By Alfred Sommer, MD, MHS
Dr. Sommer is dean of The Johns Hopkins University Bloomberg
School of Public Health.
If - and it remains a big "if" - "golden rice" and its variants prove
safe and effective, they will be a valuable new tool for controlling vitamin
A deficiency. Under the most optimistic of circumstances, however, they
will never solve the global problem by themselves. This review attempts
to place this new tool in perspective.
Vitamin A deficiency disorders encompass the full spectrum of clinical
consequences associated with suboptimal vitamin A status.(1) These disorders
are now known to include reduced immune competence resulting in increased
morbidity and mortality (largely from increased severity of infectious
diseases); night blindness, corneal ulcers, keratomalacia and related
ocular signs and symptoms of xerophthalmia; exacerbation of anemia through
suboptimal absorption and utilization of iron; and other conditions not
yet fully identified or clarified (e.g., retardation of growth and development).(2)
Magnitude and Distribution
Clinical and sero-epidemiologic studies and surveys indicate that vitamin
A deficiency is widespread throughout the developing world. Vitamin A
deficiency has long been recognized in much of South and Southeast Asia
(India, Bangladesh, Indonesia, Vietnam, Thailand, the Philippines) by
the common presentation of clinical cases of xerophthalmia (night blindness
to permanently blinding keratomalacia). Subsequent studies in Africa,
where it had been less well recognized, indicated that a large proportion
of pediatric blindness was due to acute deterioration in vitamin A status
during measles and similar childhood infections.(3, 4)
Vitamin A deficiency was found to increase childhood morbidity and mortality(2,
5-10) in populations in which xerophthalmia was not readily recognized(11)
and in greater numbers than would be expected solely from the increase
in mortality associated with xerophthalmia.(2, 12) This discovery led
to the recognition that seemingly mild biochemical deficiency, insufficient
to cause xerophthalmia, accounts for large numbers of preventable childhood
The extent and distribution of vitamin A deficiency and its consequences
are remarkably well established. Numerous local and national surveys have
been conducted. In countries where they have not been conducted, data
from nearby countries with similar characteristics (under-5-year mortality,
poverty, diet) allow for judicious extrapolation. The few intensive national
surveys linked to longitudinal studies(13) and extrapolations from sero-surveys
and community-based randomized intervention trials show that vitamin A
deficiency poses a significant problem in more than 70 countries.(14)
Recent calculations suggest that roughly 150 million children are deficient:
every year 10 million children develop xerophthalmia, 500,000 children
are permanently blinded from xerophthalmia and 1 to 2 million children
Vitamin A deficiency disorders have not been quantified in women of
childbearing age. Older anecdotal reports(16, 17) and recent surveys(18,
19) indicate that night blindness from vitamin A deficiency is common
among pregnant women in India, Indonesia, Bangladesh, Nepal and elsewhere,
particularly during the latter half of pregnancy. Most surveys reveal
rates of night blindness of 10% or more during pregnancy in populations
in which the children are commonly deficient.(1) A recent large-scale
randomized placebo-controlled trial of vitamin A or beta-carotene supplementation
in Nepali women reduced maternal mortality by approximately 40%,(20, 21)
an effect that persisted for at least one year postpartum.(22)
Vitamin A deficiency disorder affects large numbers of young children
and women of childbearing age throughout the developing world. Current
estimates do not include China, where recent visits with nutritionists
and pediatricians in the southwestern regions identified cases of xerophthalmia
and where a recent UNICEF survey revealed depressed serum retinol values
and night blindness during pregnancy in large, impoverished regions.(23-25)
The size of the global problem is therefore likely to grow as additional
data are gathered.
Origins of Deficiency
Children begin life with an urgent need for vitamin A. Full-term infants
- even those of well-nourished mothers in wealthy countries - are born
with barely enough vitamin A to sustain them during the first few days
of life. During the first six months of life they need at least 125 mg
of retinol equivalents daily to prevent xerophthalmia and about 300 mg
to thrive (and accumulate adequate liver stores of 20 mg per gram of liver).(1,
The only significant source of vitamin A for young infants is breast
milk (or equivalent formulas). Except when mothers suffer from severe
protein-energy malnutrition, the quantity of breast milk is roughly similar
around the globe, but the concentration of vitamin A in that milk varies
dramatically with the vitamin A status of the mother.(26, 28) When mothers
are vitamin A deficient, breast milk concentrations will be low. Without
supplemental vitamin A, their infants will become deficient.
