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Indian Pediatr 2015;52: 329-332 |
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Does Early Neonatal Vitamin A Supplementation
Reduce Infant Mortality?
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Source Citation: Mazumder S, Taneja S, Bhatia K,
Yoshida S, Kaur J, Dube B, et al.; for the Neovita India Study Group.
Efficacy of early neonatal supplementation with vitamin A to reduce
mortality in infancy in Haryana, India (Neovita): A randomised,
double-blind, placebo-controlled trial. Lancet.
2014;doi:10.1016/S0140-6736(14)60891-6.
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Summary
In this individually randomized, double-blind,
placebo-controlled trial in Haryana, India, 44,984 neonates were
randomly assigned to receive oral capsules containing vitamin A (retinol
palmitate 50,000 IU plus vitamin E 9·5–12·6 IU; n=22,493) or
placebo (vitamin E 9·5–12·6 IU; n=22 491) within 72 h of birth.
The primary outcome was mortality between supplementation and 6 months
of age. Between supplementation and 6 months of age, 656 infants died in
the vitamin A group compared with 726 in the placebo group (29·2 per
1000 vs 32·3 per 1000; difference –3·1 per 1000, 95% CI –6·3 to
0·1; risk ratio 0·90, 95% CI 0·81 to 1·00). There was a small excess
risk of transient bulging fontanelle (205 cases in the vitamin A group
vs 80 cases in the placebo group; RR 2·56, 95% CI 1·98, 3·32).
Commentary
Relevance: Mazumder, et al. [1] have
presented a strong justification for conducting this trial of vitamin A
versus placebo in a large cohort of newborn infants. Data from a limited
set of previous trials suggested equivocal results with supplementation.
Two Cochrane systematic reviews [2,3] provided diametrically opposite
conclusions despite concordant literature search and inclusion of the
same set of trials. The review by Haider and Bhutta [2] suggested a
clinically significant reduction in early infant (<6 mo) mortality to
the extent of 14% (RR 0.86; 95% CI 0.77, 0.97), although there was no
difference in mortality at 12 months (RR 1.03; 95% CI 0.87, 1.23). In
contrast, another Cochrane review by Gogia and Sachdev [3] published at
the same time failed to demonstrate any benefit of vitamin A
supplementation during early infancy on infant mortality (RR 0.94; 95%
CI 0.79, 1.12) at any time point. Interestingly, the authors of the two
reviews somehow managed to disagree even in the evaluation of
methodological quality of the included trials! Besides reiterating that
even best quality evidence can sometimes result in missing the forest
for the trees [4], this discrepancy set the ground for re-evaluation of
the subject. This was done through the recent Neovita trial conducted in
India, Ghana and Tanzania [1,5-7). The data from the Indian trial [1] is
briefly reviewed here and serves to highlight both the individual trial
itself, and the data in the context of clinical equipoise with regard to
the vexing issue of neonatal vitamin A supplementation to reduce infant
mortality.
Critical appraisal: Table I
summarizes the methodological aspects of the trial [1] using the
Cochrane Risk of Bias tool [8]. The trial methodology was robust and
developed through a well-planned [7] and well-documented process. In
addition, there are several other noteworthy points. The randomization
unit was the individual infant rather than a cluster of infants. The
text contains a detailed description of the population demographics,
health-seeking behavior, literacy rate, economic status etc; as well as
several details of the enrolled infants. This makes it easier while
considering generalizability of the trial results.
TABLE I Assessment of Methodological Quality
Criteria |
Assessment |
Sequence generation |
Adequate. The randomization sequence was prepared by independent
personnel who were not involved in the trial conduct. Block
randomization (with fixed block sizes of 20) was used. |
Allocation concealment |
Adequate. The allocation sequence code was not accessible to any
of the investigators.
