Mortality of infants

Am J C/in Nutr 1995;62:143-8. Printed in USA. © 1995 American Society for Clinical Nutrition I43

Mortality of infants <6 mo of age supplemented withvitamin A: a randomized, double-masked trial in Nepal�

Keith P West Jr, Joanne Katz, Sharada Ram Shrestha, Steven C LeClerq, Subarna K Khatrv,

Elizabeth K Pradhan, Ramesh Adhikari, Lee Shu-Fune Wu, Ram Prasad Pokhrel, and Alfred Sommer

ABSTRACT The effect of supplementing 1 1 918 infants < 1

mo and 1-5 mo of age with vitamin A (15 000 and 30 000 �tg

retinol equivalents or 50 000 and 100 000 IU, respectively) or a

placebo on subsequent 4-mo mortality was assessed in a random-

ized, double-masked community trial in the rural plains of Nepal.

There were 130 deaths (51.6/1000 child-y) in the control group and

150 deaths (57.1/1000 child-y) in the vitamin A group, yielding a

relative risk of 1.1 1 (95% CI: 0.86, 1.42), which is indicative of no

overall effect on early infant mortality. There was a tendency for

the relative risk of mortality among vitamin A recipients to rise

with improved nutritional status. These results suggest that distri-

bution of a large oral dose of vitamin A to infants < 5-6 mo of age

may not benefit short-term survival. This is in contrast with the

results of trials in which older infants and children in this same

population were supplemented. Am J C’lin Nutr 1995;62: 143-8.

KEY WORDS Vitamin A, supplementation, infant mortal-

ity, verbal autopsy, intolerance

INTRODUCTION

Vitamin A deficiency is widespread in many developing

countries where an estimated I 24 million preschool children

are deficient (1). Between S and 8 million children develop

xerophthalmia each year (2). Beyond its role as the leading

cause of pediatric blindness (3), vitamin A deficiency is an

important underlying cause of early childhood mortality (4);

deficiency apparently comprises the host response to severe

infection (4-6). An estimated 1.3-2.5 million infant and pre-

school child deaths annually can be attributed to vitamin A

deficiency (1).

Over the past decade several studies have examined the

effect of vitamin A on reducing mortality among children aged

� 6 mo at the time of intervention. Six community trials in

Asia (7-1 1 ) and Africa (6) reported mortality reductions of

19-54% after vitamin A supplementation either directly or

through fortification, whereas two trials observed no signifi-

cant effect (12, 13). Meta-analyses based on data from these

trials conclude that vitamin A supplementation can be expected

to reduce mortality of children aged 6-72 mo by 23-34% in

populations where xerophthalmia is at least present

(4, 5, 14, 15).

Five of the above trials observed mortality reductions of

12-62% among infants, most of whom were either stated or

presumed to be aged �‘6-1 1 mo when they were supplemented

with vitamin A (7-11). In two ofthe trials (9, 11), the reduction

was � 50% with 95% CIs that excluded 1.0. These findings

suggest the possibility that vitamin A supplementation earlier

in life, during the first 6 mo, might also reduce mortality from

infection at a time when even a modest proportional effect

could translate into substantial numbers of lives saved. How-

ever, only one of the field trials to date, performed in the

midwestern hills of Nepal (11), has reported any vital data for

infants < 6 mo of age who were supplemented with vitamin A.

Although the number per treatment group was small (ii = 300),

there was no evidence of a survival benefit. In a second, more

recent, hospital-based clinical trial in Indonesia, a significant

reduction in mortality was observed in a cohort of infants after

oral administration of 15 000 jig retinol equivalents (RE)

(SO 000 IU) vitamin A at birth (16).

We report here the findings of a large community trial that

was conducted in the rural floodplains of east central Nepal to

gain a more definitive estimate of the effect that large-dose

vitamin A supplementation in the first 6 mo of life may have on

infant mortality.

I From the Center for Human Nutrition, Department of International

Health and the Dana Center for Preventive Ophthalmology (DCPO), the

Johns Hopkins Schools of Public Health and Medicine, Baltimore; the

Nepal Nutrition Intervention Project-Sarlahi (NNIPS), Kathmandu; the

National Society for the Prevention of Blindness, Kathmandu; and the

Department of Pediatrics and Kanti Children’s Hospital, Tribhuvan Uni-

versity, Kathmandu.

