Mortality (all-cause) at Longest Follow-up (by Region): Africa5 Heterogeneity: Chi² = 9.81, df = 4 (P = 0.04); I² = 59%Risk Ratio (IV, Fixed, 95% CI)0.85 [0.73, 0.98]

 Mortality (all-cause) at Longest Follow-up (by Region): Latin America1 Heterogeneity: Not applicableRisk Ratio (IV, Fixed, 95% CI)1.00 [0.14, 7.08]

Mortality (all-cause), outcomes < 1 year since randomisation13 Heterogeneity: Chi² = 33.85, df = 11 (P = 0.0004); I² = 67%Risk Ratio (IV, Fixed, 95% CI)0.82 [0.74, 0.91]NA

Mortality due to Diarrhoea, outcomes < 1 year since randomisation5 Heterogeneity: Chi² = 5.14, df = 4 (P = 0.27); I² = 22%Risk Ratio (IV, Fixed, 95% CI)0.75 [0.59, 0.96]NA

Mortality due to LRTI, outcomes < 1 year since randomisation5 Heterogeneity: Chi² = 5.70, df = 6 (P = 0.46); I² = 0%Risk Ratio (IV, Fixed, 95% CI)0.71 [0.41, 1.21] NA

Mortality due to Measles, outcomes < 1 year since randomisation4 Heterogeneity: Chi² = 0.52, df = 3 (P = 0.91); I² = 0%Risk Ratio (IV, Fixed, 95% CI)0.85 [0.52, 1.37] NA

Mortality due to Meningitis, outcomes < 1 year since randomisation1Heterogeneity: Not applicable Risk Ratio (IV, Fixed, 95% CI)5.79 [0.22, 153.24] NA

Diarrhoea Incidence at Longest Follow-up (Sensitivity analysis using random effects model)13 Heterogeneity: Chi² = 218.62, df = 11 (P<0.00001); I² = 95%Risk Ratio (IV, Random, 95% CI)0.85 [0.72, 1.00]NA

Diarrhoea Incidence, outcomes < 1 year since randomisation10 Heterogeneity: Chi² = 49.93, df = 8 (P<0.00001); I² = 84%Risk Ratio (IV, Fixed, 95% CI)0.93 [0.89, 0.97]NA

Lower Respiratory Tract Infection Incidence, outcomes <1 year since randomisation8 Heterogeneity: Chi² = 4.47, df = 5 (P = 0.48); I² = 0%Risk Ratio (IV, Fixed, 95% CI)0.99 [0.78, 1.26]NA

Malaria Incidence, outcomes 1+ year since randomisation (by Age)1Heterogeneity: Not applicable Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.60, 0.88]NA

Measles Incidence, outcomes < 1 year since randomisation5Heterogeneity: Chi² = 0.24, df = 4 (P = 0.99); I² = 0% Risk Ratio (IV, Fixed, 95% CI)0.54 [0.36, 0.80]NA

Bitot's Spots Incidence, outcomes < 1 year since randomisation1Heterogeneity: Not applicable  Risk Ratio (IV, Fixed, 95% CI)0.93 [0.76, 1.14]NA

Bitot's Spots Prevalence, outcomes < 1 year since randomisation3 Heterogeneity: Chi² = 6.06, df = 2 (P = 0.05); I² = 67%Risk Ratio (IV, Fixed, 95% CI)0.43 [0.33, 0.56]NA

Night Blindness Prevalence, outcomes < 1 year since randomisation1 Heterogeneity: Not applicable Risk Ratio (IV, Fixed, 95% CI)0.30 [0.17, 0.52]NA

Xerophthalmia Incidence, outcomes < 1 year since randomisation2 Heterogeneity: Not applicableRisk Ratio (IV, Fixed, 95% CI)0.88 [0.72, 1.07]NA

Vitamin A Serum Level at Longest Follow-up (Sensitivity analysis using random effects model)14Heterogeneity: Tau² = 0.22; Chi² = 270.23, df = 13 (P < 0.000001); I² = 95%Std. Mean Difference (IV, Random, 95% CI)0.53 [0.27, 0.79]NA

Vitamin A Serum Level, outcomes < 1 year since randomisation11Heterogeneity: Chi² = 178.42, df 10, (P<0.000001), I² = 94%Std. Mean Difference (IV, Fixed, 95% CI)0.45 [0.37, 0.53]NA