|
Piyush Gupta, *Abhaya
Indrayan
From the Department of
Pediatrics and *Division of Biostatistics and Medical Informatics,
University College of Medical Sciences and GTB Hospital, Delhi 110 095,
India.
Correspondence to: Dr.
Piyush Gupta, Block R-6-A, Dilshad Garden, Near Telephone Exchange,
Delhi 110 095, India. E-mail: drpiyush@satyam.net.in
Manuscript received: April
10, 2002, Initial review completed: July 26, 2002,
Revision accepted: October 23, 2002.
Objective:
To review all published randomized trials
concerned with linkage of vitamin A supplementation with reduction of
mortality and morbidity in Indian children. Method: The studies
were identified by searching the PubMed, review articles, references of
available meta-analyses and bibliography of pertinent references.
Studies were extracted and the quality of each study was reviewed with
regards to 10 categories of parameters that in our opinion, were
important for a vitamin A prophylaxis trial. These included background
indicators, subjects, design, intervention, proximal measures,
field-work, sources of bias, data analysis, interpretation and
documentation. Results: Out of 12 studies satisfying the
inclusion criteria, the available 11 were examined. Two of the trials
were concerned with mortality, 6 with morbidity, and 2 with both
mortality and morbidity; 1 study assessed the impact of vitamin A on
pneumococcal colonization. Out of 4 mortality trials, only one could
satisfactorily report a significant reduction (54%) in child mortality
following vitamin A supplementation. Of 8 morbidity studies, only 3
indicated some beneficial effect of vitamin A supplementation. None of
the studies was perfect in methodology. We could not locate any study
that addressed the issue of cost-effectiveness or dietary modifications.
The results were not unequivocal and findings for mortality and
morbidity were not corroborative. Conclusion: There is no
definite evidence as yet in favor or against substantial benefit of
universal vitamin A supplementation to children in India. There is a
clear need to undertake a comprehensive trial with adequate sample size
and a standardized methodology that could give clear, unbiased, and
convincing evidence on the role of routine vitamin A supplementation.
Key words:
Mortality, morbidity, randomized controlled
trial, review, Vitamin A.
VITAMIN A deficiency is
widely
prevalent, particularly in the develop-ing world. The World Health
Organization estimates that as many as 228 million children are affected
subclinically at a severe or moderate level by vitamin A deficiency, and
that deficiency of this micronutrient is a problem in more than 75
countries(1,2). Adequate vitamin A status is important for maintenance of
good health and prevention of disease.
Evidence that has
accumulated over the last few years led to belief that improving vitamin A
status of children in communities with vitamin A deficiency as a public
health problem exerts a measurable positive impact on child mortality and
morbidity. A meta-analysis of 10 mortality and 23 morbidity trials(3)
conducted till 1993 revealed that improving the vitamin A status of
children aged six months to five years reduces mortality rates by about
23%. An important finding was that the effect on mortality was not
dependent on very high potency dosing of vitamin A. In contrast to the
very clear effect of vitamin A on mortality, no consistent effect was
demonstrated on the frequency or prevalence of diarrhea and respiratory
infection, though improved vitamin A status did appear to reduce severe
morbidity, particularly in children with measles. This meta–analysis
included one study each from Tamil Nadu and Hyderabad, conducted in Indian
children(4-6).
In India, mega dose vitamin
A prophylaxis (VAP) was started in 1970 as a program with the specific aim
of preventing nutritional blindness. The current policy is to administer
vitamin A to all children between 9 months to 3 years. For logistic
reasons, VAP has been linked to measles and first booster for DPT
immunization(7). The coverage is abysmally low at 30%(8). Universal
supplementation of vitamin A to Indian children requires enormous
resources and management skills. However, it is noteworthy that even
without any significant coverage by the national programs, the prevalence
of Vitamin A deficiency in India has declined from 2% in 1975-79 to 0.21%
in 1998(8,9). It has also been suggested that mega dose VAP as a measure
for control of keratomalacia must be phased out and efforts made to
increase the intake of vitamin A through dietary improvement(10). Green
leafy vegetables and yellow fruits, freely available in the countryside
and well within the economic reach of even the poor, if used judiciously,
could control the problem(11).
Universal vitamin A
supplementation to children has been claimed to bring down the child
mortality(3). This claim has been challenged. Massive dose of vitamin A
could actually increase child mortality in some situations(11). Therefore,
a program of such a magnitude can be undertaken only after convincing
evidence is available of substantial benefit in Indian conditions. In this
article, we critically examine the methodology of all published randomized
controlled trials concerned with linkage of vitamin A supplementation with
childhood morbidity and mortality in India.
Methods
We aimed to examine all
published randomized controlled trials of vitamin A supplementation in
Indian children for the prevention of death or morbidity from infectious
diseases, in particular respiratory and gastrointestinal diseases. To
locate primary research data, PubMed was searched independently, using
combination of the following key words: vitamin A, morbidity, mortality,
randomized controlled trial, and India. In addition, review articles,
references of the available meta-analyses, editorial and primary studies
were checked to identify other references. Efforts were not made to
identify any unpublished trial. The studies were then extracted and the
methods section of each study was reviewed with regard to parameters that
in our opinion are important for a vitamin A prophylaxis trial in
children. These parameters are detailed below:
(i) Background
indicators: Socioeconomic status of the families (literacy, income,
occupation, property owned, etc.); rural/urban area; health
access (e.g., immunization coverage); health practices (weaning,
food hygiene); representativeness of the target population.
(ii) Subjects:
Age and sex distribution.
(iii) Design:
Method of selection (random/non-random, unit of randomization, i.e.,
village, family or child, any stratification with regard to age, sex,
nutritional status, etc.); sample size (adequate for sufficient
power to detect medically important difference); masking by coding
(codes with a third party).
(iv)
Intervention: Consent; dose, frequency and length of administration;
control characteristics in terms of low dose vitamin A, other existing
vitamin programs, balanced diet, etc.
(i)
Identification and definition of proximal measures: Mortality (cause
of death); Morbidity—classification, definition of episode,
classification of severity/ frequency/duration per episode or per child;
growth and development: anthropometry, milestones; nutrition status:
xerophthalmia, serum retinol level, categorization into mild, moderate,
severe groups; associated protein energy malnutrition and its
categorization; diet: vitamin A intake as absolute and as a ratio of
other nutrients, total diet with respect to quality and quantity of
food, and distribution of food within the household.
(vi) Field
work: Quality control: reliability and validity of tools, training
and supervision of staff, manual of instruction and its implementation,
laboratory standardization; pilot study: for improvement in tools and
its methodology; baseline investigations: any refusal to participate,
difference between treatment and control group for all known
confounders; follow up: duration and frequency, differential follow up (e.g.,
retinol levels once in 3 months, infectious disease every month /diet
every week, etc.), partial follow-up (some receive all dose, some
only one dose), loss to follow up (died, moved, refused), follow up or
deletion of subjects who have or develop eye signs.