2 This study was carried out under Cooperative Agreement DANO()45-

A-5094 between the Office of Nutrition, US Agency for International

Development (USAID), Washington, DC, and DCPO as a joint undertak-

ing with the National Society for the Prevention of Blindness, Kathmandu,

Nepal, with financial and technical assistance from Task Force Sight and

Life (Roche, Basel, Switzerland), the United Nations Children’s Fund

(UNICEF), Nepal, and NIH grant RRO4O6O. The study supplements(vitamin A and placebo capsules) were a gift of Roche.

3 The Sarlahi Study Group (in addition the authors) included BDChataut, MR Pandey, D Calder, I Gmunder, I Humphrey, I Tielsch,

H Taylor, D Piet, I Canner, NN Achariya, DN Mandal, TR Sakya, BB

Shrestha, and RK Shrestha.

4 Address reprint requests to KP West Jr. Division of Human Nutrition,

Department of International Health, Room 2041, Johns Hopkins School of

Hygiene and Public Health, 615 North Wolfe Street, Baltimore, MD

21205.

Received July 20, 1994.

Accepted for publication January 27, 1995.

by guest on February 22, 2014

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144 WEST El AL

SUBJECTS AND METHODS

This trial was part of a large, randomized, double-masked,

placebo-controlled community trial that evaluated the effect of

vitamin A supplementation every 4 mo on preschool child

mortality. Basic methods (10, 17), all-cause mortality findings

for children � 6 mo of age at the time of dosing (10, 18), and

short-term tolerance of infants < 6 mo of age to a large dose of

vitamin A were reported (19). The present study, carried out

between September 1989 and December 1991, addressed the

effects on mortality of supplementing infants < 6 mo of age at

the time of dosing.

Two hundred sixty-one wards in 29 contiguous village de-

velopment areas (VDAs) in the District of Sanlahi were mapped

and ‘�‘33 000 households were numbered. Written consent was

obtained from leaders for the trial to be conducted in their

communities. At the time of household enrollment parental

consent was obtained verbally. Participation was voluntary at

all times.

After a random start, wards were systematically assigned,

blocked on VDAs, for infants to receive an oral dose of vitamin

A [15 000 RE (SO 000 IU) in �3 drops of oil for neonates (< 1

mo of age) and 30 000 RE (100 000 IU) in “�‘6 drops of oil for

infants 1-S mo of age] on placebo [75 RE (250 IU) or 150 RE

(500 IU), respectively] from gelatinous capsules of identical

appearance (Roche, Basel, Switzerland). All supplements also

contained � IU vitamin E pen drop, added as an antioxidant.

A child census was conducted at baseline (visit 1). Infants� S mo of age were enrolled, their dates of birth recorded, a

1-wk morbidity history obtained, left midupper-arm circumfer-

ence (MUAC) measured with an insertion tape (20), and the

age-titened dose of the study supplement was administered. If,

after repeated attempts, a team member failed to dose an infant,

a capsule was left with a responsible adult along with instruc-

tions for dosing. A current history of breast-feeding was ob-

tamed for infants in a 15% random sample of wards. At each

subsequent 4- mo household visit (visits 2-6) these procedures

were repeated and surviving infants born during the last inter-

val were enrolled. Infants 4-S mo of age at any visit remained

in the trial for another 4 mo (ie, until 8-9 mo of age). Infants

who were � 6 mo of age at any visit were excluded from this

analysis.

Births and deaths were reported by the above 4-mo census

and, independently, every 2 mo by a mobile vital surveillance

team. Usually within 3 mo of the reported date of death of an

infant, a “verbal autopsy” interview was conducted in an at-

tempt to reconstruct the occurrence of events in the weeks

preceding the child’s death. Verbal autopsy reports were mdc-

pendently reviewed by two physicians (SKK and RA) who

standardized their reviews for �‘S0 prestudy death reports.

Each assigned up to four associated causes of death. Un-

weighted K scones (with 95% CIs) for deaths nonexclusively

attributed to acute respiratory infection, diarrhea on dysentery,

and wasting malnutrition (three major, associated causes of

death in this study) were 0.92 (0.87, 0.97), 0.82 (0.75, 0.89),

and 0.77 (0.69, 0.84), respectively.

Baseline comparisons were evaluated by the chi-squane test.