Children in developing countries are at risk of consuming a vitamin
A-deficient diet throughout life, not just during early infancy. Although
Western populations receive abundant preformed vitamin A from animal products
(eggs, butter, cheese, liver, processed foods fortified with vitamin A),
poor rural populations in developing countries rely on beta-carotene,
a precursor of vitamin A found in dark-green leafy vegetables, carrots
and colored fruits (mango and papaya). Even when abundant, these are poor
substitutes for animal sources of the preformed vitamin: many children
do not like dark-green leafy vegetables; fruits are often costly, sold
as a cash crop or highly seasonal (e.g., mangos); and many vegetables
bind beta-carotene tightly to their cellular matrices, yielding little
during digestion. Recent data indicate that the bioavailability (and bioconversion)
of dark-green leafy vegetable sources of beta-carotene is much lower than
previously supposed,(29, 30) with perhaps no more than 2% to 4% being
absorbed, converted to vitamin A, and made available to meet metabolic
Children in the developing world probably need more vitamin A than do
their better nourished Western counterparts. Diarrhea, childhood exanthematous
diseases and respiratory infections are more common in poor rural populations,
further reducing vitamin A absorption (diarrhea) while increasing utilization
(measles) and excretion (respiratory infection).
Why young children in developing countries are deficient in vitamin
A is clear. Their greatest risk of becoming vitamin A deficient is during
the first few years of life, when their diets are the least diverse, growth
(hence need) is greatest and they are at highest risk of life-threatening
infections. As they enter their school-age years these factors begin to
moderate even though deficiency persists and mild manifestations (e.g.,
night blindness and Bitot's spots) remain common.
Why women are so frequently deficient is less clear. They also have
a similarly unvaried diet that is largely deficient in good sources of
preformed vitamin A. Pregnancy and lactation place additional burdens
on their meager vitamin A stores. Other consequences of pregnancy probably
explain why deficiency is most severe - and night blindness most common
- during the latter half of pregnancy. Even though pregnancy-related night
blindness spontaneously disappears during the early postpartum period,
the underlying deficiency does not. As a consequence these women suffer
an increase in mortality for at least one year postpartum.(20-22)
Combating Vitamin A Deficiency
There is global agreement on the need to combat vitamin A deficiency.(2,
14) More than 70 countries have formal intervention programs, although
only a few (Nepal, Indonesia, Tanzania, Bangladesh, Vietnam) have made
significant, discernible progress. Three basic strategies exist for increasing
vitamin A intake: increasing the consumption of foods rich in vitamin
A and provitamin A; fortifying commonly consumed dietary items with vitamin
A (or beta-carotene); and providing large, periodic, vitamin A supplements
to high-risk populations.
Many nutritionists consider increasing the consumption of natural dietary
sources of vitamin A to be the logical long-range solution to deficiency.
Despite occasional demonstration projects and correlational analyses,(31)
little definitive evidence exists that vitamin A sufficiency can be achieved
- let alone sustained - through traditional food sources, particularly
those available to poor, rural, high-risk populations. As noted, vegetables
are poor sources of provitamin A beta-carotene. Although they contain
considerable quantities of beta-carotene, these are not readily bioavailable.
It needs to be shown that vulnerable children can consume quantities of
dark-green leafy vegetables sufficient to normalize their vitamin A status.
Adults may be able to obtain sufficient vitamin A by consuming far larger
amounts of vegetables and fruits than children consume or through the
greater diversity of their diet, but this too needs documentation. In
at least two studies, women provided daily with large helpings of dark-green
leafy vegetables failed to significantly improve their vitamin A status(29,
32) in contrast to those fed cookies containing pure synthetic (therefore
readily absorbed) beta-carotene.(29) Introducing animal sources of preformed
vitamin A (e.g., eggs) into the diet might make a significant difference
but remains beyond the resources (and cultural patterns) of many of the
populations at highest risk.
