Vitamin A deficiency and attributable mortalityamong under-5-year-olds*J.H. Humphrey,1 K.P. West Jr,2 & A. Sommer3

Reported are estimates of the prevalence in developing countries of physiologically significant vitamin Adeficiency and the number of attributable deaths. The WHO classification of countries by the severityand extent of xerophthalmia was used to categorize developing countries by likely risk of subclinicalvitamin A deficiency. Using vital statistics compiled by UNICEF, we derived population figures and mor-tality rates for under-5-year-olds. The findings of vitamin A supplementation trials were applied to popu-lations, at-risk of endemic vitamin A deficiency to estimate the potential impact of improved vitamin Anutriture in reducing mortality during preschool years. Worldwide, over 124 million children are estima-ted to be vitamin A deficient. Improved vitamin A nutriture would be expected to prevent approximately1-2 million deaths annually among children aged 1-4 years. An additional 0.25-0.5 million deaths maybe averted if improved vitamin A nutriture can be achieved during the latter half of infancy. Improvedvitamin A nutriture alone could prevent 1.3-2.5 million of the nearly 8 million late infancy and preschool-age child deaths that occur each year in the highest-risk developing countries.

Until the past decade, interest in vitamin A deficien-cy focused on its ocular manifestation, xerophthal-mia, the leading cause of childhood blindness indeveloping countries (1, 2). Beginning in the early1980s, however, a series of studies in different cul-tures revealed that even subclinical vitamin A defi-ciency has broader consequences in developingcountries in terms of child morbidity and mortality.Thus, a longitudinal study from West Java,Indonesia, reported a two- to threefold higher risk ofrespiratory infection and diarrhoea (3) and a fourfoldincreased risk of mortality among children with mildxerophthalmia (4). Two controlled field trials in nor-them Sumatra and West Java, Indonesia, reportedreductions of 34% and 46%, respectively, in themortality of preschool-age children administeredsemiannual vitamin A supplements (5) and fortifiedcommercially distributed monosodium glutamate (6).In India, mortality among preschool-age childrenwas lowered by 54% upon distribution of small,weekly doses of vitamin A (7), while in Nepal, per-

* From the Johns Hopkins University, 120 Wilmer, 600 NorthWolfe Street, Baltimore, MD 21205-2179, USA.I Instructor, Department of Ophthalmology. Requests for reprintsshould be sent to this author.2 Associate Professor. Departments of Ophthalmology andInternational Health.3Dean, School of Hygiene and Public Health.Reprint No. 5270

iodic administration of large doses of vitamin A(200 000 IU) reduced mortality by ca. 30% (8, 9).The small reductions reported in some trials (10)indicate that the impact of vitamin A on mortalitycan be expected to vary within and between regions.

Vitamin A appears to enhance survival duringthe acute phase of severe infection, as evidenced bystudies on measles. Case fatality among childrenwith moderate-to-severe measles has been repeatedlyreduced by 50% or more through the use of oral vita-min A therapy on admission to hospital (11-13). Insurvivors, the severity of acute illness is modulated,and is accompanied by more rapid recovery (13, 14).

These studies have redirected scientific inquiry,increased the funding of vitamin A research and pre-ventive activities, and led to a number of officialmeetings and statements within the United Nations(15-17)a and other international agencies (18, 19)bcalling for the prevention and control of vitamin Adeficiency.

Estimates of the magnitude of blinding malnutri-tion published in 1981 (1) have served as a usefulbasis for intemational planning purposes. The pre-sent article addresses the parallel issue of the

a Prevention and control of vitamin A deficiency: meeting ofinterested parties. Proposal for a 10-year programme of supportto countries. Unpublished WHO document NUT/84.5, Rev. 1.b Grant, J.P. Ending hidden hunger. UNICEF, New York,October 1991 (Document No. CF/EXE-IC/1991-032).

Bulletin of the World Organization, 70(2): 225-232 (1992) © World Health Organization 1992 225

J. H. Humphrey et al.

likely scale and extent of physiologically significantvitamin A deflciency and the number of childhooddeaths directly attributable to this preventable condi-tion.

