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Vitamin A defi ciency: slow progress towards elimination
Gretchen Stevens and colleagues’ study1 in The Lancet
Global Health analyses 134 reports from 83 countries
of population-representative data for serum retinol
concentration and shows several trends in vitamin A
defi ciency. First, prevalence is diminishing in a statistically
signifi cant way in east and southeast Asia and Oceania.
Second, Latin America and Caribbean nations might be
making progress. Third, prevalence remains unchanged
in sub-Saharan Africa and south Asia. Stevens and
colleagues’ most interesting conclusion is that this
“evidence for both prevalence and absolute burden of
vitamin A defi ciency should be used to reconsider, and
possibly revise, the list of priority countries for high-dose
vitamin A supplementation”.
However, several caveats need to be considered,
including the use of cross-sectional data, exclusion of
children younger than 6 months, absence of clinical
vitamin A defi ciency assessments, gaps in serum retinol
data for certain populations and for 55 countries, use
of mortality data from randomised controlled trials of
vitamin A supplementation for diarrhoea and malaria
rather than population-level data, the assumption
that all post-neonatal measles deaths occur in children
aged 6–59 months old, and use of serum retinol as the
biomarker of defi ciency.
Nonetheless, we might need to focus on retinol
concentration not mortality to assess and guide
our eff orts to eliminate vitamin A defi ciency, as
recommended by WHO for population-level surveys,
even though this measure can be problematic in
individuals because of the well known eff ects of acute
infl ammation due to infection or injury on serum retinol
concentrations.2 Controlling for acute infl ammation
by including biomarkers for it3 might not be necessary
at the population level, because adequate vitamin A
status might, by itself, diminish infl ammation through
a reduction in the frequency or severity of infections in
these populations.
Despite these limitations, the authors provide
important estimates, with uncertainty distributions,
for the prevalence of vitamin A defi ciency, and a clear
picture of trends from 1991 to 2013. The association
between vitamin A defi ciency and eye pathology and all-
cause mortality is well known, as is the contribution of
vitamin A defi ciency to reduced resistance to infections,
especially diarrhoea and measles, and increased mortality
in children younger than 5 years.4 These benefi ts have
driven the scale-up of vitamin A supplementation
programmes as preventative public health measures
around the world. However, the coverage of these
programmes has not been effi cient in east or southern
Africa (67%) and south Asia (53%).5 Lagging coverage
and continued evidence of vitamin A defi ciency is the
basis for the suggestion by Stevens and colleagues that
future eff orts refocus on these regions. This suggestion
makes sense if we are confi dent that progress elsewhere
would not be compromised as a result.
During the past two decades, mortality from
diarrhoeal disease has substantially decreased and
measles has been eliminated as a public health issue
wherever eff ective immunisation programmes fl ourish.
Continued eff orts to control diarrhoeal disease and
enhance measles vaccine coverage per se suggest
that vitamin A supplementation programmes should
now focus on the reduction of defi ciency rather than
diarrhoea or measles morbidity or mortality as the
outcome.
What then should be done to accelerate progress
towards elimination of vitamin A defi ciency in children?
Initiation of supplementation programmes where
they do not exist and strengthening of programmes
where coverage is poor is step one. However, high-dose
supplementation only provides protection from hypo-
retinolaemia for 2–3 months in children younger than
5 years and favourably shifts the distribution of serum
retinol for less than 2 months,6 indicating that biannual
supplementation is not suffi cient by itself to prevent
vitamin A defi ciency. Improvement of dietary intake of
foods rich in vitamin A (eg, animal products) or beta-
carotene is a more sustainable solution, but high-cost,
access, and cultural dietary practices have restricted
its potential to alleviate vitamin A defi ciency. Other
options have been tested or are under development,
such as fortifi cation of centrally processed foods
(although these might not reach poor populations in
rural areas); addition of vitamin A sprinkles to food in
the home, day-care centres, and schools;7 promotion of
beta-carotene rich foods such as sweet potatoes;8 and
genetically engineered crops with high concentrations
of beta-carotene such as golden rice.9 By addressing
See Articles page e528
Comment
e503
www.thelancet.com/lancetgh Vol 3 September 2015
gaps in vitamin A suffi ciency around the world,
redirecting attention to areas of the world struggling
to make progress while continuing to monitor other
regions through systematic population-representative
sampling of serum retinol, promotion of research into
sustainable dietary solutions including a campaign to
legitimise genetically modifi ed crops high in vitamin A
or precursors, and alignment of all of these eff orts with
Sustainable Development Goal 2 to “end hunger, achieve
food security and improved nutrition and promote
sustainable agriculture”,10 we can not only sustain the
favourable trends described by Stevens and colleagues
but also hasten progress in other parts of the world.
