Neonatal vitamin A supplementation for prevention of mortality and morbidity in infancy: systematic review of randomised controlled trials
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b919 (Published 27 March 2009) Cite this as: BMJ 2009;338:b919
All rapid responses
The systematic review by Gogia and Sachdev (1) is a lucid
illustration of posing an appropriate question, which
examines the relevant evidence in entirety to aid policy
formulation. Their approach reflects conventional
methodology and wisdom, and is in sharp contrast to
framing a misleading
question solely on the basis of positive trials (three of
the four trials in South Asia rather than all global
trials). Sub-group analyses, especially those based on
region rather than biological plausibility, are at best
exploratory in nature and never definitive to frame policy.
Further, a regional policy cannot be adopted on the basis
of only three trials from the most deprived settings in
South Asia.
At issue is the central biological question of whether
vitamin A given to newborns (neonates) at risk of
developing vitamin A deficiency can reduce infant
mortality? The issue is not whether Vitamin A
supplementation acts as a “magic bullet” in selected
regions. The systematic review (1) elegantly illustrates
that there are no biological predictors of heterogeneity
for the mortality effect amongst the entire global trials,
which has also been described in detail earlier (2,3). The
authors had also meticulously discussed their rationale for
methodological criteria including the comparator group and
the effect of varying assumptions on the pooled estimates
and conclusions. Their results and conclusions remain
robust despite varying the assumptions (1). Even after
excluding the Nepal trial (4) and comparing intervention
with a control group irrespective of maternal vitamin A
supplementation status in the Bangladesh trial (5), there
was no evidence of a reduced risk of mortality in infancy
for intervention within the first 48 hours (RR 0.89, 95% CI
0.73 to 1.09; P=0.256) or seven days (RR 0.88, 95% CI 0.73
to 1.07; P=0.196). Also, if the choice of a control group
in one trial alters the conclusion of a pooled analysis
radically, the evidence is considerably weak to justify a
translation into policy. Thus West et al.’s insistence on
raising these issues again is only an attempt to confuse
the reader and create doubts about the credibility of the
systematic review.
The declaration of no competing interest by West et al. is
not only perplexing but could also deceive the readers
because in earlier publications an institutional link with
a leading manufacturer of vitamin A had been revealed (6).
In their final bid to compel South Asian populations to
adopt a doubtful intervention immediately, they advocate a
“holier than thou attitude” by stating “programming that
awaits a fourth Asian trial will condemn a million Asian
infants to die during the five years needed to complete
it”. The call of the hour is that policy should primarily
be framed by representatives of those who will have to live
with the recommendations (7). The policy makers and
scientists of these South Asian populations have ample
qualities of head and heart to decide what is best for
their people!
References
1 Gogia S, Sachdev HS. Neonatal vitamin A supplementation for
prevention of mortality and morbidity in infancy:
systematic review of randomised controlled trials. BMJ
2009; 338: b919.
2 Benn CS, Whittle H, Fisker A, Aaby P. Neonatal vitamin A
supplementation in South Asia: Rapid implementation or
understanding the variation. bmj.com, 11 Jul 2008.
http://www.bmj.com/cgi/eletters/336/7658/1385#198676
accessed on April 21, 2009.
3 Gogia S, Sachdev HS. Vitamin A supplements in newborns and
child survival. bmj.com, 10 Jul 2008.
http://www.bmj.com/cgi/eletters/336/7658/1385#198607
accessed on April 21, 2009.
4 West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK,
Pradhan EK, Adhikari R, Wu LS, Pokhrel RP, Sommer A.
Mortality of infants <_6 xmlns:a="urn:x-prefix:a" xmlns:_62="urn:x-prefix:_62" mo="mo" of="of" age="age" supplemented="supplemented" with="with" vitamin="vitamin" a:_="a:_" a="a" randomized="randomized" double-masked="double-masked" trial="trial" in="in" nepal.="nepal." am="am" j="j" clin="clin" nutr="nutr" _1995="_1995" _62:_143-148.="_62:_143-148." p="p"/>5 Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA,
Katz J, Sommer A, West KP Jr. Newborn vitamin A
supplementation reduced infant mortality in rural
Bangladesh. Pediatrics 2008; 122: 242-250.