MethodsReference dataBased on preliminary assessment reports and datafrom surveys over the past 25 years, WHO has clas-sified 63 developing countries into three categories,according to the likely severity and extent of blind-ing vitamin A deficiency.c Category I includes 23countries that, according to available data, harbourthe highest risk of vitamin A deficiency. Four ofthese (India, Indonesia, Bangladesh, and thePhilippines) have endemic vitamin A deficiency, asindicated by sound, population-based xerophthalmiaprevalence data (Table 1). These four countries haveprovided the basis for the currently accepted esti-mates of xerophthalmia and blindness from vitaminA deficiency (21). Intervention trials carried out inIndonesia and India (5-7, 10) and in nearby Nepal(8, 9) have reported the impact of vitamin A in redu-cing preschool-age child mortality. Thus, studies inthese four countries (plus Nepal) provide the strong-est data and most conservative estimates of the glob-al extent of vitamin A deficiency and its associatedmortality.

Category II countries in the WHO classificationare those where xerophthalmia is likely to be apublic health problem in certain regions but forwhich there are insufflcient national, population-based data. Category III countries are those wherethe prevalence of xerophthalmia is probably low,although cases have been occasionally observed.Finally, there are "other" developing countries thathave not been classified by WHO but which, in viewof their high infant and child mortality rates, are like-ly to harbour vitamin A deficiency. Here, developingcountries refer to the 81 nations identified in 1991by UNICEF to have infant mortality rates exceeding30 per 1000 live births per year, excluding the USSRand Guyana (22). In this article, category II and IIIcountries have been aggregated with these "other"developing countries and are referred to as "non-category I" countries. Estimates of the number ofinfant and 1-4-year-old child deaths in category Iand non-category I countries are based on 1989demographic estimates compiled by UNICEF (Table1) (22).

c Global situation - vitamin A deficiency. Based on reportsreceived by WHO as of October, 1988. Expanded Programmeon Immunization Update, December 1988.

Standard indicators of vitamin A statusAmong the indicators of vitamin A deficiencyemployed in the studies cited in this article are thefollowing (with diagnostic cut-offs): ocular signs ofxerophthalmia (night blindness, conjunctival or cor-neal xerosis) (23); serum retinol level (<20 jg/dl)(24); the relative dose response (RDR) test (>20%positivity) (25, 26); and conjunctival impressioncytology (CIC-A) (abnormal epithelium) (27). Inaccord with WHO recommendations (28), dietarydata reflecting inadequate vitamin A intake wereconsidered as suggestive that a vitamin A deficiencyproblem may exist.

Results and discussion

Numbers of children with vitamin A deficiencyIn population-based studies in Indonesia (29) and thePhilippines (30), half of all clinically normal chil-dren had serum vitamin A levels below 20 jg/dl. Areport from Brazil using the RDR test suggests thateven children with serum vitamin A levels equal tothis cut-off value may have suboptimal vitamin Anutriture (26). Altogether, 86% of children withserum retinol levels of 20-30 gg/dl and 26% of thosewith serum levels of 30-40 gg/dl were positive in theRDR test. If these rates of RDR positivity areapplied to a typical distribution of serum retinolamong clinically normal Indonesian children, wewould expect 70% to have suboptimal liver stores(J.H. Humphrey et al., unpublished observations,1991).

Several studies have used CIC-A to detect sub-clinical vitamin A deficiency. Two case-controlstudies from Indonesia found 22% (31) and 41%(32) of nonxerophthalmic children to be abnormal bythis method. Population-based studies in Micronesia(33) and India (34) reported that 42% and 25%, res-pectively, of clinically normal children were CIC-Aabnormal. Allowing for an estimated 5-10% falsepositivity in CIC-A (27), these studies suggest that15-40% of clinically normal children in category Icountries may have abnormal epithelial differentia-tion and disturbed physiological function, secondaryto vitamin A deficiency.

The combined results of these serological, RDR,and cytological findings indicate conservatively thatapproximately 40% of children (or 97 million) livingin category I countries have physiologically signifi-cant vitamin A deficiency (Table 2).