All analyses were performed on an intent-to-treat basis, that is,

by randomized treatment group irrespective of individual com-

pliance to the dosing regimen. Mortality rates were calculated

on a person-time (child-y) basis and accumulated oven all 4-mo

intervals of observation. One-third of a child-y follow-up was

assigned for each completed 4-mo interval. Infants who with-

drew on died during an interval were assigned one-sixth of a

child-y of observation for the interval in which the event

occurred. Relative risk (RR) estimates (vitamin A/control mor-

tality rates) were calculated to estimate the overall and strati-

fled effects of vitamin A supplementation on mortality. Ninety-

five percent CIs were computed by the method of Katz et al

(21). All 95% CIs for RR estimates were inflated by 10% (ie,

variances were inflated by 22%) to account for loss in precision

in mortality rate estimation at this age due to the design effect

(22). Data analysis was carried out by using SAS (version 6.1,

SAS Institute, Cany, NC) on a Solbourne microcomputer

(Longmont, CO).

The protocol and procedures for the trial were reviewed and

approved by the Nepal Medical Research Council, Kathmandu,

and the Joint Committee on Clinical Investigation at the Johns

Hopkins University School of Medicine, Baltimore.

RESULTS

A total of 1 1 918 infants (n = 5832 control, ii = 6086

vitamin A) were enrolled during visits 1-6, representing �‘98%

of all surviving infants in the study area at the times of the

household visits. Nearly 90% of enrolled infants were regis-

tered at the visit after their birth. Those not enrolled were

mostly neonates who had been born away from or secluded in

their homes for the first weeks of life; of these, �‘90% were

registered at the next household visit when they were �4 mo of

age.

Infants recruited into the two treatment groups were compa-

nable at entry with respect to sex, age, morbidity in the previous

weeks, nutritional status (MUAC), and proportion being breast-

fed (Table 1). A similar, but atypical, age distribution of

infants in each group was caused by the underenrollment of

newborns and their subsequent enrollment at �4 mo of age and

by the small proportion of infants 4 and S mo of age who were

only eligible to enter the trial at visit 1. Virtually all infants in

the random sample in both groups were currently being breast-

fed, 91% � 10 times per day.

Socioeconomic and demographic characteristics of house-

holds with � 1 infant in the trial were similar by treatment

group. Three percent of study households in both groups cx-

penienced an infant death in the previous 12 mo; �36% of

mothers in both groups had one or more child die previously.

Approximately 85% of newly enrolled infants in each group

were supplemented directly by field staff whereas capsules

were left at home for ‘�13%; �2% in each group did not

receive their first intended dose. Periodic follow-up of parents

during the trial suggested that, in both groups, �6O% of cap-

sules left for administration had been given to infants. Thus, on

average, > 90% of enrolled infants were dosed at each visit.

Oven the six 4-mo intervals 5832 and 6086 infants pantici-

pated in the trial, generating 7666 and 7998 infant visits or

2517 and 2625 child-y of observation in the control and vita-

mm A groups, respectively (Table 2). There were 130 deaths

among control subjects and 150 deaths among vitamin A-sup-

plemented infants yielding mortality rates of 51.6 and 57.1

deaths per 1000 child-y, respectively, and a RR of 1.11 (95%

CI: 0.86, 1.42), indicative of no overall effect on mortality.


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TABLE 1

Characteristics of study infants < 6 mo of age at time of entry into trial

by treatment allocation’

85

� 75

� 65

= 0

�45

�35

25

15

VITAMIN A AND EARLY INFANT MORTALITY 145

Control(n = 5832)

Vitamin A(n 6086)

n(%) n(%)

SexMale 2914 (50.0) 3114 (51.2)

Female 2918 (50.0) 2972 (48.8)

Age20 mo 791 (13.6) 830(13.6)

1 mo 1499(25.7) 1572 (25.8)

2 mo 1352 (23.2) 1362 (22.4)

3 mo 1170(20.1) 1269 (20.9)

4 mo 736 (12.6) 773 (12.7)

S mo 284 (4.9) 280(4.6)

Morbidity (� I d

in past week)

Diarrhea 587 (1 1.9) 616 (12.0)

Cough and rapid

breathing 359 (7.3) 406 (7.9)

Fever 443 (9.0) 467 (9.1)

Total sample3 4931 (84.6) 5153 (84.7)

Arm circumference

< 8.5 cm 221 (4.5) 217 (4.2)

0.5-10.4 cm 1279 (25.9) 1264 (24.5)

10.5-12.4 cm 2283 (46.3) 2407 (46.7)

� 12.5 cm 1 151 (23.3) 1270 (24.6)

Total sample1 4934 (84.6) 5158 (84.8)

Breast-feeding

None 1 (0.2) 6 (0.6)

1-10 times/d 80 (8.2) 85 (8.0)

> 10 times/d 889 (91.5) 966 (91.4)

Total sample4 970 (98.0) 1057 (98.6)

‘ 1325 control infants and 1415 vitamin A-supplemented infants < 6mo of age entered the trial at visit 1; 4507 and 4671 infants, respectively,

� 4 mo of age entered the trial at visits 2-6.