6 Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C,
Devi S, et al. Impact of supplementing newborn infants with
vitamin A on early infant mortality: a community-based
randomized trial in southern India. BMJ 2003; 327: 254.
7 Oxman AD, Lavis JN, Fretheim A. Use of evidence in WHO
recommendations. Lancet 2007; 369: 1883-89.
Competing interests:
None declared
Competing interests: No competing interests
Nihilism means a tendency to negate, to the point of rejection of
possibility, (from 'nihil', meaning 'nothing'). Academic nihilism is a
modern contagious disease, which has infected NICE and Cochrane, and now
finally has filtered into the editorial rooms of the BMJ.
Gogia and Singh's analysis of neonatal vitamin A supplementation is a
case in point (1). They conclude: "There is thus no justification for
initiating (Vit A) supplementation as a public health intervention in
developing countries for reducing infant mortality and morbidity".
The correct conclusion is: "Vitamin A deficiency is known to be
important for immune function, (2), and is common in some developing
countries (3). Thus treatment with Vitamin A to those who need it can be
important, (4). Nevertheless, supplementing vitamin A to healthy neonates
at birth produces only a nonsignificant reduction in mortality, with
confidence limits which include harm. Possible explanations for these
conflicting results include poor trial quality or numbers, inadequate
contribution of Vit A to all-cause mortality, infrequency of Vit-A
deficiency in some populations, and counterbalancing harmful effect of
supplementation in those who do not need it.
Because this analysis does not support routine vitamin A
supplementation for all neonates in the populations studied, future
research needs to establish ways of identifying more easily those at need,
and to clarify the putative benefits and harms in such individuals.
Meanwhile, addressing vitamin A deficiency remains important in certain
common situations, such as measles."
Such accuracy makes for less eye-popping headlines, but also less
inappropriate debasement of important interventions.
refs:
1. Gogia, S., Sachdev, H.S., "Neonatal vitamin A supplementation for
prevention of mortality and morbidity in infancy: systematic review of
randomised controlled trials" BMJ 2009;338:b919
2. Stephenson CB Vitamin A, infection and immune function, Annu Rev
Nutr 2001;21:167-92.
3. Busie, B.M-D. et al, "Vitamin A Deficiency Is Prevalent in
Children Less Than 5 y of Age in Nigeria" J. Nutr. 136:2255-2261
4. D'Souza RM, D'Souza R, "Vitamin A for the Treatment of Children
with Measles—A Systematic Review" Journal of Tropical Pediatrics 2002
48(6):323-327
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
The recent systematic review by Gogia and Sachdev (1) on efficacy of
newborn vitamin A supplementation in reducing infant mortality illustrates
how inappropriate adherence to a popular analytical tool can frame the
wrong question and produce misleading findings.
At issue is the central question of whether vitamin A, given to
newborns in South Asia, can reduce infant mortality? This issue should
have been addressed because it arises from findings of improved infant
survival following newborn vitamin A receipt in three, double-masked,
randomized, controlled trials in Indonesia (2), India (3) and Bangladesh
(4) designed to address this question. It is unfortunate the authors
confused the issue by including in their analysis older neonates from an
earlier study never designed to reach newborns (5). Secondly, their
insistence to pool studies from South Asia and Africa suggests both
regions pose homogeneous risks, an assumption belied by long-known
differences in maternal, infant and child health (6), vitamin A deficiency
(7), and infant feeding practices (6) which would anticipate geographic
variation in impact. Third, despite claiming to include trials
irrespective of maternal vitamin A supplementation status, they in fact
excluded two-thirds of ~8000 placebo newborns in Bangladesh, whose mothers
received weekly vitamin A or beta-carotene as part of a larger trial into
which the newborn study was nested (4), leaving their rationale wanting.
The exclusion does not materially alter the effect estimate, but reduces
sample size and weakens this major trial’s contribution to the analysis.
Gogia and Sachdev emphatically conclude that ”no justification”
exists for neonatal vitamin A supplementation, in direct conflict with
all available data in Asia relevant to this question, while calling for
additional trials in Africa and Asia to define regional differences.