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Blinding of participants, personnel
and outcome assessors
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Adequate. Elaborate precautions were taken to ensure that the
intervention (vitamin A) and
placebo capsules were physically alike. The packaging was also
similar. Printed labels with
participant serial numbers were affixed on the packages ensuring
that no substitution was
possible. Personnel measuring the outcomes were unaware of the
allocations. However, there
is no description of whether research personnel or participating
families could guess the contents of the package at any time
during the study. |
Incomplete outcome data |
There was a very small number of participants whose data were
unavailable at the time of primary outcome assessment at 6
months (0.02% and 0.01% in the intervention and placebo arms
respectively). At the longest follow-up (12 months), only 0.12%
and 0.08% were unavailable for outcome assessment. The data were
analyzed per protocol, rather than intention-to-treat. |
Selective outcome reporting |
All relevant outcomes have been reported viz mortality at 6
months (primary outcome), neonatal mortality, infant mortality,
hospitalization for any cause till 6 mo, and several adverse
events (mortality within 72 hours of intervention, bulging
anterior fontanelle, vomiting, diarrhea, seizures, poor feeding,
lethargy and various other local and systemic events). |
Other sources of bias |
No obvious bias.
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Overall assessment |
Low risk of bias.
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The trial procedures are described in detail,
including participant enrolment, exclusion criteria, baseline data
collection, administration of intervention, measurement of primary
outcomes, and recording of potential adverse events. Other quality
assurance measures included random monitoring of the research personnel,
evaluation by an independent data safety monitoring board, and
supervision of WHO. Serial evaluation of trial capsules for vitamin A
content (indirect measure of potency and stability) was done with
satisfactory results.
Outcomes were measured at serial intervals and
several data variables were collected for analysis. A key adverse event
(bulging fontanelle reported to be significantly more frequent with
vitamin A supplementation in previous trials and systematic reviews) was
evaluated by research staff, and also confirmed by a physician. Data
were entered directly into computers reducing the risk of transcription
errors, and facilitating immediate flagging of potentially incorrect
entries.
Robust statistical methodology was used. Sample size
was calculated a priori with stringent limits for type I and type
II errors. The sample size was tweaked upward during the course of the
trial, based on advisory recommendations. Appropriate statistical tests
were used. However, per protocol rather than intention-to-treat
analysis was used. Nevertheless, this may not adversely impact the
results as very few participants were unavailable for outcome
assessment.
The investigators measured serum retinol and
C-reactive Protein (CRP) in a randomly selected subset of participants
at two time-points (15 d and 3 mo). This data is useful for evaluation
of a pathophysiologic mechanism for the observed results.
The trial did not show a statistically significant
benefit of vitamin A supplementation on mortality at any time-point.
Relative risk for mortality at 6 mo was 0.90 (95% CI 0.81, 1.00); at 12
mo 0.94 (95% CI 0.86, 1.02); and at day 28, it was 0.94 (95% CI 0.80,
1.11). There was no beneficial effect of supplementation on
hospitalization within 6 mo of birth (RR 0.96, 95% CI 0.90, 1.04).
Despite multiple methodological refinements, there
are some issues with data interpretation. For example, although the
baseline infant mortality rate in the catchment population was 60 per
1000 live births, the recorded mortality in the trial population was
only about half this value. This leads to the possibility that either
the trial participants or trial catchment area or both were not truly
representative of the local population. The other possibility is that
the catchment area was popular for other research-based intervention
strategies also, and hence had a pre-existing low infant mortality rate
compared to the district average. Of course, Hawthorne effect wherein
population behavior changes while under observation [9] cannot be ruled
out.
The authors have suggested that vitamin A
supplementation may reduce early infant mortality by almost 10%, and
perhaps even more by 12 months (judging by the survival curves). This is
difficult to grasp given that, even after supplementation, both groups
had mean serum retinol levels below the cut-off level for vitamin A
deficiency, despite an impressive P value for inter-group
comparison. Similarly at three months, both groups had comparable mean
retinol concentration, which was just at the cut-off level in both
groups. There could be three explanations. Either the subgroup in which
retinol levels were measured did not truly represent the trial
participants; or the dosage of vitamin A used was inadequate to raise
retinol to a sufficient level; or serum measurements are inappropriate
surrogates for tissue levels and/or body stores. More important, the
absence of difference between the intervention and placebo groups
suggests that the marginal differences in mortality at 6 and 12 months
of age, as emphasized by the diverging survival curves, are unlikely to
be related to vitamin A supplementation.