It is more difficult to estimate the extent of sub-clinical deficiency in non-category I developingcountries. The above data suggest that where xeroph-thalmia is a public health problem the number of

226 WHO Bulletin OMS. Vol 70 1992

Vitamin A deficiency among under-5-year-olds

Table 1: Demographic data for WHO-classified category I vitamin A deficient and other non-category I developingcountries

No. of deathsamong 1-4-year-olds

(x1 000)

No. of deaths among infants aged:

<12 months 6-11 monthsb(xl 000) (x1 000)

Total category

Four Asian countries

IndiaIndonesiaPhilippinesBangladesh

Others

Sub-Saharan AfricacEastern MediterraneandLatin America/CaribbeaneAsia'

Total non-category 19Sub-Saharan AfricahMiddle EasVNorth AfricaiLatin America/CaribbeanAsiak

Total

243 900

164 000

113 40022 7009100

18 800

79 900

50 8004400

19 8004900

269 90039 70045 90032 600

151 700

513 800

3042

1784

127713456

317

1258

10247610952

1734538249130817

4776

5478

3493

250336587

540

1985

1497114274100

37049346633531754

9182

1827

1165

83412229180

662

499389233

1235311221118585

3062a Derived from ref. 22, Tables 1 and 5.b Estimated by assuming that deaths among infants aged 6-11 months represent a third of all deaths among those aged <12 months.c Benin, Burkina Faso, Chad, Ethiopia, Ghana, Malawi, Mali, Mauritania, Mozambique, Niger, Nigeria, United Republic of Tanzania,and Zambia.d Sudan.

e Brazil, Haiti.f Nepal, Sri Lanka.9 UNICEF has identified 81 countries with infant mortality rates (IMR) of >30 per 1000 live births (22). All of these countries are inclu-ded in the non-category country calculations, except Guyana, for which demographic information was not available, and the USSR.Non-category countries where vitamin A deficiency is known to exist but where the IMR is <30 per 1000 have been excluded fromthese estimates.h Angola, Botswana, Burundi, Cameroon, Central African Republic, Congo, Cote d'lvoire, Gabon, Guinea, Kenya, Lesotho, Liberia,Madagascar, Namibia, Rwanda, Senegal, Sierra Leone, Somalia, South Africa, Togo, Uganda, Zaire, and Zimbabwe.Algeria, Egypt, Iran, Iraq, Jordan, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Saudi Arabia, Syrian Arab Republic, Tunisia,

Turkey, and Yemen.i Argentina, Bolivia, Colombia, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Paraguay, Peru,and Venezuela.k Afghanistan, Bhutan, Cambodia, China, Laos, Mongolia, Myanmar, Pakistan, Papua New Guinea, and Viet Nam.

children with subclinical vitamin A deficiency is 10

times the number with xerophthalmia. Survey dataindicate that inadequate dietary intake of vitamin A iswidespread (35, 36). In China, where 40% all pres-

chool-age children in non-category I developingcountries live, and where 16% of all deaths of 1-4-year-olds occur, the results of four large surveys sug-gest that 1% of these children may have xerophthal-mia (22, 28). Taken together with the above-mentioned tenfold factor this indicates that 10%of Chinese preschool-age children have subclinical

vitamin A deficiency. Applying this same propor-tion to other non-category I developing countriessuggests that nearly 27 million children may sufferfrom physiological vitamin A deficiency. World-wide, over 124 million preschool-age children are

estimated to be vitamin A deficient (Table 2).

Associated child mortality

Studies that have reported a significant impact ofadministering vitamin A supplements in category I

WHO Bulletin OMS. Vol 70 1992

No. of<5-year-oldsa

(x1 000)

227

J. H. Humphrey et al.

Table 2: Estimated percentage and number of preschool-age children with physiologically significant vitamin Adeficiency

No. of Estimated % with No. with<5-year-oldsa vitamin A vitamin A deficiency

(XlOOO) deficiencyb (x1000)

Total category 1 243 900 40 97 200Four Asian countriesc 164 000 40 65 600Others 79 900 40 31 960

Total non-category 1 269 900 10 26 990

Total 513 800 124 190a See Table 1 in ref. 22.b See text for derivation of proportions.c India, Indonesia, Philippines, and Bangladesh.

countries have found reductions of 26-54% in the12-month mortality levels of children aged 1-4 yearswho received the supplements (5-9). An even greaterimpact has been projected (41-74% reduction inmortality) for maximum coverage levels (37, 38).Therefore, in category I countries, improved vitaminA nutriture could potentially reduce preschool-agechild mortality by an estimated 30-55% (0.91-1.67million deaths averted per year) (Table 3).