Additional African trials are needed, but programming that awaits a fourth
Asian trial will condemn a million Asian infants to die during the five
years needed to complete it.
References
1. Gogia S, Sachdev HS. Neonatal vitamin A supplementation for
prevention of mortality and morbidity in infancy: systematic review of
randomised controlled trials. BMJ 2009;338:b919
2. Humphrey JH, Agoestina T, Wu LSF, Julianti A, Septian S, Ichord
RN, Widjaja H, Cerreto MC, Katz J, West KP Jr. Neonatal vitamin A
supplementation: Effect on development and growth at 3 years of age. Am
J Clin Nutr 1998;68:109-117.
3. Rahmathullah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi
S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C. Impact of
supplementing newborn infants with vitamin A on early infant mortality:
community based randomised trial in southern India. BMJ 2003;327:254-259
4. Klemm RDW, Labrique AB, Christian P, Rashid M, Shamim AA, Katz J,
Sommer A, West KP Jr. Newborn vitamin A supplementation reduced infant
mortality in rural Bangladesh. Pediatrics 2008;122:242-250.
5. West KP Jr, Katz J, Shrestha SR, LeClerq SC, Khatry SK, Pradhan
EK, Adhikari R, Wu LS, Pokhrel RP, Sommer A. Mortality of infants <6
mo of age supplemented with vitamin A: a randomized, double-masked trial
in Nepal. Am J Clin Nutr 1995;62:143-148.
6. Ramalingaswami V, Johnson U, Rohde J. Commentary: The Asian
enigma. In: The Progress of Nations 1996: Nutrition. New York, NY:
UNICEF, 1997 http://www.unicef.org/pon96/nuenigma.htm. (accessed 31
March 2009)
7. West KP Jr. Extent of vitamin A deficiency among preschool
children and women of reproductive age. J Nutr 2002;132:2857S-2866S.
Competing interests:
None declared
Competing interests: No competing interests
When, who all and what doses ought to be supplemented with synthetic Vitamin A for safety of both mother and infant
In view of the potential toxic and teratogenic effects, high doses of
vitamin A are questionable to be administered to pregnant/ lactating women
or neonate/ infant. Pregnant and lactating women with symptoms of night
blindness should be treated with vitamin A in dosage not exceeding 10,000
IU per day, as per guidelines1. They can be given vitamin A till symptoms
of night blindness disappear. There are no clear cut evidence to support
that the supplementation of synthetic Vitamin A during pregnancy will
benefit the fetus or not2 and recent evidence suggests overdose can be
dangerous to both mother and fetus3,4. Available data are not robust
enough to persuade us to recommend a policy of vitamin A supplementation
for the purpose of mortality reduction in children1. If pregnant mothers (
mostly adults) cannot be given the dose above 10,000 IU per day then the
administration of mega doses to tiny neonates and children (1,00,000 IU at
ninth month of life with measles vaccination + 4 doses of 2,00,000 IU ,
six monthly upto 3 years of age) should as well be out of question.
1. National Consultation on Benefits and Safety of Administration of
Vitamin A to Pre-school Children and Pregnant and Lactating Women.
Compiled by HPS Sachdev and Umesh Kapil. Indian Pediatrics 2001; 38: 37-42
2. van den Broek N, Kulier R, G?lmezoglu AM, Villar J. Vitamin A
supplementation during pregnancy. Cochrane Database of SystematicReviews
2002, Issue 4. Art. No.: CD001996. DOI: 10.1002/14651858.CD001996.
3. Exp Lung Res.Pasquali MA, Gelain DP, Oliveira MR, Behr GA, Motta
LL, Rocha RF, Klamt F, Moreira JCVitamin A supplementation induces
oxidative stress and decreases the immunocontent of catalase and
superoxide dismutase in rat lungs. Exp Lung Res. 2009 Jun;35(5):427-38.
4. Ganapati Mudur Deaths trigger fresh controversy over vitamin A
programme in India
BMJ 2001; 323 : 1206 doi: 10.1136/bmj.323.7323.1206 (Published 24 November
2001)
Competing interests: No competing interests