(vii)
Identification of potential sources of bias: Contact effect; recall
(weekly/monthly); differential follow up (loss in the treatment and
control group may be the same but the type of children lost may be
different); time lag between baseline assessment and start of the study,
a new health facility, appointment of staff, flood, drought; mortality:
expired children no longer contributing to morbidity.
(viii) Data
analysis: Appropriate adjustment for baseline imbalance, loss to
follow up including differential loss in the two groups,
disproportionate sample size in subgroups of age, sex, nutrition,
etc.; assess effect of infectious disease load (diversity, severity,
frequency, duration), seasonality (in case of malaria, respiratory
inections, diarrhea) if follow up is in fraction of years; impact of
breast feeding, weaning and maternal nutrition in children 6-12 months;
impact on children with different nutrition status of different age, sex
and vitamin A status; analysis of data on children who show improvement
versus those who do not show improvement so as to delineate the
benefiting group, multivariate analysis to evaluate net effect of
individual variables, particularly of intervention.
(ix)
Interpretation. Internal consistency among results: mortality
reduced but not morbidity, morbidity reduced in stunted children but not
in those who are stunted as well as wasted; plausibility: adequate
biological explanation of large reduction in mortality in a short time,
reduction in disease not connected with vitamin A deficiency; efficacy
versus effectiveness, statistical significance whether interpreted in
accordance with medically significant difference (for example n =
300 in each group, baseline xerophthalmia prevalence was 8.2% in
treatment group vs 4.5% in control group (P > 0.05), after
treatment prevalence was 5.2% in treatment and 1.5% in control group (P
< 0.05), even though the decline was similar (3.7%) in both groups);
multiple tests at 5% level may give a different result.
(x)
Documentation: Mortality, morbidity, growth, retinol level,
xerophthalmia with conclusion on each aspect separately, resolving
conflict, if any; six monthly trend, if available.
Results
A total of 12 articles
(4-6,12-20) fulfilled the inclusion criterion. The manuscript by Biswas
et al.(20) could not be retrieved and omitted from the present
analysis. Another multicentric study conducted in India, Ghana, and
Peru(21) was also not considered, as separate data for Indian children was
not available from the published article. Out of 11 articles available for
scrutiny, two dealt with reduction of both mortality and morbidity (6,12).
In addition, Rahmathullah et al. (4,5) and Agarwal et al.
(14,15) published two papers each, studying the impact of vitamin A
supplementation on mortality and morbidity separately. Another four
articles examined the impact on morbidity alone(13,16-18). A recent study
did not directly study the morbidity or mortality following vitamin A
supplementation; instead, it concentrated on nasopharyngeal pneumococcal
colonization, an indirect determinant of illness or death due to
infections with Streptococcus pneumoniae(19).
Table I
provides a brief summary of the studies included in this review. The
following account scrutinizes the methodology of these studies.
TABLE I – Summary of Studies Linking Vitamin A with Reduction of Mortality and Morbidity
Study and
area
|
Sample
|
Intervention
|
Outcome
|
Overall Reduction
|
|
age (mo)
|
size
|
adequacy
|
(Vitamin A)
|
measures
|
mortality
|
morbidity
|
Rahamathullah
et al.(4,5),
Trichy, rural
Tamil Nadu
|
6-60
|
15419
|
not
mentioned
|
8333 IU per
week
|
mortality(inclued
accidental deaths)
morbidity (ARI,
diarrhea);
long recall period
|
yes
|
no
|
Vijayraghavan
et al. (6) rural
Hyderabad
|
12-60
|
15775
|
not
mentioned
|
2,00,000 IU
6 monthly,
2 doses
|
mortality (cause not
ascertained), morbidity
(ARI, diarrhea);
severity not assessed
|
no
|
no
|
Kothari(12),
urban slum,
Mumbai
|
<12
|
387
|
not
mentioned
|
2,00,000 IU,
doses?
duration?
frequency?
|
mortality (cause not
ascertained), morbidity
(not defined) follow up
over 3 years
|
yes
|
no
|
Ramakrishnan
et al. (13), rural
Tamil Nadu
|
6-36
|
583
|
adequate to
detect 25%
reduction in
morbidity
|
1,00,000 IU
to <1 yr,
2,00,000 IU
to > 1yr,
4 monthly
for 1 yr
|
morbidity (ARI, diarrhea)
defined and assessed for
frequency and duration
|
-
|
no
|
Agarwal et al.
(14-15), rural
Varanasi
|
1-72
|
15247
and
2514
|
not
mentioned
|
50,000 IU to
<6 mo,
1,00,000 IU
to >6 mo,
4 monthly
for 1 yr
|
mortality (cause
ascertained), morbidity
(measles, ARI, Otitis
media, skin infections)
|
yes?
|
yes
|
Bhandari
et al. (16), urban
slum, New Delhi
|
12-60
|
900
|
adequate to
detect 25%
reduction in
diarrhea
|
2,00,000 IU
single dose
|
morbidity (ARI, diarrhea)
defined and assessed for
3 months after acute
diarrheal episode
|
-
|
no
|
Dewan et al.
(17), tertiary hospital,
New Delhi
|
6-60
|
216
|
not
mentioned
|
1,00,000 IU
single dose
|
duration of acute
diarrheal episode,
no long term follow-up.
|
-
|
no
|
Venkatarao
et al. (18), rural
Tamil Nadu
|
newly
born
and her
mother
|
909
pairs
|
adequate to
detect 10%
reduction in
ARI/diarrhea
incidence
|
3,00,000 IU
to mother
and
2,00,000 IU
to infant at 6
mo of age
|
morbidity (ARI,
diarrhea) defined
and assessed for
incidence, severity
and duration,
till 1 yr of age
|
-
|
no
|
Coles et al.
(19), rural
Tamil Nadu
|
0-6
|
465
|
power to
detect
differences
was low
|
7000 µg
retinol, 2
doses within
48 h of birth
|
nasopharyngeal
pneumococcal
carriage at 2,4,6
mo of age, mortality,
morbidity not analyzed
|
-
|
-
|
ARI– acute respiratory infection
Background indicators
Eight studies were
conducted in the rural settings (5 in Tamilnadu alone), 2 in urban slums
(one each in Mumbai and Delhi) and one was hospital based. Only 4 studies
provided socio-economic details. None of the study was multicentric or
truly represented the entire target population, i.e., the children
of India.