*Davidson H Hamer, Gerald T Keusch
Center for Global Health and Development, Boston University
School of Public Health (BUSPH), Boston, MA 02118, USA (DHH);
Department of Global Health, BUSPH, Boston, MA, USA (DHH);
Section of Infectious Diseases, Department of Medicine, Boston
Medical Center, Boston, MA, USA (DHH, GTK); Tufts University
Friedman School of Nutrition Science and Policy, Boston, MA, USA
(DHH); and National Emerging Infectious Diseases Laboratories,
Boston University School of Medicine, Boston, MA, USA (GTK)
dhamer@bu.edu
We declare no competing interests.
Copyright © Hamer et al. Open Access article distributed under the terms of
CC BY-NC-ND.
1 Stevens GA, Bennett JE, Hennocq Q, et al. Trends and mortality eff ects of
vitamin A defi ciency in children in 138 low-income and middle-income
countries between 1991 and 2013: pooled analysis of population-based
surveys. Lancet Glob Health 2015; 3: e528–36.
2 Thurnham DI, McCabe GP, Northrop-Clewes CA, Nestel P. Eff ects of
subclinical infection on plasma retinol concentrations and assessment of
prevalence of vitamin A defi ciency: meta-analysis. Lancet 2003;
362: 2052–58.
3 Bresnahan KA, Chileshe J, Arscott S, et al. The acute phase response aff ected
traditional measures of micronutrient status in rural Zambian children
during a randomized, controlled feeding trial. J Nutr 2014; 144: 972–78.
4 Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A
supplements for preventing mortality, illness and blindness in children
aged under 5: systematic review and meta-analysis. Br Med J 2011;
343: 1–19.
5 UNICEF. UNICEF Global Databases. Nutrition: vitamin A supplementation.
October, 2014. http://data.unicef.org/nutrition/vitamin-a (accessed
June 13, 2015).
6 Palmer AC, West KP, Dalmiya N, Schultink W. The use and interpretation of
serum retinol distributions in evaluating the public health impact of
vitamin A programmes. Public Health Nutr 2012; 15: 1201–15.
7 Varma JL, Das S, Sankar RS, Mannar MGV, Levinson FJ, Hamer DH.
Community-level micronutrient fortifi cation of a food supplement in
India: a controlled trial with pre-school children aged 36-66 months.
Am J Clin Nutr 2007; 85: 1127–33.
8 Hotz C, Loechl C, Lubowa A, et al. Introduction of ß-carotene rich orange
sweet potato in rural Uganda resulted in increased vitamin A intakes
among children and women and improved vitamin A status among
children. J Nutr 2012; 142: 1871–80.
9 Tang G, Qin J, Dolnikowski GG, Russell RM, Grusak MA. Golden Rice is an
eff ective source of vitamin A. Am J Clin Nutr 2009; 89: 1776–83.
10 Dubé L, Pingali P, Webb P. Paths of convergence for agriculture, health,
and wealth. Proc Natl Acad Sci U S A 2012; 109: 12294–301.