Fortification by Conventional Means
Fortifying dietary items with preformed vitamin A or beta-carotene is
a proven strategy for preventing deficiency.(33) In the early 1900s Denmark
legislated vitamin A fortification of margarine because its growing dairy
exports deprived the poorer classes of once-abundant butter, for which
they initially substituted vegetable oil-based margarine, which is naturally
devoid of vitamin A. In the United States, Western Europe and most wealthy
countries, a wide variety of dietary items is fortified with vitamin A
(milk, margarine, cereal products). Developing countries have experimented
with fortifying a range of products with vitamin A (monosodium glutamate,
wheat, noodles, sugar). To date, only sugar fortification, primarily in
Latin America, has taken hold.(34)
Traditional fortification techniques require a dietary item that is
consumed in suitable quantities by the groups at highest risk; is processed
at a limited number of sites where the fortificant can be conveniently
added; stabilizes vitamin A during its normal shelf life in the marketplace
(vitamin A is unstable in salt, making salt unsuitable for vitamin A but
fine for delivering iodine); results in little increase in cost to the
consumer; and has acceptable organoleptic qualities (color, smell, taste).
These requirements have been difficult to achieve for high-risk poor populations
that generally consume a monotonous diet devoid of expensive, centrally
Fortification by Genetic Modification
In an attempt to overcome some of the obstacles facing conventional
fortification, scientists have begun to genetically modify traditional
dietary items to produce beta-carotene. Monsanto produced rape seed and
mustard rich in beta-carotene and, more recently, scientists funded by
the Rockefeller Foundation produced a strain of rice - golden rice - genetically
modified to produce beta-carotene.(35) This may well herald an important
strategy for controlling vitamin A deficiency, particularly because rice
is the dietary staple of many of the most-deficient populations.
Some hurdles need to be surmounted before golden rice or its variants
can have an effect. The strains must be able to grow under the varied
conditions in countries with vitamin A-deficient populations. The yield
and the cost must be attractive to the farmer (or benefit from public
sector subsidization). The organoleptic qualities of the rice must be
acceptable to the target population (women and children). The beta-carotene
needs to be bioavailable, the degree dependent on its concentration in
the rice, the matrices to which it is bound, the effect of traditional
cooking methods and the amount consumed.
Although genetically modified rice could go a long way toward controlling
vitamin A deficiency, it will never completely solve the problem. Many
deficient populations do not consume rice, and even within traditional
rice-consuming countries, some high-risk groups will not be able to afford
Vitamin A (retinol) supplements - naturally occurring (as in cod liver
oil) or synthetically derived (multivitamin preparations) - have long
been used to prevent vitamin A deficiency and its associated disorders.(2,
36) Vitamin A is a component of prenatal and infant multivitamins routinely
consumed by Western populations. Periodic administration of large doses
of vitamin A to children was pioneered in India(37) and advanced globally
after the first major international meeting on the control of vitamin
A deficiency in 1974.(32)
Periodic supplementation is the most widely implemented intervention
for controlling vitamin A deficiency in the developing world. Countries
have found these programs to be relatively easy and quick to initiate
at relatively modest marginal cost.(2, 38) Supplements are extremely inexpensive,
at 2 to 4 cents per dose of 200,000 international units (IU). Most of
the cost is for the gelatin capsule; the cost for the vitamin A is less
than 1 cent.
The major cost for (and impediment to) population-wide supplementation
is the delivery system. Recommendations called for the administration
of 200,000 IU every 4 to 6 months to all children 12 to 60 months of age.
Unfortunately, that often requires a delivery mechanism such as that presently
used successfully in a number of countries (e.g., Nepal and Bangladesh).
In Nepal, 37,000 village women volunteers reach more than 2 million children
during special "Vitamin A Days" held twice every year.(39)
To better use existing delivery channels, many countries have piggybacked
vitamin A distribution onto regular immunization efforts. In particular,
25,000 or 50,000 IU of vitamin A is given to young children at ages 6,
10, and 14 weeks when they receive their diptheria, pertussis and tetanus
immunizations. A fourth dose (100,000 IU) is administered at age 9 months
with measles immunization.(40) The rationale for this schedule is that
an existing distribution mechanism is available, minimizing the marginal
cost of delivery; a high risk of deficiency exists during the first year
of life (200,000 IU is given to mothers 6 to 8 weeks postpartum to boost
breast milk vitamin A concentration); and infants are at greatest risk
for the consequences of deficiency, particularly mortality. Coverage achieved
by supplement distribution programs has dramatically risen in the past
two years, largely because vitamin A administration was included in national
immunization days, which were designed to deliver polio vaccine. More
than 40 countries reported covering more than 80% of their target children
with vitamin A supplements during 1998.(1, 41)
Although randomized controlled clinical trials have demonstrated the
value of periodic supplementation,(2) in practice it has proved difficult
to reach children after the first year of life; indeed, with immunization
rates falling below expected targets, these too have not met their goals.