What does this trial add to the existing body of
knowledge? On the one hand, the contrary opinions expressed in the two
Cochrane reviews [2,3] led the WHO to strongly recommend against
neonatal vitamin A supplementation in 2011 [10]. However, at the same
time, WHO also led a set of three Neovita trials addressing the same
issue [1,5,6], suggesting that it lacked confidence in its
recommendation. Data from these trials is briefly summarized in
Table II which shows some differences between the three sites.
One additional recent trial by Benn, et al. [11] randomized 6048
neonates to receive either 50,000 units Vitamin A (n=2015),
25,000 Units vitamin A (n=2011) or placebo (n=2022) soon
after birth. Mortality was primarily assessed at 12 months. The first
and third arms are comparable to the Neovita trials; the respective
mortality rates were 50/1378 infant-years and 45/1377 infant-years,
suggesting the absence of any benefit with supplementation.
TABLE II Overview of the Trials in Neovita Study
Country |
|
India |
Tanzania |
Ghana |
|
|
Vitamin A |
Placebo |
Vitamin A |
Placebo |
Vitamin A |
Placebo |
Randomized |
|
22493 |
22491 |
15995 |
16004 |
11474 |
11481 |
28 d
|
Dead |
281 |
298 |
213 |
206 |
147 |
130 |
|
LFU |
0 |
0 |
318 |
294 |
27 |
22 |
|
Alive |
22212 |
22193 |
15464 |
15504 |
11300 |
11329 |
6 mo |
Dead |
375 |
428 |
194 |
166 |
131 |
1118 |
|
LFU |
4 |
3 |
249 |
246 |
102 |
106 |
|
Alive |
21833 |
21762 |
15021 |
15092 |
11067 |
11105 |
12 mo |
Dead |
223 |
213 |
159 |
174 |
93 |
80 |
|
LFU |
24 |
16 |
742 |
715 |
212 |
195 |
|
Alive |
21586 |
21533 |
14120 |
14203 |
10762 |
10830 |
Overall LFU |
|
28 (0.12%) |
19 (0.08%) |
1309 (8.18%) |
1255 (7.84%) |
341 (2.97%) |
323 (2.81%) |
LFU=lost to follow-up |
Haider and Bhutta have published an editorial with
fresh meta-analysis [12], including the three Neovita trial data, but
not the data from Benn 2014 [11]. Although the new meta-analysis
(pooling data from 10 trials) showed no overall benefit with vitamin A
supplementation, the authors suggested that trials in Asia showed
reduction in infant mortality while trials from Africa did not. However,
it is important to note that the authors clubbed together trials with
varying durations of follow-up. Thus trials with 4 mo follow-up [13]
were analyzed together with trials having follow-up of 6 mo and 12 mo.
Interestingly, the authors chose to include the 6 mo follow-up data from
the three Neovita trials rather than the 12 mo outcomes. Similarly,
there are some errors in data extraction from other trials as well,
making this meta-analysis unreliable. The authors conceded that contrary
to their previous position, neonatal vitamin A supplementation may not
be as beneficial as thought previously.
On the bright side, vitamin A appears to be safe as
there was no increase in mortality or serious adverse events after
supplementation. This may be particularly relevant because of recent
concerns about a potential increased risk of mortality with vitamin A
[14]. However as expected, the risk of bulging anterior fontanelle
(necessitating observation of infants over a period of days, and
possibly health-care interventions in some cases) was higher with
vitamin A. It is interesting that the rates of this adverse event vary
significantly at the three Neovita study sites; with India having the
highest frequency in both arms.
Extendibility: The data in this randomized
controlled trial (RCT) can be directly extrapolated to most Indian
settings, although it must be emphasized that the infant mortality rate
observed in the trial was about half of the expected rate; and hence the
intervention could work differently in a setting with high(er) infant
mortality. Although a trend towards better survival at 12 mo was
evident, there is no plausible biological basis or explanation for this
in relation to neonatal vitamin A supplementation.