The impact of vitamin A supplementation onchild mortality in non-category I countries has notbeen investigated. Therefore, estimates for thesepopulations have been derived (with several assump-tions) from the data for category I countries.Although a longitudinal study of Indonesian childrensuggested that nearly 20% of all preschool-agedeaths in endemic areas could be prevented bycontrolling xerophthalmia alone (4), most interven-tion trials have suggested that supplementation canlower mortality among children who are marginally(but not clinically) deficient in vitamin A. Since 10%of children in non-category I developing countriesare assumed to have subclinical vitamin A deficiency(compared with 40% in category I countries), it isestimated that the impact of vitamin A on mortalitywould also be roughly a quarter of that observed incategory I countries, i.e., 10-15%. This wouldaccount for an additional 173 000-260 000 deathsamong children aged 1-4 years in non-category Icountries that might be prevented by improved vita-min A nutriture (Table 3).

A "best estimate" range of the potential impactof improved vitamin A nutriture on 1-4-year-oldmortality in populations with clinically apparent orsubclinical deficiency is 1.09-1.93 million deathsaverted per year (Table 3). It should be noted,however, that vitamin A trials have also reportedreductions in mortality in the sixth and seventhyears of life (5, 8), ages for which demographic esti-

mates of mortality are often not specified. Thus, thisrange of preventable child deaths is, by definition,conservative.

Associated mortality in late infancy

In developing countries infants may be at risk ofvitamin A deficiency because mothers can be defi-cient in the vitamin during pregnancy (39), may deli-ver newborns with reduced vitamin A stores (40),and may remain deficient during lactation (41).Nevertheless, breast-feeding appears to be vital inkeeping infants adequately nourished with vitamin A(42, 43).

Mortality intervention trials have not adequatelyaddressed the impact of vitamin A on infant mortali-ty. Five studies have reported reductions of 12-72%in mortality when vitamin A supplementation wasinitiated, on average, at 6 months of age or later ininfancy (5-9). This mortality experience was obser-ved over a subsequent 4-12 month period, which ten-ded to overlap into the second year of life. Thus, it isestimated that adequate vitamin A nutriture mayreduce mortality among older infants by 10-25% incategory I countries (183 000-457 000 deaths aver-ted) (Table 3). Consistent with the above-mentionedassumptions for 1-4-year-olds, we estimate that aquarter of this impact (3-6%) may be observed innon-category I developing countries, i.e., 37 000-74 000 additional deaths averted each year. A total of220 000-531 000 late infant deaths may be preventedannually by improved vitamin A nutriture (Table 3).

Worldwide, between 1.3 and 2.5 million out of atotal of 7.8 million deaths among infants and pre-school-age children (late infancy up to age 4 years)could be prevented each year by improving vitaminA nutriture (Table 3). The number of infant deathsprevented may be considerably greater if vitamin Anutriture were truly adequate from conception, and

WHO Bulletin OMS. Vol 70 1992228

Vitamin A deficiency among under-5-year-olds

Table 3. Estimated impact of Improving vitamin A nutriture on reducing preschool-age mortality

Low impacta High impact8

No. of deaths/year No. of deaths No. of deaths(x1000) % reduction averted (xl 000) % reduction averted (x1000)

Age: 1-4 years (Total) 4776 1085 1933

Total category 1 3042 30 912 55 1673Four Asian countriesb 1784 30 535 55 981Others 1258 30 377 55 692

Non-category 1734 10 173 15 260Age: 6-11 months (Total) 3062 220 531

Total category 1827 10 183 25 457Four Asian countriesb 1165 10 117 25 291Others 662 10 66 25 166

Non-category 1 1235 3 37 6 74

Total 7838 1305 2464a See text for derivation of low and high estimates of impact.b India, Indonesia, Philippines, and Bangladesh.

thus had an opportunity to have an impact on fetalwastage and early infant mortality in ways that havenot yet been investigated.