2 A nonuniform age distribution resulted from restricting enrollment at

visits 2-6 to infants born since a previous visit (ie, � 4 mo of age). A lower

enrollment of neonates is attributable, in part, to local practices of fre-

quently giving birth at the mother’s parents’ home and of domiciliary

seclusion during the first 14 d after birth.

3 The total number and percent of infants for whom a 1-wk morbidity

history or baseline arm circumference were obtained.

4 The total number and percent of control (n = 990) and vitamin

A-supplemented (n 1072) infants in the random subsample of wards for

whom a breast-feeding history was obtained. There are 20 and 15 missing

values for control and vitamin A groups, respectively.

Age-specific RRs varied from 1.38 among infants I mo of age

to 0.78 for infants S mo of age at dosing. All 95% CIs included

1 .0. The cumulative estimate of RR after the first year of the

trial suggested a modest, protective effect for vitamin A (RR =

0.90), which led to the trial’s continuation; however, this

pattern changed in the second year: the cumulative RR after 20

mo was 1.03 and the final RR after 24 mo of the trial was 1.11

(Figure 1).

Among males, mortality appeared to be higher in the vitamin

A than in the control group (61.0 compared with 49.4 per 1000

child-y, respectively; RR = 1.24; 95% CI: 0.86, 1.78) whereas

rates were virtually identical among females (53.0 compared

with 53.9 per 1000 child-y; RR 0.98; 95% CI: 0.68, 1.42).

Absolute mortality declined with improved nutritional status;

however, the risk of mortality tended to rise among vitamin

A-recipient infants relative to control infants with increased

arm circumference. Although 95% CIs were wide, the trend

was consistent at each age (Table 3).

Wasting malnutrition was most frequently assigned as an

associated cause of death, followed by acute lower respiratory

infection, and diarrhea on dysentery, for “SO%, �cc40%, and

=33% of all deaths, respectively, in each group (Table 4). A

substantial proportion of deaths in both groups occurred sud-

denly in the absence of apparent infection or other causes: 17%

among control infants and 13% among vitamin A recipients.

Also, histories were vague, leading to uncertainty in cause

assignment for 20% of all deaths in both groups. Cause-

associated mortality was not significantly different between

groups.

DISCUSSION

Previous trials have clearly shown that supplementing chil-

dren 6 mo to 7 y of age with vitamin A, by a variety of means,

can markedly reduce mortality (4-11, 14, 15). In this same

Nepalese population a 30% overall decrease in mortality was

observed for infants > 6 mo of age, including a 22% reduction

among infants who were 6-i 1 mo of age at the time they

received 30 000 RE (10). Whether or not children 0-S mo of

age would benefit to the same extent oven the short-term

remains uncertain; this is an important omission considering

program opportunities that exist for improving vitamin A status

during the first 6 mo of life and the different nature and

mortality risk of very young infants.

Vitamin A supplementation at < 6 mo of age had no overall

effect on 4-mo survival in this population. The power (1-/3) to

have detected the observed 1 1 % increase in mortality with 95%

confidence (considering the design effect) was 13%. The trial

had sufficient power (85%), however, to detect a 30% differ-

ence in mortality between groups, as would have been pre-

dicted from the findings in olden infants and children (10, 18).

The absence of effect observed in this trial is consistent with

findings of another, smaller field trial in the western hills of

Nepal (Jumla) where the RR of death for infants < 6 mo of age

after receipt of 15 000 RE vitamin A was 1.0 (1 1). The lack of

apparent benefit at this age may be because of the protection

95

�. IfD ff If ifRR=O.90 0.94 0.90 0.97 1.03 1.11

I I I I I I

4 8 12 16 20 24

Duration of Trial (Months)

FIGURE 1. Cumulative mortality rate (with 95% CI) of infants < 6 moof age at dosing by treatment group with duration of trial. (0) control, (#{149})vitamin A.


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146 WEST El AL

I Excludes 33 and 34 children with missing MUAC values for control and vitamin A groups, respectively. MR, mortality rate per 1000 child-y.