Subjects
Effect of vitamin A
supplementation was considered in different age groups ranging from birth
to 6 years (Table I). Number of subjects in agewise sub-categories
did not conform to that in the general population. Both sexes were
represented equally. Pre-existing vitamin A status of study subjects not
ascertained in most studies.
Design
Except one study(12), all
others were randomized trials. A placebo was not used in two of the
trials. Out of 4 mortality trials, 3 had enrolled more than 15,000
subjects each(4,6,14) but did not calculate or mention the adequacy of
sample size and power of these studies. In other studies, where sample
size was calculated, it was not sufficient enough to detect differences in
sub-categories of age and sex.
Intervention
Various doses of vitamin A
were employed (Table I). None of the studies compared vitamin A
supplementation with balanced diet or attempted supplementation through
diet alone.
Adequacy
Out of 11 studies, only 2
trials(13,19) fulfilled the criterion for adequate trial execution and
statistical analysis. The first(13) showed no significant impact of
vitamin A supplementation on frequency and duration of diarrhea and
respiratory tract infection related morbidity. The results of the
later(19) can not be generalized as it included only children aged 0-6
months, and was not planned to study a direct relation with mortality or
morbidity. None of the mortality trials were considered adequate for
execution and analysis.
Bias
Potential sources of bias
existed in all the studies considered for this review. None attempted to
identify them and make appropriate statistical corrections. See
Appendix for detailed study-wise identifica-tion of bias.
The studies quoted in this
review were not without their merits. Three of them had a sample size in
excess of 15,000. Most were community based trials and published in
reputed Journals; and few had been included in meta-analyses on the
subject(3,22). Individual study-wise details on each of the parameter
(including merits and demerits) are provided in the Appendix.
Discussion
The issue of reduction in
childhood mortality with prophylactic vitamin A supplementation is
addressed to in 4 trials on Indian children, out of which 3 have concluded
that vitamin A supplementation has a significant impact on bringing down
the child mortality. The maximum mortality reduction (78%) was observed in
1-5 year mortality in a trial(12) that was very inadequate in design,
quality control, and had the maximum sources of bias; the analysis was
inadequate and confounders were not studied. The same trial, however
failed to document any decline in the infant mortality rate! Marked
reduction in child mortality (54%) was reported in another well conducted
trial(4) that supplemented weekly vitamin A at the level of dietary
allowances for a year. In the other two trials(6,14) employing mega dose
vitamin A supplementation (range 50000 to 200 000 IU) given at 4-6 month
intervals, no significant impact was noted on childhood mortality, though
the latter study(14) asserted reduction in mortality despite
non-significant difference.
Nine studies
(5-6,12-13,15-19) were examined for possible relationship of vitamin A
supplementation and reduction of morbidity. Of these, 5 trials (5-6,12-15)
were conducted in otherwise well children. Different supplementation
schedules were followed including weekly low dose vitamin A, or megadose
vitamin A given 4-6 months apart. Three reports (5,6,13) with relatively
better study design reported no significant impact on morbidity; Agarwal
et al.(15) reported a mild (10%) reduction in overall morbidity.
Kothari(12) also reported some decline in morbidity but important details
were lacking, including unvalidated results and conclusions. Two
supplementation trials(16,17) were carried out in children with acute
diarrhea. The outcome measure in one of these studies(17) was duration of
the acute diarrheal episode while the other study(16) aimed to examine the
reduction in subsequent morbidity. Vitamin A supplementation was neither
found to affect the duration of acute diarrhea, nor did it lower the
incidence of subsequent diarrhea and acute respiratory tract infections.
In another study(18), morbidity in infancy was not found to be affected by
mega dose vitamin A to the mother soon after birth or to her infant at 6
months of age.
Coles, et al.(19)
tried to link vitamin A supplementation at birth to delayed naso-pharyngeal
colonization with pneumococci. Though they did not consider mortality as
an outcome measure, it was noted that the number of deaths (amongst the
children who dropped out) was equal in both supplemented and placebo
group, up to 6 months of age. This fact was not discussed in the study.
It is abundantly cleat that
on the basis of current studies, no consensus statement can be made. All
these trials suffer from methodological flaws, the most important and
common are highlighted. Firstly, the sample size, when divided into
age-sex groups, nutrition status or health access may not be adequate to
detect medically important differences between the treatment and control
groups. Secondly, information is lacking on: (i) assured masking
till the analysis of data, and (ii) quality control and reliability
of the intended procedures and their field imple-mentation. Thirdly,
parameters such as diet and health access are not considered as possible
confounders and the role of frequent contacts (Hawthorne effect) has not
been studied. No attempt has been made to identify the kind of children
who could really benefit from the supplementation. Fourthly, multi-variate
analysis of data has not been done (except in one study) that would have
facilitated the individual net effect of different variables. Potential
sources of bias were not identified and corresponding adjustments were not
made. Intermediary trend was not analyzed, perhaps due to small sample
size. Lastly, none of the studies has addressed the issue of efficacy
versus effectiveness, or conducted cost-effectiveness of such inter-vention
as against the other measures. All the trials are aimed at only
supplementation but none addressed the issue of adequate supply of vitamin
A through diet alone, and its impact on childhood morbidity and mortality.
The results of the trials done so far are not un-equivocal, particularly
findings for mortality and morbidity are not corroborative. We can
conclude that there is no definite evidence as yet of substantial benefit
of universal vitamin A supplementation to children in India. There is a
clear need to undertake a comprehensive trial with adequate sample size
and a standardized methodology that could give clear, unbiased, and
convincing evidence one way or the other. Since India is a vast country
with enormous diversity in baseline characteristics, a multicentric trial
with common protocol may provide the final answer.
Contributors:
AI conceived the idea for this paper and provided the study design. Both
the authors were involved in final study design; and collecting,
synthesizing and analysing the data. The manuscript was drafted by PG and
AI. PG shall stand as guarantor for the paper.
Funding:
None
Competing interests:
None stated.
APPENDIX
Details of Studies Linking
Vitamin A with Reduction of Mortality and Morbidity
Studies 1, 2
Rahamatullah et al.(4,5)
conducted two trials in villages of Trichy district, Tamil Nadu, and
concluded that child mortality reduced on an average by 54% (from 10.5 to
4.8 per 1000) by weekly low dose vitamin A supplementation at the level of
dietary allowance. The incidence, severity or duration of diarrhea and
respiratory illness was not affected.
Mortality trial
Background:
Drought-prone area. Only 1% received vitamin A supplementation under
routine program. Yet, very low U5MR–8.1/1000. Socio-economic details not
provided.
Subjects:
Age 6 to 60 months–increasing from 20.0% in 1-2 years to 22.4% in 4-5
years (contrary to general pattern). Males are 52%, which is fine.