CaveatsThese estimates were developed systematically, butare based on data of mixed quality and on a numberof assumptions.

First, standard demographic projections, as com-piled and reported by UNICEF, were used to estima-te the annual numbers of births, infant deaths, chil-dren under 5 years of age, and deaths that occur eachyear among l-4-year-olds. The number of deathsamong infants aged .6 months was assumed to be athird of the published infant mortality rate: errorsgenerated from this process will affect the estimates.

Second, in estimating the ratio of subclinicaldeficiency to xerophthalmia as 10:1, we have drawnupon the results of different investigators, in differ-ent countries, who used a variety of techniques.Thus, this ratio cannot be expected to apply acrossall populations, but represents a best estimate basedon current data. The apparent consistency of thisrelationship is reassuring, however.

Third, we assumed that the prevalence and se-verity of vitamin A deficiency in all countries clas-sified as category I by WHO are the same as thosein the four well-studied Asian countries from whichmost data have come, and that the impact of vitaminA supplementation on mortality would be similar tothat in the three countries (India, Indonesia, andNepal) where this has been measured. However,

most of other category I countries were classified onthe basis of less tangible evidence.

Fourth, we have not accounted for any potentialimpact that vitamin A may have in the first half ofinfancy, as there are insufficient data available fromwhich to derive estimates. It should be noted that theestimates of impact in later infancy represent theeffect that could be achieved among infants whoreceive vitamin A supplements between 6 to 11months of age.

Finally, we assumed an "average risk" of vita-min-A-related mortality for all provinces in a givencountry, although, in reality, vitamin A deficiencytends to cluster (i.e., within provinces, districts, orvillages) (44).

Despite these limitations, the analyses and esti-mates obtained provide a useful indication forcoming to grips with the probable magnitude of theproblem: from 1 in 7 to 1 in 3 deaths involving over-6-month-olds up to preschool-age children in devel-oping countries might be prevented by improvingvitamin A nutriture.

One final comment should be noted: vitamin Adeficiency is not a proximal determinant of death.Children in developing countries die primarily frominfections such as diarrhoea, respiratory disease, andmeasles (22). Vitamin A deficiency presumablyalters the incidence, duration or severity of suchinfections or the child's ability to withstand theirconsequences (20, 45). Interventions that reduce theincidence of these infections (e.g., measles immuni-zation) would decrease the net impact of vitamin Asupplementation on mortality. However, even well-

WHO Bulletin OMS. Vol 70 1992 229

J. H. Humphrey et al.

organized immunization programmes, with theirless-than-complete coverage and efficacy, may leavean important role for improved vitamin A nutriturein reducing the number of infection-related deaths.dTherefore, until protected water supplies, improvedhygiene, universal immunization and other child-survival services are effectively delivered, controlof vitamin A deficiency could enhance child healthand survival.

AcknowledgementsThis paper was prepared under Cooperative AgreementNo. DAN 0045-A-5094 between the Dana Center forPreventive Ophthalmology, the Johns Hopkins University,and the Office of Nutrition, Bureau for Science andTechnology, United States Agency for InternationalDevelopment, with additional assistance from Task ForceSight and Life (Roche).

Resume

Carence en vitamine A et mortalit6associee chez les moins de 5 ansJusqu'a ces dix dernieres ann6es, on s'est sur-tout interess6, en ce qui concerne la carence envitamine A, a la x6rophtalmie, cause majeure dececit6 de l'enfant dans les pays en developpe-ment. Recemment, toutefois, plusieurs 6tudes ontmontr6 que meme une carence infraclinique envitamine A peut avoir d'importantes cons6-quences chez les populations mal desservies parles systemes de sante. Etant donn6 le d6velop-pement croissant des politiques nutritionnelles etdes programmes de pr6vention de la carence envitamine A, il est urgent de connaltre l'ampleurmondiale de ce probleme et l'impact potentiel desprogrammes de suppl6mentation en vitamine Asur la mortalite chez l'enfant.