TABLE 2

Effect of vitamin A on cumulative 4-mo mortality of infants < 6 mo of age at time of dosing’

Treatment variables

and mortality

< 1 Mo

Vitamin

Control A

1 Mo

Vitamin

Control A

2 Mo

Vitamin

Control A

3 Mo

Vitamin

Control A

4 Mo

Vitamin

Control A

5 Mo

Vitamin

Control A

0-5 Mo

Vitamin

Control A

Infantvisits 791 830 1499 1572 1352 1362 1263 1361 1355 1379 1406 1494 7666 7998

Withdrawals 6 11 21 21 16 19 21 12 14 17 21 14 99 94

Deaths 34 38 32 46 20 22 11 15 15 14 18 15 130 150

Child-y 256.9 268.4 490.8 512.8 444.7 447.2 415.7 449.2 446.8 454.5 462.2 493.2 2517.1 2625.3

Mortality rate 132.3 141.6 65.2 89.7 45.0 49.2 26.5 33.4 33.6 30.8 38.9 30.4 51.6 57.1

Relative risk 1.07 1.38 1.09 1.26 0.92 0.78 1.11

95% CI (0.66, 1.72) (0.85, 2.24) (0.56, 2.12) (0.54, 2.95) (0.41, 2.03) (0.37, 1.65) (0.86, 1.42)

1 Infants < 1 mo of age received 15 000 �ig RE; those 1-S mo of age received 30 000 �g RE. Mortality rate expressed as deaths per 1000 child-y.

from vitamin A deficiency already conferred by extensive

breast-feeding early in life. Olden infants may be more suscep-

tible to vitamin A deficiency as vitamin A intake diminishes

with less breast-feeding, which may result in inadequate vita-

mm A to meet metabolic demands, as has been observed

among older children with respect to risk of xerophthalmia in

this (23) and other populations (24-26).

There was a suggestion that mortality risk may be increased

among infants 1-3 mo of age receiving 30 000 RE (100 000

IU) vitamin A. Although not statistically significant (ie, 27%

for 1-3 mo combined, 95% CI: - 1 1%, 89%), the finding

raises concern that this single dose may be excessive for very

young infants, although no untoward effects were observed in

a previous, smaller placebo-controlled trial in Jordan where 90

young infants received three times this dosage (100 000 RE)

(27). In infants aged 4 and S mo the protective effect of 30 000

RE vitamin A began to emerge, reflected by 8% and 22%

reductions in mortality at these ages, respectively, which were

consistent with the 22% reduction observed among infants

given this same amount of vitamin A in the second 6 mo of life

(10). Similar age effects were observed by Clausen (28) in

1932: whereas cod liver oil administered to infants < 6 mo of

age had no apparent effect on severity of illnesses, in older

infants (6-24 mo) there was a 10-fold decrease in the incidence

TABLE 3

of severe infections (eg, pneumonia, septicemia) compared

with control infants. The smaller dose (15 000 RE) given in the

first month of life did not appear problematic.

Subgroup analyses also revealed a perplexing, dose-respon-

sive rise in RRs of mortality among supplemented children

who were least wasted (as measured by arm circumference).

Although not statistically significant for any one comparison,

the trend was consistent at each age, irrespective of the abso-

lute RR observed in the most wasted group, suggesting that the

effect (though underpowered and not easily explained) may

have been real. This effect was not apparent, however, from

verbal autopsy findings in which the estimated RR of mortality

associated with wasting malnutrition was 1.16 (Table 4). These

data are also not easily resolved with findings of a hospital-

based vitamin A dosing trial of newborns in Indonesia where

vitamin A (SO 000 IU) dramatically reduced mortality in the

better-nourished infants (16). One striking observation in the

present study (unrelated to vitamin A supplementation) is the

enormous potential impact that the elimination of wasting

malnutrition, reflected by a low MUAC, could have on reduc-

ing early infant mortality, an observation that has been repeat-

edly made in older children (10, 29, 30).

Adverse effects of vitamin A supplementation in the first 6

mo of life could not be predicted from the occurrence or

Effect of vitamin A on mortality of infants < 6 mo of age by allocation and midupper-arm circumference (MUAC) at time of dosing’

MUAC

Control Vitamin A .