Design:
Randomized controlled masked trial. Number of Panchayat Unions was three.
Criteria of selection not mentioned. As many as 206 clusters formed of
variable size (50 to 100 subjects). Unit of randomization was cluster.
Total 15,419 children—treatment group 7764 and control group 7655. No
mention of adequacy of sample size and power of the study.
Intervention:
Weekly 8333 IU vitamin A (same as dietary allowances) + 46 mmol vitamin E/mL
for one year. Placebo was weekly 46 mmol vitamin E/mL.
Proximal measures:
Six monthly ocular examination, anthropometric measurement and morbidity
history (recall period not mentioned). Finger-prick blood and dietary
history taken (presumably six-monthly). Diseases studied but their
definition not specified. Mortality (including accidental death) is the
main outcome measure.
Field work:
Steps taken for quality control of data. Pilot study not mentioned. For
baseline, equivalence of age-sex, incidence of diarrhea and respiratory
diseases, anthropometry, xerophthalmia, U5MR, household economic and
hygiene status, and serum retinol level mentioned but no data shown.
Health access not studied. Percentage that refused to participate not
mentioned. Finger-prick blood and dietary history taken for only 2% random
subsample (n = 280). Nearly 12% lost to follow up. Nearly 42%
received all the doses (433,000 IU) and 90% received at least 307,000 IU.
Children with eye signs continued in the follow-up.
Potential sources of bias:
(i) Large dose of vitamin A given to children with xerophthalmia
(11%) and they continued to be part of the study subjects. (ii)
Doses were missed in many children. (iii) Possible large effect of
weekly contact. (iv) Recall period for morbidity not mentioned. (v)
Possible differentials in nutrition status of children lost to follow-up
(12%). (vi) No mention about time lag between baseline assessment
and start of the trial.
Analysis:
Rise in variance (stated as 30%) due to cluster sampling recognized and
adjusted. Effect of large dose to children with xerophthalmia ruled out.
No analysis done for the effect of missed doses. Contact effect ruled out
but substantial difference in mortality in the first 8 weeks not
explained. Analysis done to indicate that significant association between
treatment and mortality persisted when simultaneously adjusted for age,
sex and nutrition status. Extent of decline in mortality not assessed as
the baseline level is not mentioned. Cost-effectiveness not studied.
Documentation:
Data for baseline comparison not provided. Morbidity information is
absent. Very few deaths by respiratory diseases not explained.
Morbidity trial
See preceding Mortality
trial for details. Episode of diarrhea and respiratory infection defined.
Other morbidity symptoms recorded but not analyzed. Nutritional status
cate-gorized as normal, stunted, wasted and stunted+wasted. Detailed
analysis of morbidity and growth in children with nutritional status
presented. Factors such as health access and diet not considered.
Study 3
Vijayraghavan et al.(6)
conducted a trial in villages around Hyderabad with six monthly vitamin A
doses (maximum 2 doses of 200,000 IU each ) to children aged 1-5 years.
The study failed to demonstrate any significant impact on mortality or
morbidity. Mortality declined in both treatment and control group with
higher number of contacts. Salient features are given below.
Background:
Villages in backward district. Yet lower child mortality (6/1000) than
national average (20/1000). No distribution of vitamin A done in this
area. Socioeconomic details not mentioned.
Subjects:
Age 1 to 5 years—nearly equal in age 0-1, 1-2, 2-3 and 3-4 years but less
than half in 4-5 years. Almost equal representation of the two sexes.
Design:
Double-blind placebo controlled trial. Study area comprised five PHCs
(criteria of selection not mentioned). Unit of randomization is village
(84) with (presumably) 42 villages in treatment and control group. Of
15,775 children, 7691 are in treatment group and 8084 in control group. No
mention of sample size determination and power.
Intervention:
Vitamin A 200,000 IU six-monthly (max. 2 doses). Placebo is arachis oil.
Proximal measures:
Mortality noted without cause of death. Disease (diarrhea and respiratory)
defined but only frequency considered (severity and duration of sickness
not considered). Height and weight taken every six months. Vitamin A
status assessed by xerophthalmia (corneal involvement considered severe
deficiency). Serum retinol level not measured. For PEM, children
categorized by wt-for-ht<80% and 80% but result not mentioned. Diet not
studied.
Field work:
Quality control done by deploying trained staff and supervision. Pilot
study not reported. Baseline stated similar for income, age-sex,
wt-for-age, birth rate and death rates, but not supported by data. Refusal
to participate not mentioned. Mortality and morbidity recorded at
three-monthly visits but recall for morbidity was one month (thus many
episodes might have been missed). Clinical examination done every six
months. First dose given soon after first examination and thus no gap
between baseline and start of the trial. Nearly 58% received both the
doses in either group, others one or no dose. Lost to follow-up not
mentioned. Children with corneal involvement excluded.
Source of bias:
(i) One-month recall for morbidity whereas the visit was quarterly.
(ii) Decoding of treatment and placebo done after the data
collection (presumably before data analysis). (iii) Nutritional
status differential possible in lost to follow-up. (iv) Unequal
children (397 in treatment and 638 in placebo group) received no dose.
Analysis:
Mortality separately analyzed for children with and without xerophthalmia
(no significant association found).
Documentation:
No result provided on vitamin A supplementation and mortality. Instead
substantial part devoted to the association between diseases and
xeroph-thalmia (no association found).
Study 4
Kothari(12) reported the
impact of 200,000 IU vitamin A supplementation on morbidity and mortality
in urban slum children of Bombay. There was lowering of 1-5 year mortality
rate from 16.8 to 3.64 per 1000 (in 3 years) in the experimental group as
compared to 19.75 to 18.9 per 1000 in the control group. There was no
lowering of infant mortality rate. The study also observed a significant
difference in number of children getting more than four spells of illness
per calendar year, between the two groups.
Background:
Two slum areas, 6 km apart within distant suburbs of Bombay. No concrete
data provided on socio-economic status demographic profile, immunization
coverage health practices or health access.
Subjects:
Age at enrollment <1 year; study not planned for sex differentials.
Design:
No sample size calculations done. No
randomization. No mention of masking.
Intervention:
Consent not obtained. Supplementation given to every alternate infant
(<1year) in one slum (n = 195; possible 433). Every alternate child
in the other slum (n = 192; possible 416) served as control.
Supplementation consisted of vitamin A 200,000 IU, Details on number of
doses, frequency of administration and length of administration not
specified. No mention of any supplementation/placebo to the control group.