La classification OMS des pays selon l'impor-tance de la x6rophtalmie et de la cecite d'originenutritionnelle sur la sant6 publique, les r6sultatsd'6tudes sur le terrain et d'essais cliniques por-tant sur la vitamine A, ainsi que les estimationsd6mographiques types de la mortalite juvenilepermettent d'evaluer ces parametres. Dans lepresent article, les pays de categorie I sont ceuxdans lesquels la xerophtalmie est presente ouprobablement presente, et les pays dits "n'entrant

d Guidelines for the use of vitamin A in immunization programs:a report of the International Vitamin A Consultative Group(IVACG). Preliminary draft submitted to WHO, September 1990.

pas dans la categorie I" sont 93 autres pays end6veloppement ou le risque de carence en vita-mine A est plus faible.

En consid6rant globalement les donn6esserologiques, la relation dose-reponse et lesobservations cytologiques, nous estimons que40% des enfants d'age prescolaire vivant dansles pays de categorie I (environ 97 millionsd'enfants) presentent une carence en vitamine Asignificative sur le plan physiologique. S'y ajou-tent quelque 10% des enfants des pays n'entrantpas dans la cat6gorie I (environ 27 millionsd'enfants).

La plupart des etudes qui ont mesur6 l'impactde l'administration de vitamine A sur la mortalit6juv6nile dans les pays d'Asie entrant dans lacat6gorie I mentionnent des r6ductions de 31 a53% lorsque les enfants reqoivent une suppl6-mentation en vitamine A entre 1 et 4 ans. Enaugmentant la couverture de cette intervention, ilest probable que l'impact sera encore plus grand(41 a 74%). Par cons6quent, chez les enfantsdes pays de categorie 1, une amelioration del'apport de vitamine A devrait pouvoir reduire lamortalite de 30 a 55% chez les enfants de 1 a 4ans (c'est-a-dire 6viter 1,1 a 1,9 million de d6cespar an).

Dans les pays n'entrant pas dans la cat6go-rie 1, on estime que 10% des enfants pr6sententune carence infraclinique en vitamine A (contre40% dans les pays de la categorie 1). Comme lesessais de suppl6mentation ont mis en evidenceune r6duction de la mortalit6 chez les enfantssans x6rophtalmie clinique, on suppose quel'impact de la vitamine A sur la mortalite serait6gal a environ un quart de celui observe dans lespays de la cat6gorie I (soit 10 a 15%). L'am6lio-ration de I'apport de vitamine A pourrait parcons6quent pr6venir 173 000 a 260 000 d6ceschez les enfants d'age pr6scolaire dans les paysn'entrant pas dans la cat6gorie 1.

Plusieurs 6tudes d'intervention font appa-raltre une r6duction potentielle de la mortalit6 de12 a 72 % lorsque les supplements de vitamine Asont donn6s des l'age de 6 mois. Nous estimonspar consequent qu'un apport suffisant en vitami-ne A des cet age pourrait reduire la mortalit6 de10 a 25% dans les pays de la categorie I (c'est-a-dire eviter 183 000 a 457 000 deces). Dememe que chez les enfants de 1 a 4 ans, nousestimons que la reduction de la mortalite dans lespays en developpement n'entrant pas dans lacat6gorie I serait 6gale au quart de celle obser-v6e dans les pays de la categorie 1, soit 3 a 6 %(37 000 a 74 000 deces evites si la supplementa-tion a commence avant l'age d'un an).

230 WHO Bulletin OMS. Vol 70 1992

Vitamin A deficiency among under-5-year-olds

En resume, nous estimons qu'a l'echellemondiale, plus de 124 millions d'enfants d'ageprescolaire presentent une carence en vitamineA. En ameliorant l'apport en vitamine A, 1,1 a 2millions de deces chez les enfants de 1 a 4 ans,et 0,2 a 0,5 million de d6ces chez les nourrissonsde 6 mois a 1 an, pourraient etre evites chaqueannee.

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232 WHO Bulletin OMS. Vol 70 1992