Relative

risk 95% CIDeaths Child-y MR Deaths Child-y MR

< 1 Mo of age

< 8.5 cm8.5-10.4cm

� 10.5 cm

34

1110

1

257

25119

28

132

44488

36

38

108

2

268

26119

31

142

38567

64

1.07

0.870.80

1.76

(0.65, 1.76)

(0.36, 2.10)(0.29,2.21)

(0.13, 24.45)

1-3 Mo of age

<8.5cm

8.5-10.4 cm

10.5-12.4cm

� 12.5 cm

63

16

17

10

2

1351

42

283

619

234

47

376

60

16

9

83

16

26

18

8

1409

39

280

651

264

59

413

93

28

30

1.26

1.10

1.55

1.71

3.52

(0.88,1.80)

(0.54,2.25)

(0.80, 3.02)

(0.73,4.00)

(0.64, 19.42)

4-S Mo of age< 8.5 cm8.5-10.4 cm

10.5-12.4 cm

� 12.5 cm

33S

10

8

7

909S

37

304454

36

962

268

26

15

29

3

6

8

11

948

6

33

320

480

31

546

180

25

23

0.84

0.57

0.67

0.95

1.49

(0.49, 1.45)

(0.14, 2.33)

(0.23, 1.97)

(0.32, 2.79)

(0.52, 4.23)


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VITAMIN A AND EARLY INFANT MORTALITY 147

TABLE 4

Cause-associated mortality rates based on verbal autopsy for infants < 6 mo of age at dosing by allocation’

Associated cause

(n

Control2517 child-y)

Vitami(n = 2625

n A

child-y)Relative

risk 95% CIDeaths MR Deaths MR

Malnutrition 63 25.0 76 28.9 1.16 (0.81, 1.67)

ALRI2 SO 19.9 63 24.0 1.21 (0.81, 1.82)Diarrhea or dysentery 44 17.5 48 18.3 1.04 (0.66, 1.63)

Whooping cough S 2.0 6 2.3 1.15 (0.31, 4.26)Meningitis 9 3.6 0 - - - -

Sudden death 22 8.7 19 7.2 0.83 (0.42, 1.63)

Uncertain 25 9.9 30 11.4 1.15 (0.64, 2.06)

, Nonmutually exclusive causes of death assigned based on two independent physician-reviews of completed questionnaires with up to four causes being

assigned for each death based on a combination of predetermined algorithms, written history, and clinical judgment (RK Adhikari et al, unpublished

observations). Deaths that were sudden or were of uncertain cause exclude other causes. Excludes infant deaths for which none of the listed causes wereassigned (n = 2 control, n = S vitamin A). Total number of deaths was 130 in control group and 150 in vitamin A group.

2 Acute lower respiratory infection.

severity of acute side effects after receipt of vitamin A in this

population. A substudy of this trial revealed no acute side

effects attributed to receipt of a single, 15 000-RE supplement

in neonates and only infrequent, transient disturbances associ-

ated with receipt of 30 000 RE from 1 to 6 mo of age (0.5%

excess rate of transient, bulging fontanel and a 2% excess rate

of vomiting, unrelated to acute nutritional status) (19). Higher

transient side effect rates have been observed in young infants

given 15 000 RE at the time of each diptheria-pertussis-tetanus

vaccination (31).

Notwithstanding chance governing these observations,

mechanisms that could explain any increased risk in mortality

after receipt of a large dose of vitamin A are unclear. There

could be disruption of selective immune mechanisms. A mas-

sive dose of vitamin A given to chickens (1000 mg/kg body wt

on 150-200 times more than the dose given in this study on a

weight basis) reduced antibody production and proliferative

blast transformation responsiveness to a mitogen (32, 33),

which was associated with increased mortality (33). However,

immune enhancement was observed after administration of

vitamin A at 6-7 times the weight-adjusted dose in this trial

(32). Newborn piglets exhibited a reduced intracellular capac-

ity for their leukocytes to kill Escherichia coli within 3 wk of

being injected with 25 000-SO 000 IU (7500-15 000 RE) vita-

mm A palmitate. However, the dose of vitamin A improved

mitogen-induced lymphocyte proliferation (34), in accordance

with immune enhancement that appears to follow vitamin A

repletion of deficient animals (35) and older preschool children

(36-38).

In summary, this trial has not revealed any short-term (4-mo)

apparent survival benefit of directly supplementing infants

< 5-6 mo of age with 30 000 RE (100 000 IU) vitamin A,

although the results do not challenge recommendations that

older infants, 6-11 mo of age, be given this amount (39) to

reduce mortality where vitamin A deficiency is a public health

concern (4, 5). It also suggests that infants as young as 4-S mo

may benefit from vitamin A supplementation, with an effect

comparable with that in older infants (9-1 1). Infants < 4 mo of

age receiving � 30 000 RE as a single bolus may be disadvan-

taged, especially those who are less wasted. On the other hand,

a smaller dosage (15 000 RE) given within 24 h after birth (16)

on provided physiologically through vitamin A-enriched breast

milk from mothers who are supplemented with vitamin A

shortly after they give birth may enhance vitamin A status (40)