Proximal measures:
Primary outcomes were mortality and morbidity. Cause of death not
ascertained. Episodes (spells) of morbidity not defined. Malnutrition
identified as one of the morbidities but magnitude or severity not
documented. Morbidities not classified with respect to severity, frequency
or duration of each spell. Anthropometric data not collected. Nutrition
status not graded. Prevalence of xerophthalmia not assessed. Dietary
survey not done.
Field work:
No quality control tools employed. Details of field methods are lacking.
No refusals to participate! Baseline characteristics of the two groups not
provided or compared. Follow-up dose at 6 monthly intervals using health
interview, health examination and examination of records for 3 years. No
follow up/deletion of subjects who have or develop eye signs.
Potential sources of bias:
(i) Very long recall period, i.e., 6 months. (ii)
Observing cause-effect over a very long period of time (3 years) without
studying any of the possible confounding factors. (iii)
Non-randomized study, baseline characteristics could have been different.
(iv) Placebo-effect of supple-mentation not countered. (v)
Median age at supplementation and morbidity/nutritional status at the time
of supplementation not studied. (vi) Sex distribution in two groups
not mentioned. (vii) Differential health access for two groups is
possible. (viii) Dietary assessment lacking. (ix) Causes of
mortality not analyzed. Factual morbidity data not presented. (x)
Possible different nutrition status in two groups. (xi) No mention
about specific treatment/inclusion/exclusion of those with xerophthalmia.
Analysis:
No baseline adjustments done. Details of analysis not provided. Though the
follow-up was 6 monthly, the data was not analyzed intermittently.
Nutrition, breast feeding, immunization, dietary intake not considered as
confounders. No multivariate analysis performed. No details of statistical
analysis provided in terms of tests of significance. Statistical
validation of differ-ences not done. No attempt at elimination of biases
as mentioned above.
Interpretation:
Important details lacking. No mention of randomization, placebo or
masking. Too long a recall (6 months). Statistical methods not adequate.
Results and conclusions not validated.
Documentation:
Presentation of the study is inadequate. Results not generalizable.
Confounders not studied.
Study 5
Ramakrishnan et al.(13)
provided vitamin A supplementation (1 lac IU to <1-year-old and 2 lac IU
to 1 year old at four monthly intervals, thrice a year), in children 6-36
months, from villages in Tamil Nadu. Supplementation did not appear to
reduce common morbidity in children who have mild to moderate vitamin A
deficiency.
Background:
The trial was carried out in villages where Growth Monitoring Research
project was going on for two years. Thus, access to health care was good
and immunization more than 90%. All children older than 1 year routinely
dewormed. Socioeconomic status of the families also assessed.
Subjects:
Subjects are children of age 6 to 36 months with nearly equal males and
females.
Design:
Randomized double blind placebo control intervention trial. Unit of
randomization is child. Treatment group finally had 309 children and
control group 274. No mentioned about adequacy of sample size. Power
calculated post-study showed adequacy to detect 25% reduction in
morbidity.
Intervention:
Vitamin A 100,000 IU to children less than 1 year and 200,000 IU to
children 1 year and above three times four months apart. Placebo not
described.
Proximal measures:
Mortality was not considered. Morbidity (particularly diarrhea and
respiratory illness) assessed in terms of percent time ill, incidence and
mean duration per episode. Weekly visits done and recall time was one week
only. Episode of different disease defined. Height, weight, and midarm
circumference measured at the beginning and at the end of the study.
Ophthalmic signs of vitamin A deficiency and serum retinol level assessed
at the beginning and at the end. Dietary intake of b-carotene and
preformed vitamin A estimated by using a quantitative food frequency
questionnaire. Stunting, under weight and wasting defined. Growth
monitored in half the villages.
Field work:
Morbidity data collected by trained village nutrition workers on weekly
basis. Clinical criteria could not be included. Forms routinely checked by
supervisors. Ophthalmic signs assessed by trained ophthalmologist. Pilot
study not mentioned. Percentage that refused to participate not mentioned.
Baseline characteristics of the children (age, sex, ht-for-age,
wt-for-age, serum retinol, vitamin A intake, bottle feeding, birth order
and immunization) compared between treatment and control but not the
prevalence of xerophthalmia. Socioeconomic status of the parents also
compared. Follow-up was for one year. Serum retinol level assessed only
for 366 (63%) subjects. Children with signs of xerophthalmia, severe
malnutrition (defined) and serious illness (not defined) excluded (55
children). Out of 715, only 583 (82%) used for analysis–others (including
55 just mentioned) lost due to migration, death and inadequate morbidity
data.
Potential sources of bias:
(i) Effect due to weekly contact. (ii) Children lost (18%)
not examined for baseline characteristics. (iii) Treatment group
has substantially more females than males and maternal education more in
treatment group (though not statistically significant at a = 0.05). (iv)
Serum retinol level available only for 63% of this truncated group.
Analysis:
Adjustment for possible bias described above not done. Infectious disease
load analysed for diversity, frequency and duration but not for severity.
Analysis done by sex, growth monitoring, nutrition status (serum retinol
level and degree of stunting, wasting and under-weight). Multivariate
analysis also done to adjust for factors as age, sex, nutrition status,
immunization status, economic status, vitamin A intake and mother’s
education.
Interpretation:
Results seem internally consistent. Since multivariate analysis was also
done, higher error due to multiple tests is ruled out. Power calculated
post-study.
Documentation:
Does not discuss mortality but the study looks complete for morbidity.
Studies 6, 7
Agarwal et al.(14),
in a trial in villages of Varanasi, concluded that vitamin A
administration to children under six years protects against overall
mortality, in particular deaths due to gastroenteritis and severe
malnutrition. In another trial(15), they demonstrated that vitamin A
supplementation for one year resulted in 10% overall reduction in
morbidity in children of 1-72 months from villages of Varanasi.
Mortality trial
Background:
Villages in Varanasi district, but less than 15% belonged to lower
socioeconomic class. No mention of health access in the selected villages.
Socioeconomic data provided.
Subjects:
Children one month to six years of age but 0-1
nearly twice as many in the treatment group as in 1-2 year age-group – a
feature not present in the control group. Also, children of age 5-6 years
are more than of 4-5 years. M-F ratio 1000:810 in both the groups.
Design:
Randomized double blind trial. Unit of randomization is subcenter. By
mistake 12 of subcenters (instead of 8) received treatment and only 4
received placebo. Children in treatment group are 9987 and in placebo
group 5260 (not in the expected ratio of 3 : 1 as for subcenter). No
mention of sample adequacy, size and power. Second phase was one time
measurement after one year of withdrawal of intervention.
Intervention:
Treatment group received 50,000 IU vitamin A plus 10 IU vitamin E if child
is 1-6 months and 100,000 IU vitamin A plus 10 IU vitamin E if child is
7-72 months, every 4 months for 12 months. Placebo is only vitamin E.