... After being declared safe for consumption in four countries (Australia, New Zealand, Canada and the United States) (Greedy, 2018), it is the Philippines that was the first to approve its cultivation, which is expected to happen in Bangladesh soon, too. Since Potrykus and Beyer developed its first version in 1999 (Qamar et al., 2020;Ye et al., 2000), Golden Rice has been facing sustained criticism that undoubtedly delayed the progress of this humanitarian project to help alleviate the health and economic burden of vitamin A deficiency (Wesseler and Zilberman, 2014). ...
... It is important to emphasize that this crop is not, or should not, be framed as a silver bullet-or a golden bullet, as it were-for ending micronutrient malnutrition. Rather, it has an important role in addressing a particular micronutrient deficiency that still imposes a considerable burden on public health and that requires innovative but cost-effective and culturally appropriate interventions that go beyond conventional vitamin A supplementation programs that typically target high priority population groups (children of 6-59 months old) (Hamer and Keusch, 2015). Implementing food-based solutions is particularly important as these are less vulnerable to disruptions caused by funding shortfalls or catastrophes, as shown most recently by the drop in vitamin A supplementation rates due to COVID-19 (HKI, 2020). ...
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... A study revealed that Vitamin A deficiency prevails, and 30% of preschool children in Developing Countries have vitamin A deficiency in sub-Saharan Africa despite National supplementation and food fortification programs, (UNSSCN, 2010). Hamer and Keusch (2015) in their study observed that Vitamin A deficiency (VAD) is a widespread nutritional disorder in the Developing Countries, and is still a public health concern globally. It is seen as main causative factor of preventable blindness in children. ...
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... It is clear that progress in combatting VAD has been significant, a reduction from 23 to 34% of under-five child deaths in the 1990s to circa 2% in these two countries in 2013, the latest data available [31]. The 2013 data are useful as a proxy for comparison between countries, but has limitations [32] including that the "total VAD" deaths reported are actually solely deaths where measles or diarrhea are reported on a death certificate. But these are not the only causes of death due to immune system insufficiency due to VAD, and reporting may anyway be patchy in remote, poor districts. ...
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On July 21, 2021, Golden Rice was registered in the Philippines allowing cultivation and consumption. Research, as an intervention to combat vitamin A deficiency (VAD), started in 1991, and proof of concept for what was to become Golden Rice, was achieved in 1999. In the 1990s, 23-34% deaths globally of children less than 5 years old were caused by VAD, and in developing countries, the percentage was even higher. By 2013, progress against the Millennium Development Goals had reduced <5-y child deaths globally from VAD to about 2% of all such deaths. The progress included significant vaccination programs against measles, and better access to clean water, as well as vitamin A supplementation, all delivered through community health programs. Economic development and education about diet reduced food insecurity. In contrast to continuing VAD deaths, the Covid-19 pandemic has attracted huge political attention, including in low-and middle-income countries. Community health programs have been adversely affected by the pandemic. There is a danger that as a result VAD rates, child and maternal mortality climbs again toward 1990's levels. Adoption of Golden Rice provides a safe, culturally simple amelioration and is costless. Other countries should seize the opportunity. Bangladesh is first in line, possibly followed by Indonesia and India.
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Children participating in the Integrated Child Development Service (ICDS) in India have high rates of iron and vitamin A deficiency. The objective was to assess the efficacy of a premix fortified with iron and vitamin A and added at the community level to prepared khichdi, a rice and dal mixture, in increasing iron and vitamin A stores and decreasing the prevalence of iron deficiency, anemia, and vitamin A deficiency. This cluster, randomized, double-blind, controlled trial was initiated in 30 Anganwadi centers (daycare centers) in West Bengal state, India. Children aged 36-66 mo (n = 516) attending village-based ICDS centers were randomly assigned to receive either a fortified or a nonfortified premix for 24 wk. Blood was drawn at 0 and 24 wk by venipuncture for the measurement of hemoglobin, serum ferritin, and serum retinol. The change in the hemoglobin concentration of anemic children was significantly different between fortified and nonfortified khichdi groups (P < 0.001). Prevalence rates of anemia, iron deficiency, and iron deficiency anemia were significantly lower after 24 wk in the fortified-khichdi group than in the nonfortified-khichdi group (P < 0.001). There were no significant differences in serum retinol concentrations or in the prevalence of vitamin A deficiency between the fortified- and nonfortified-khichdi groups. A premix fortified with iron, vitamin A, and folic acid and added to supplementary food at the community level can be effective at increasing iron stores and reducing the prevalence of iron deficiency and anemia.