and survival (41) during the first year of life. These approaches

can also reach more high-risk infants (as peninates) in contrast

with periodic, one-time delivery as carried out in the present

study, which missed dosing =80% of all infants who died < 6

mo (92% < 2 mo) of age because they were born and died

between dosing rounds (KP West, 5K Khatry, J Katz, SC

LeClenq, L Wu, EK Pradhan, SR Shrestha, unpublished data,

1995). The diverse outcomes of this and other studies suggest

that much more research is needed to understand the effects of

improved vitamin A nutniture on early infant survival. A

We thank Y Vaidya and KB Shrestha at the Nutrition Section of the

Central Food Research Laboratory in Kathmandu for carrying out potency

analyses of study supplements.

REFERENCES

1. Humphrey JH, West KP Jr. Sommer A. Vitamin A deficiency andattributable mortality among under-S-year-olds. Bull World Health

Organ 1992;70:225-32.

2. International Conference on Nutrition. World declaration and plan of

action for nutrition. Rome: FAO and WHO, 1992.

3. Sommer A. Nutritional blindness: xerophthalmia and keratomalacia.

New York: Oxford University Press, 1982.4. West KP Jr (rapporteur). Proceedings of Public Health Significance of

Vitamin A Deficiency and its Control, Bellagio Study and Conference

Center of the Rockefeller Foundation, February 3-7, 1992. New York:Helen Keller International, 1993.

S. Beaton GH, Martorell R, Aronson KI, et al. Effectiveness of vitamin

A supplementation in the control of young child morbidity and mor-

tality in developing countries. ACC/SCN State-of-the-Art Series Nu-

trition Policy Discussion Paper no. 13. Geneva: World Health Orga-

nization, 1993.

6. Ghana VAST Study Team. Vitamin A supplementation in northernGhana: effects on clinic attendances, hospital admissions and childmortality. Lancet 1993;342:7-12.

7. Sommer A, Tarwotjo I, Djunaedi E, et al. Impact of vitamin A

supplementation on childhood mortality. A randomized controlled

community trial. Lancet 1986;1:1 169-73.8. Muhilal, Permeisih D, Idjradinata YR. Muherdiyantiningsih, Karyadi

D. Vitamin A-fortified monosodium glutamate and health, growth, andsurvival of children: a controlled field trial. Am I Clin Nutr 1988;48:

1271-6.


ajcn.nutrition.orgD

ownloaded from



148 WEST El AL

9. Rahmathullah L, Underwood BA, Thulasiraj RD. et al. Reduced mor-

tality among children in Southern India receiving a small weekly dose

of vitamin A. N Engl I Med 1990;323:929-3S.10. West KP Ir, Pokhrel RP, Katz I, et al. Efficacy of vitamin A in

reducing preschool child mortality in Nepal. Lancet 1991;338:67-71.1 1. Daulaire NMP, Starbuck ES, Houston RM, Church MS. Stukel TA,

Pandey MR. Childhood mortality after a high dose of vitamin A in ahigh risk population. Br Med I 1992;304:207-10.

12. Vijayaraghavan K, Radhalah G, Surya Prakasam BS, Rameshwar

Sarma Ky, Reddy V. Effect of massive dose vitamin A on morbidityand mortality in Indian children. Lancet 1990;2:1342-5.

13. Herrera MG, Nestel P. El Amin A, Fawzi WW, Mohamed Kit, Weld

L. Vitamin A supplementation and child survival. Lancet 1992;340:267-71.

14. Fawzie WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin Asupplementation and child mortality: a meta-analysis. JAMA 1993;

269:898-903.

15. Glasziou PP, Mackerras DEM. Vitamin A supplementation in infec-

tious diseases: a meta-analysis. Br Med I 1993;306:366-70.

16. Humphrey I, Agoestina T, Taylor G, Usman A, West KP Jr. Sommer

A. Acute and long term risks and benefits to neonates of 50,000 lU oralvitamin A. Report of the 16th IVACG Meeting, Chiang Rai, Thailand,

October 24-28, 1994. Washington, DC: The Nutrition Foundation,1995.

17. Pradhan EK, Katz I, LeClerq SC, West KP Jr. Data management for

large community trials in Nepal. Control Clin Trials 1994;15:220-34.18. Pokhrel RP, Khatry 5K, West KP Ir, et al. Sustained reduction in child

mortality due to vitamin A in Nepal. Lancet 1994;343:1368-9.