Proximal measures:
Primary outcome is mortality. Cause of death also assessed. Morbidity also
studied but details not provided (see possibly morbidity trial below).
Nutritional status graded on the basis of wt-for-age. Immunization and
xerophthalmia status recorded. Serum retinol level and diet not assessed.
Field work:
No mention of training or supervision as also of pilot study. Baseline
age-sex and nutrition stated to be similar without statistical test.
Significantly high mortality in the experimental group than control groups
at baseline. Xerophthalmia 3.6% in treatment and 2.4% in control group.
None refused to participate yet nearly 15% received no dose. No mention of
how many received all the doses.
Potential sources of bias:
(i) Contact effect not considered. (ii) Differential
follow-up in terms of doses administered (nearly 10% of treatment group
and 20% of control group received no dose). (iii) Differential
mortality at baseline. (iv) Unusual predominance of infants in the
subjects. (v) Possible differential health access.
Analysis:
Mortality analyzed by immuniza-tion and nutrition status including for
xerophthalmia. Cause of death also analyzed. No adjustment done for bias
mentioned above. Disease load not considered. Reduction in mortality
asserted despite non-significant difference. Most differences were not
significant anyway but multiple statistical tests used on one group at a
time has a risk of showing unreal significance.
Interpretation:
Role of confounding factors such as frequent contacts and differential in
base line not discussed. Statistical signifi-cance achieved on the basis
of increased mortality in control group and decreased in the treatment
group, each of which may not be significant.
Documentation:
No result provided for morbidity. Four-monthly trend in mortality not
studied.
Morbidity trial
Background:
Villages in Varanasi district with IMR 100 and
low birth weight deliveries 26%, socioeconomic details provided. Nearly
25% received immunizations.
Subjects:
Children of age 1 month to 6 years. Age distribution not provided. Males
and females nearly equal.
Design:
Randomized double blind controlled trial. Six villages randomly selected
out of 112 in a PHC area. Three each randomly allocated to the treatment
and control group. Number of children 1665 in the treatment group and 1440
in the control group. No mention of adequacy of sample size and power to
detect strategically important difference.
Intervention:
Treatment group received 50,000 IU vitamin A plus 10 IU vitamin E if child
is 1-6 months and 100,000 IU plus 10 IU vitamin E of child is 7-72 months,
every 4 months for 12 months. Placebo only vitamin E.
Proximal measures:
Nutritional categories by Gomez classification (weight-for-age). Morbidity
assessed in terms of sickness days, episodes per child, duration of
episodes, etc. Disease included measles, respiratory infection, otitis
media and skin infections. Xerophthalmia recorded at baseline but no
mention of its status at the end of the trial. Serum retinol level not
measured. Diet not assessed.
Field work:
No mention of training or supervision or a pilot study. Social factors
(literacy, family size, access to potable water) not different in the
study and control group. Xerophthalmia slightly higher in control group
(3.2%) compared to treatment group (2.1%). Nearly 13.5% children of
control and 18.5% of treatment group could not be contacted. No mention of
how many received all the doses and how many only one or two doses.
Follow-up 2-weekly for morbidity and four-monthly for drug administration.
Children with xerophthalmia administered 200,000 IU and excluded from
analysis.
Potential sources of bias:
(i) Differential follow-up in terms of doses administered. (ii)
Baseline vitamin A status not considered. (iii) Increase in
morbidity in control group. (iv) Possible diet differential.
Analysis:
Overall morbidity analyzed by age, sex, immunization status, nutrition
status and social factors (type of family, family size, source of drinking
water, literacy) in univariate set-up. Multivariate analysis not done.
Disease load assessed for diversity, frequency and duration but not
severity. Source of bias due to differential doses not considered. Age
wise analysis of individual diseases not done.
Interpretation:
Too many statistical tests at 5% level that could enormously increase
total error. Yet, many results provided without statistical tests. Role of
2-weekly contact for morbidity assessment not ruled out.
Documentation:
Mortality not studied (see mortality trial above). Four-monthly trend not
provided. Effectiveness and cost-effective-ness not considered.
Study 8
Bhandari et al.(16)
studied the impact of single dose vitamin A 200,000 IU on morbidity from
acute respiratory tract infections and diarrhea in children with acute
diarrhea in an urban slum of New Delhi. Results were consistent with a
lack of impact on acute lower respiratory tract related morbidity or
incidence of diarrhea. Authors noted a 36% reduction of diarrhea with
fever in vitamin A supplemented children of age more than 23 months.
Background:
Urban slum. Socioeconomic background provided. Immunization coverage for 3
doses of DPT 74 %. Health access facility average. No distribution of
vitamin A in preceding three years. Representativeness of the target
population questionable as only children with acute diarrhea were
enrolled.
Subjects:
Age 12 months to 60 months. Approximately half (49.4%) in 12 months-23
months. Males 52%. Only those with acute diarrhea and weight for height
70% of NCHS 50th percentile enrolled (n = 900), out of possible
1258. Those with clinical vitamin. A deficiency (n = 120) excluded.
Maximum prevalence of clinical vitamin A deficiency seen in 24-36 months
age group (5.3%).
Design:
Double blind placebo controlled trial. Unit of randomization is child.
Treatment group finally had 422 children and control group 420. Sample
size calculations provided. The trial size was adequate to detect a 25%
reduction in the incidence and prevalence of diarrhea but not to detect a
similar impact on the incidence of pneumonia; with a power of 90%. No
sample size calculation or post-hoc analysis for age subgroup categories
(£23 months vs ³24 months) that the authors have used.
Intervention:
Single dose vitamin A 200,000 IU. Placebo not described.
Proximal measures:
Mortality was not considered. Morbidity assessed in terms of incidence and
mean daily prevalence of acute respiratory tract infection and diarrhea.
Episodes of different diseases defined both in terms of onset and
recovery. Severity of diarrhea measured in terms of presence/absence of
fever, but not graded for dehydration. Severity of ALRI measured only in
terms of lower chest indrawing, and/or presence of pneumonia. Visits made
every three days. Weight and length/ height measured at enrolment (data
provided) and at the end of the study (data not provided/analyzed). Those
with xerophthalmia excluded at the start but no mention of those who
developed xerophthalmia during the study. Serum vitamin A level estimated
in 40 (5%) randomly selected children in each group, before and a month
after supplementation. Dietary intake not assessed.
Field work.
Informed consent taken. Household visits made by a trained field assistant
every 3 days. Reassessment made by supervisors in one-third to one-half of
recalls/measurements. No mention of laboratory standardization, any manual
of instruction to field workers, or a pilot study. Refusal to participate
7.8%. Baseline socio-economic and clinical characteristics of children
compared and found not different. No comparison done for dietary intakes.