To compound the problem, national immunization days will soon be phased
A recent multinational trial sponsored by the World Health Organization
(WHO) suggests that the present regimen of dosing mothers with 200,000
IU postpartum and their children three times in the first 14 weeks of
life with 25,000 IU does not improve vitamin A status much beyond age
6 months.(42) In response, a recent informal consultation organized by
WHO recommended that doses to infants and mothers be increased: 400,000
IU to postpartum women (in two doses during the preconceptual period)
and 50,000 IU to infants at least three times before age 6 months. Although
the effect of these increases is yet to be ascertained, evidence suggests
they will be safe and effective.(27)
Undue concern over vitamin A toxicity, a rare and transient condition,(43)
has complicated the design of intervention strategies and unnecessarily
diverted attention and commitment from effective control strategies. Because
safety relates to the prevention of deficiency, only two issues arise:
teratogenicity and acute toxicity.
Very large doses of vitamin A during the first trimester of pregnancy
can be teratogenic, so high-dose supplementation of women of childbearing
age is only recommended during the infertile postpartum period.(40) Acute
toxicity, although harmless and transient, can result in nausea and vomiting.
If mothers notice and are concerned, it might result in lower compliance
rates, so supplement size is adjusted for the child's age. Even so, young
children who might inadvertently receive multiples of the recommended
dose (in addition to increased amounts in breast milk) will not suffer
significant, permanent sequelae.(1) The implications for intervention
strategies are minimal.
Traditional foods cannot produce teratogenic or toxic effects. For deficient
populations the primary source of vitamin A is vegetables, which lack
the preformed vitamin. Ingesting large quantities of carrots and other
carotenoid-rich vegetables may produce high carotene levels, but these
are harmless. Because the body regulates conversion of beta-carotene to
vitamin A, serum retinol does not rise to toxic levels.
Programs that add retinyl palmitate (preformed vitamin A) to dietary
items carefully adjust the level of fortification to benefit consumers
whose diets are most deficient without exposing wealthier segments of
society, whose diets might be richer in preformed vitamin A, from consuming
excessive amounts. These programs take pains to achieve a balance that
best serves both groups. The choice of vehicle can optimize this relationship.
Fortifying a product or a specific package of that product (e.g., the
smallest packets of monosodium glutamate) uniquely ingested by those who
are most deficient increases the amount of vitamin A that can be safely
added. Nonetheless, ongoing surveillance is valuable in identifying isolated
groups or individuals who purposely purchase and consume large doses of
supplements on a sustained basis.
Fortification through genetic modification poses no risks of vitamin
A toxicity. Genetically modified crops (e.g., golden rice, enriched canola
oil) produce beta-carotene, not preformed vitamin A.
This intervention is potentially the most problematic because it is
theoretically possible to overdose the recipient through frequent, inadvertent
dosing. From a practical standpoint, however, serious or sustained side
effects require very high, frequent and persistent dosing (50,000 to 100,000
IU daily for 3 to 6 months).(1, 27, 40, 43) An often expressed concern
is that a child might receive three or even four high-dose supplements
within a month (a regular distribution, a dose during measles, plus a
third or fourth from an overly zealous local health worker). The worst
result, however, would be a day or two of nausea and vomiting. This risk
pales in comparison with the millions of children who would otherwise
die or be blinded.
A decade ago the public health and nutrition communities recognized
the need to improve the vitamin A status of young children throughout
the developing world.(44) The World Bank has estimated that vitamin A
supplementation (the only approach they modeled) was among the most cost-effective
health interventions available, at less than US$1 per disability-adjusted
life year.(45) Although more than 70 countries have embraced the global
goal of eliminating vitamin A deficiency as a public health problem, progress
has been slow, largely because of the costs and logistical challenges
to changing behavior (diets), delivering large-dose supplements regularly,
and fortifying traditional dietary items. A number of bilateral and international
agencies recently recommitted themselves to these efforts, even as continuing
research expands the implications of deficiency. New tools, such as genetically
modified staple crops, could provide important strategies and stimulate
these global efforts.
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