Conclusions: This well-designed RCT confirms the
absence of any benefit of neonatal vitamin A supplementation on neonatal
mortality, early infant (6 mo) mortality and infant mortality; although
vitamin A supplementation was reasonably safe barring increased risk of
bulging anterior fontanelle.
References
1. Mazumder S, Taneja S, Bhatia K, Yoshida S, Kaur J,
Dube B, et al.; for the Neovita India Study Group. Efficacy of
early neonatal supplementation with vitamin A to reduce mortality in
infancy in Haryana, India (Neovita): A randomised, double-blind,
placebo-controlled trial. Lancet.
2014;doi:10.1016/S0140-6736(14)60891-6. [Epub ahead of print]
2. Haider BA, Bhutta ZA. Neonatal vitamin A
supplementation for the prevention of mortality and morbidity in term
neonates in developing countries. Cochrane Database Syst Rev.
2011;10:CD006980.
3. Gogia S, Sachdev HS. Vitamin A supplementation for
the prevention of morbidity and mortality in infants six months of age
or less. Cochrane Database Syst Rev. 2011; 10: CD007480.
4. Mathew JL. Evidence in health-care practice!
Missing the forest for the trees? Clin Epidemiol Glob Health.
2015;2:97-100.
5. Masanja H, Smith ER, Muhihi A, Briegleb C, Mshamu
S, Ruben J, et al.; for the Neovita Tanzania Study Group. Effect
of neonatal vitamin A supplementation on mortality in infants in
Tanzania (Neovita): A randomised, double-blind, placebo-controlled
trial. Lancet. 2014;doi:10.1016/S0140-6736(14)61731-1. [Epub ahead of
print]
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Thomas G, et al. Effect of early neonatal vitamin A
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10.1016/S0140-6736(14)60880-1. [Epub ahead of print]
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Dube B, Edmond K, Fawzi W, et al. Efficacy of early neonatal
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8. No authors listed. The Cochrane Collaboration’s
Tool for Assessing Risk of Bias. Available from:
http://ohg.cochrane.org/sites/ohg.cochrane.org/files/uploads/Risk%20of%20bias%20assessment%20tool.pdf.
Accessed March 13, 2015.9. No authors listed. Hawthorne Effect.
Available from: http://en.wikipedia.org/wiki/Hawthorne_effect.
Accessed March 13, 2015.
10. WHO. Guideline: Neonatal Vitamin
ASsupplementation. Geneva: World Health Organization, 2011. Available
from: http://www.ncbi.nlm.nih.gov/books/NBK185152/pdf/TOC.pdf.
Accessed March 13, 2015.
11. Benn CS, Diness BR, Balde I, Rodrigues A, Lausch
KR, Martins CL, et al. Two different doses of supplemental
vitamin A did not affect mortality of normal-birth-weight neonates in
Guinea-Bissau in a randomized controlled trial. J Nutr. 2014;144:1474-9.
12. Haider BA, Bhutta ZA. Neonatal vitamin A
supplementation: Time to move on. Available from:
http://dx.doi.org/10.1016/S0140-6736 (14)62342-4. Accessed March 14,
2015.
13. West KP Jr, Katz J, Shrestha SR, LeClerq SC,
Khatry SK, Pradhan EK, et al. Mortality of infants <6 mo of age
supplemented with vitamin A: A randomized, double masked trial in Nepal.
Am J Clin Nutr. 1995;62:143-8.
14. Lund N, Biering-Sørensen S, Andersen A, Monteiro
I, Camala L, Jorgensen MJ, et al. Neonatal vitamin A
supplementation associated with a cluster of deaths and poor early
growth in a randomised trial among low-birth-weight boys of vitamin A
versus oral polio vaccine at birth. BMC Pediatr. 2014;14:214. doi:
10.1186/1471-2431-14-214.
Joseph L Mathew
Department of Pediatrics,
PGIMER, Chandigarh, India.
Email:
[email protected]
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