Follow up done for 90 days after recovery. Out of 900 enrolled, 842
(93.5%) available for final analysis – others lost due to non-availability
(n = 46), withdrawl of consent (n = 5), and severe illness (n
= 7) including tuberculosis, cardiac disease or severe anamia. Serum
vitamin A levels available for only 80 subjects. No mention of those who
developed eye signs of VAD during the study.
Potential sources of bias:
(i) Children lost (6.5%) not examined for baseline characteristics.
(ii) Contact effect not considered. (iii) Unusual prominence
of <2 year olds (reflects the age preference for diarrhea?) (iv)
Severity of initial enrollment diarrheal episode not quantified in terms
of associated dehydration. (v) Characterization of severity of
diarrheal or respiratory illness not proper. (vi) Duration of study
and season not mentioned. (vii) No mention of any mortality in the
study subjects.
Analysis:
Initial socio-economic and clinical characteristics in the two groups
shown not different. Serum vitamin A concentration in the two groups found
not different. Relative risk of ARIs not different from one. Adjustment
for possible bias described above not done. Seasonality not considered.
Impact of breast feeding, weaning and maternal nutrition not studied.
Characteristics of those who showed improvement not delineated.
Multivariate analysis not done.
Interpretation:
Adequate.
Documentation.
Does not discuss long-term follow up beyond 3 months. Generalizability is
inadequate since only those with acute diarrhea considered and clinical
vitamin A deficiency not included.
Study 9
This is another
hospital-based study that administered 100,000 IU vitamin A to children
with acute diarrhea(17). No long-term outcome was seen and the impact of
supplementation was observed on the duration of acute diarrheal episode.
Vitamin A supplementation did not significantly reduce the duration of a
diarrhea episode except in those with pre-existing vitamin A deficiency
and associated malnutrition.
Background:
Hospital based study in subjects reporting to a tertiary care center for
treatment of diarrhea
Subjects:
Age 6 months to 5 years of either sex. Mean age approximately one year. No
data provided for different age categories. Subjects not classified by
sex.
Design:
Randomized controlled trial. Method stated as simple random sampling. No
placebo used. Not masked. Justification for sample size not mentioned. No
stratification done for age-sex but done for socio-economic status. Prior
equivalence of case and control group is plausible.
Intervention:
Single dose vitamin A given orally to 108 cases with acute diarrhea
(100,000 IU to the others). An equal number of controls enrolled from the
same clinic. (Children with xerophthalmia in control group denied
treatment till the diarrhea episode was over, which could have compromised
ethics.)
Proximal measures:
Mortality and long term morbidity not studied. Effect of vitamin A
supplementation observed only on an acute episode of diarrhea. Outcome
measure was mean duration of diarrhea. Onset of diarrhea not defined
though termination is defined. Xerophthalmia was noticed in 11.1% of cases
and 12.9% of controls and they continued to be the part of the study.
Serum retinol level not studied but conjunctival impression cytology was
possible in around 88% of enrolled subjects. Diet was not assessed.
Field work:
Hospital based study. No mention of quality control, or pilot study.
Method of selection of cases (only 108 cases of diarrhea enrolled in more
than 9 months in a tertiary care center!) and controls not specified.
Duration of maximum follow up not specified. Frequency and method of
follow up are also not specified. Refusal to participate not mentioned
(probably because no consent was obtained). Cases and controls stated not
different for age-sex distribution, feeding pattern, socio-economic
status, nutritional status, stool frequency, hydration, associated
symptoms but no data provided to substantiate this. Immunization status,
duration of exclusive breast feeding, time of weaning, dietary intake,
health practices, water supply, housing, etc. not considered. Loss in
follow up not reported for any of the cases or controls!
Potential sources of bias:
(i) Selection of cases and controls not specified. (ii)
Cases and controls not studied for several parameters such as immunization
status, duration of exclusive breast feeding, weaning time and foods,
dietary intake, health practices, water supply, housing that affect
vitamin A status or onset termination of diarrhea. (iii) Contact
effect not considered. (iv) Period of recall not mentioned. (v)
Children with xerophthalmia continued to be part of the study.
Analysis:
Adjustments for baseline imbalances not needed as none was detected. Power
of the study to detect clinically important difference not studied. Impact
of breast feeding-weaning not studied. No multivariate analysis done.
Interpretation:
Conclusion that vitamin A supplementation has beneficial effect in cases
with pre-existing VAD is fine with univariate analysis but its validity
under multivariate analysis is not known when factors such as age,
socioeconomic status, weaning are also considered.
Documentation:
Restricted only to diarrhea episodes, and morbidity, mortality, retinol
level, and xerophthalmia not studied.
Study 10
Venkatarao et al.(18)
studied the impact of 300, 000 IU vitamin A to the mother soon after
delivery and to the infant (200, 000 IU) at six months on morbidity in
infancy in a field trial in rural Tamil Nadu. Authors concluded that
prophylactic administration of vitamin A megadose to mother soon after
delivery and to the infant at six months do not have any beneficial impact
on the incidence of diarrhea and ARI in infancy.
Background:
51 villages in Tamil Nadu, No mention of health access to inhabitants.
Socio-economic details partially mentioned. Immunization coverage 75%,
58%, 83% and 56% for BCG, DPT, OPV and measles respectively. No mention of
routine/previous vitamin A distribution in the area.
Subjects:
A newly delivered mother and her infant formed a pair of subjects. Newly
born child followed up till 1 year of age. Equal sex representation. Only
909 (68.1%) pairs enrolled out of possible 1335 child births.
Design:
Double-blind placebo controlled trial. Unit of randomization was the
mother-infant pair. Sample size adequate to detect a 10% difference in the
incidence of diarrhea/ARI with a power of 90% (post-hoc calculations); but
not analyzed for two age categories, i.e., 0-6 and 6-12 months.
Intervention:
Both mother and infant received vitamin A (300,000 IU for mothers and
200,000 IU for children) in 311 instances (AA); mother received vitamin A
but infant received placebo in 301 instances (AP); and both mother and
infant received placebo (PP) in 297 instances. Mother given
supplementa-tion between 7-14 days after delivery and the infant received
vitamin A or placebo at 6-6½ months of age. Consent obtained from village
leaders but not from individual mothers. Placebo to mothers was 600 mg of
vitamin E and to infants was 2 mL of sesame oil.