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Genetically engineered "Golden Rice" contains up to 35 microg beta-carotene per gram of rice. It is important to determine the vitamin A equivalency of Golden Rice beta-carotene to project the potential effect of this biofortified grain in rice-consuming populations that commonly exhibit low vitamin A status. The objective was to determine the vitamin A value of intrinsically labeled dietary Golden Rice in humans. Golden Rice plants were grown hydroponically with heavy water (deuterium oxide) to generate deuterium-labeled [2H]beta-carotene in the rice grains. Golden Rice servings of 65-98 g (130-200 g cooked rice) containing 0.99-1.53 mg beta-carotene were fed to 5 healthy adult volunteers (3 women and 2 men) with 10 g butter. A reference dose of [13C10]retinyl acetate (0.4-1.0 mg) in oil was given to each volunteer 1 wk before ingestion of the Golden Rice dose. Blood samples were collected over 36 d. Our results showed that the mean (+/-SD) area under the curve for the total serum response to [2H]retinol was 39.9 +/- 20.7 microg x d after the Golden Rice dose. Compared with that of the [13C10]retinyl acetate reference dose (84.7 +/- 34.6 microg x d), Golden Rice beta-carotene provided 0.24-0.94 mg retinol. Thus, the conversion factor of Golden Rice beta-carotene to retinol is 3.8 +/- 1.7 to 1 with a range of 1.9-6.4 to 1 by weight, or 2.0 +/- 0.9 to 1 with a range of 1.0-3.4 to 1 by moles. Beta-carotene derived from Golden Rice is effectively converted to vitamin A in humans. This trial was registered at clinicaltrials.gov as NCT00680355.
Article
Background: Vitamin A deficiency adversely affects child morbidity and survival. This deficiency is estimated by measurement of plasma retinol concentrations, but because plasma retinol is reduced by clinical and subclinical infection, this proxy measure can lead to overestimation. Infection and trauma are accompanied by rises in concentrations of acute-phase proteins in plasma. We aimed to estimate vitamin A deficiency more accurately by measuring changes in plasma retinol and acute-phase proteins associated with subclinical infection or convalescence. Methods: We analysed data for concentrations of plasma retinol and one or more acute-phase proteins (alpha1-acid-glycoprotein, alpha1-antichymotrypsin, C-reactive protein, or serum amyloid A) from 15 studies of apparently healthy individuals. We generated summary estimates of differences in retinol concentrations for incubation, early, and late convalescent phases of infection between people with none and those with one or more raised acute-phase proteins. We compared these groups in two, three, and four group analyses. We also compared a subgroup of apparently healthy preschool (1-5 years) children with results from all other studies. Findings: For all four proteins, retinol values were much higher in people with normal concentrations of protein, than in individuals with raised concentrations (16% higher for alpha1-antichymotrypsin, 18% for alpha1-acid-glycoprotein, 25% for C-reactive protein, and 32% for serum amyloid A). Estimates of the reduction in plasma retinol for individuals with infection compared with healthy individuals, were 13% (incubation), 24% (early convalescent), and 11% (late convalescent). Estimates of vitamin A deficiency in individuals with no raised acute-phase proteins (healthy group) were much the same as those obtained by adjustment of plasma retinol concentrations in the whole group using acute-phase proteins. Interpretation: We recommend that surveys to estimate vitamin A deficiency should include measurements of serum C-reactive protein and alpha1-acid-glycoprotein concentrations. Information about acute-phase proteins will enable plasma retinol concentrations to be corrected where sub-clinical infection exists, and the healthy sub-group to be identified.