19. West KP Jr. Khatry 5K, LeClerq SC, et al. Tolerance of young infantsto a single, large dose of vitamin A: a randomized community trial in

Nepal. Bull World Health Organ 1992;70:733-9.

20. Zerfas AJ. The insertion tape: a new circumference tape for use in

nutritional assessment. Am I Clin Nutr 197S;28:782-7.

21. Katz D, Baptista I, Azen SP, Pike MC. Obtaining confidence intervals

for the risk ratio in cohort studies. Biometrics 1978;34:469-74.

22. Katz I, Zeger SL. Estimation of design effects in cluster surveys. Ann

Epidemiol l994;4:295-301.

23. Khatry 5K, West KP Jr. Katz I, et al. Epidemiology of xerophthalmiain Nepal: a pattern of household poverty, childhood illness and mor-

tality. Arch Ophthalmol 199S;113:425-9.24. Tarwotjo I, Sommer A, Soegiharto T. Dietary practices and xeroph-

thalmia among Indonesian children. Am I Clin Nutr 1982;3S:S74-81.25. West KP, Chirambo M, Katz I, Sommer A. Breast-feeding, weaning

patterns, and the risk of xerophthalmia. A case-control study in South-ern Malawi. Am I Clin Nutr 1986;44:690-7.

26. Mahalanabis D. Breast feeding and vitamin A deficiency among

children attending a diarrhoea treatment centre in Bangladesh: a case-

control study. Br Med I 1991;303:493-6.

27. Pathwardan VN, Kamel WW, Pharaon H. Studies on vitamin A

deficiency in infants and young children in Jordan. Part II. A pilot trial

of vitamin A prophylaxis in Jordanian infants (February, 1965-

August, 1966). Geneva: Public Health Service Research/World Health

Organization, 1966.

28. Clausen SW. The effects of moderate deficiency of vitamins. Bull N Y

Acad Med 1934;10:471-82.

29. Sommer A, Loewenstein M. Nutritional status and mortality. A pro-

spective validation of the QUAC stick. Am I Clin Nutr 1975;28:287-

92.

30. Pelletier DL. The relationship between child anthropometry and mor-

tality in developing countries: implications for policy, programs and

future research. I Nutr 1994;124:2047S-81S.

31. de Francisco A, Chakraborty I, Chowdhury HR, et al. Acute toxicity

of vitamin A given with vaccines in infancy. Lancet 1993;342:S26-7.

32. Friedman A, Sklan D. Antigen-specific immune response impairment

in the chick as influenced by dietary vitamin A. I Nutr 1989;119:

790-S.

33. Friedman A, Meidovsky A, Leitner G, Sklan D. Decreased resistance

and immune response to Eschermchia co/i infection in chicks with low

or high intakes of vitamin A. I Nutr 1991;121:39S-400.

34. Hoskinson CD, Chew BP, Wong TS. Effects of injectable /3-carotene

and vitamin A on lymphocyte proliferation and polymorphonuclear

neutrophil function in piglets. Biol Neonate 1992;62:32S-36.

35. Ross AC. Vitamin A status: relationship to immunity and the antibody

response. Proc Soc Exp Biol Med 1992;200:303-20.

36. Semba RD. Muhilal, Scott AL, et al. Depressed immune response to

tetanus in children with vitamin A deficiency. I Nutr 1992;122:101-7.

37. Semba RD, Muhilal, Ward BI, et al. Abnormal T-cell subset propor-

tions in vitamin-A-deficient children. Lancet 1993;341:S-8.

38. Coutsoudis A, Kiepiela P, Coovadia HM, Broughton M. Vitamin A

supplementation enhances specific IgG antibody levels and total lym-

phocyte numbers while improving morbidity in measles. Pediatr Infect

Dis I 1992;11:203-9.

39. WHOIUNICEF/IVACG Task Force. Vitamin A supplements. A

guide to their use in the treatment and prevention of vitamin A

deficiency and xerophthalmia. Geneva: World Health Organization,

1988.

40. Stoltzfus RI, Hakimi M, Miller KW, et al. High dose vitamin A

supplementation of breast feeding Indonesian mothers: effects on the

vitamin A status of mother and infant. I Nutr 1993;123:666-7S.

41. de Francisco A, Yasin Y, Chakraborty I. Vitamin A supplementation

given to mothers after delivery reduces infant mortality and increased

symptoms of morbidity. Report of the 16th IVACG Meeting, Chiang

Rai, Thailand, October 24-28, 1994. Washington, DC: The Nutrition

Foundation, 1995.


ajcn.nutrition.orgD

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