Proximal measures:
Mortality and cause of death assessed. Morbidity (diarrhea and ARI)
assessed in terms of incidence, frequency of episodes and number of
infected days. Episodes of diarrhea and ARI defined. Severity definition
not appropriate, i.e., all episodes of lower respiratory tract
infection (assumed in children with difficulty in breathing for <30 days
in children <2 months old, and associated with cough in those ³2
month old) were equated with those requiring hospitalization. Criteria for
hospitalization not specified. Similarly episodes of diarrhea associated
with vomiting were considered severe but not graded as per the hydration
status. Management of an episode not standardized or clarified in the
manuscript (who treated, where and how?). Weight recorded at birth at 6-6½
months and one year. Nutrition status not studied on individual basis.
Serum retinol levels not obtained either in the mother or infant. Dietary
intake of neither the mother nor infant studied.
Field work:
Field workers trained intensively and procedures standardized during field
testing. No mention of instruction manual. No standardization of treatment
protocol for morbidities. Supervision initially in 10% random sample and
subsequently by spot checking once a week (number or percentage not
mentioned). Not preceded by a pilot study. Out of 1335 possible
enrollment, 909 (68.1%) enrolled. No reason provided for 135 mother-infant
pair exclusions. Of the 909 randomized, final analysis was available for
233, 228 and 228 pairs in three groups respectively. Follow up loss 24.2%.
Of 220 drop outs, there were 20 deaths, 13 medical exclusion, 79
migrations and 23 miscellaneous reasons. No reason provided for exclusion
of 85 (10.7%) of randomized subjects. There was no refusal to participate
because the consent was not asked for! Baseline characteristics (sex,
literacy, maternal age, parity, family size, housing, immunization, breast
feeding habits, neonatal weight) were not different in three groups;
however data not provided. Side effects of vitamin A monitored.
Potential sources of bias:
(i) Maternal anthropometry, illnesses, hemoglobin, albumin and
retinol level not studied. (ii) Newborns were included irrespective
of their weight, gestation and appropriateness for gestation. (iii)
Exclusive breast feeding rate was not studied or compared in three groups.
(iv) Age of weaning, detailed dietary history not obtained. (v)
Infants not classified as per their nutritional status. (vi) Weight
gain during second half of 1st year of life was only 1.0 kg. (vii)
High unaccounted follow up loss, both before and after randomization. (viii)
Recall period approximately two weeks. (ix) Possible differential
management of morbidities. (x) Children with clinical xerophthalmia
continued to be part of the study, not detected separately.
Analysis:
No adjustments for above biases. No Intention to Treat analysis done. No
analysis done for possible confounders such as maternal nutrition, birth
weight, gestation, exclusive breast feeding, weaning, diet, serum retinol,
and nutritional status. No multivariate analysis done. Analysis provided
separately for 0-6 and 6-12 months ages and compared for all outcome
variables.
Interpretation:
Though not significant, a higher incidence of diarrhea was observed in
vitamin A supplemented groups. Similar trend was seen with the number of
diarrheal episodes and ARI, and illness days, for 0-6 month age analysis.
In 6-12 months children also the incidence of diarrhea, mean number of
diarrheal episodes, median days with diarrhea was lesser in the placebo
group, though statistically not significant. This was not discussed.
Documentation:
Not comprehensive. Sample size for mortality analysis is incomplete.
Retinol levels not considered.
Study 11
Coles et al.(19)
studied the impact of two doses of 7000 micrograms retinol equivalent
doses of vitamin A at birth in reducing the pneumococcal colonization in
infants from a rural area in Tamil Nadu with endemic vitamin A deficiency.
The risk of colonization among infants aged 4 months who were not
colonized by age 2 months was significantly reduced in vitamin A
supplemented group. The odds of colonization were 27% lower in the
supplemented group. No difference was detected in the prevalence of
invasive serotypes. The risk of colonization with penicillin resistant
isolates was 74% lower in the vitamin A group than placebo group at 2
months of age. However, the preva- lence of penicillin resistant isolates
was only 4%.
Background:
Natham in rural Tamil Nadu is endemic for vitamin A deficiency and has a
high incidence of ARI. No mention of any routine vitamin A supplementation
programs. Socio-economic indicators provided. No mention of immunization
coverage, health access and health practices.
Subjects:
539 infants randomized at birth and followed up at 2 monthly interval up
to the age of six months. Slight male preponderance (56.6%).
Design:
Double blind placebo controlled trial. Unit of randomization was mother,
stratified by cluster and blocked within geographical cluster area. Sample
size calculated, though the power to detect differences between treatment
groups was relatively low, sample size was inadequate to assess the impact
of vitamin A supplementation on prevalence of penicillin-resistance
strains (due to low prevalence – nearly 4% in this population). Masking
appears adequate and coding remained with a third party.
Intervention:
Newborn received either two doses of 7000 mg retinol equivalents of oil
soluble vitamin A or placebo within 48 hours of birth. Verbal consent was
obtained from the subjects. Nature of placebo not mentioned.
Proximal measures:
Mortality data available for drop-outs. Number of deaths was equal (seven
each) in both the groups. Morbidity data not provided. Primary outcome of
interest was the prevalence of pneumococcal nasopharyngeal carriage.
Secondary outcome of interest were (i) prevalence of invasive
serotypes of pneumococci, and (ii) prevalence of penicillin
resistant pneumococci. Growth, development, nutrition status, dietary
intake not considered nor recorded.
Field work:
Quality control, laboratory standardization maintained. Reliability of
data ascertained. Treatment groups not different at baseline for sex,
birth weight, siblings, colostrum feeding, maternal night blindness,
cooking fuel, property, maternal education and housing. Treatment groups
comparable at baseline with respect to known risk factors for ARI but
neither the factors specified, nor the data presented. Follow up was done
at 2 (n = 464), 4 (n = 406), and 6 (n = 359) months
after birth. Refusal to participate mentioned. All losses to follow-up
were accounted for. Morbidity assessed at every 15 days but data not
provided.
Potential sources of bias:
Treatment and control group not compared with respect to maternal
nutrition, maternal vitamin A status, and infants retinol level, mucosal
immunity and secretory IgA levels, that could have affected the prevalence
of colonization. In addition, exclusive breast feeding and weaning
methods/age not compared.
Analysis:
Appropriate adjustment for baseline imbalances made. Analysis done by
Intention to Treat. Bias as highlighted above not taken care of.
Multivariate analysis carried out.
Interpretation:
Adequate within the constraints mentioned above.
Documentation:
Mortality not different between groups. Morbidity, growth data, retinol
level not provided. Colonization studied only upto the age of 6 months.
|
Key Messages |
• Of the 11 trials
concerned with linkage of vitamin A supplementation with reduction
of mortality and morbidity in Indian children, none was perfect in
methodology, the results were not unequivocal and the issues of
cost-effectiveness and dietary modifications were not considered.
• There is no definite evidence as
yet in favor or against substantial benefit of universal vitamin A
supplementation to children in India.
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