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

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The effect of supplementing 11,918 infants < 1 mo and 1-5 mo of age with vitamin A (15,000 and 30,000 micrograms retinol equivalents or 50,000 and 100,000 IU, respectively) or a placebo on subsequent 4-mo mortality was assessed in a randomized, 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 1.11 (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 distribution 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.
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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 with
vitamin 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.
2This 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.
3The Sarlahi Study Group (in addition the authors) included BD
Chataut, 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.
4Address 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.
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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
Smo 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 Kscones (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)
Age2
0 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)
Smo 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 <6
mo of age entered the trial at visit 1; 4507 and 4671 infants, respectively,
4 mo of age entered the trial at visits 2-6.
2A 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.
3The total number and percent of infants for whom a 1-wk morbidity
history or baseline arm circumference were obtained.
4The 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 Smo 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 7y 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
. IfDff If if
RR=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 mo
of age at dosing by treatment group with duration of trial. (0) control, (#{149})
vitamin A.
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146 WEST El AL
IExcludes 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
5Mo
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)
1Infants <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 cm
8.5-10.4cm
10.5 cm
34
11
10
1
257
25
119
28
132
444
88
36
38
10
8
2
268
26
119
31
142
385
67
64
1.07
0.87
0.80
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
188
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 cm
8.5-10.4 cm
10.5-12.4 cm
12.5 cm
33
S
108
7
909S
37
304
454
36
962
268
26
15
29
3
6
8
11
9486
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 Control
2517 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 were
assigned (n = 2 control, n= S vitamin A). Total number of deaths was 130 in control group and 150 in vitamin A group.
2Acute 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.
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... Figure 1 shows the results of literature search. We included sixteen studies for vitamin A supplementation [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], thirty three studies in probiotics supplementation and no study was found for dextrose gel supplementation. ...
... Three trials had multiple arms of interventions [24,25,31]. The included studies were conducted in 10 different countries with 4 studies in India [29,33,34,37], 3 studies conducted in Guiana Bissau [23][24][25], 2 studies in Bangladesh [28,30] and one each in Indonesia [27], Nepal [36], Ghana [26], Tanzania [32], Zimbabwe [31], China [35] and Pakistan [22]. Thirteen studies were conducted in the community settings while three Nutrients 2020, 12, 791 6 of 21 studies were conducted in the hospital settings and included very low birth weight babies [29,35,37]. ...
... Overall, all the included studies were randomized controlled trials. Thirteen studies were individually randomized [23][24][25][26][27][28][29][31][32][33][34][35]37] and 3 studies were cluster-randomized [22,30,36]. Three trials had multiple arms of interventions [24,25,31]. ...
Article
Full-text available
Background: Suboptimal nutritional status of a newborn is a risk factor for short- and long-term morbidity and mortality. The objectives of this review were to assess the efficacy and effectiveness of neonatal synthetic vitamin A supplementation, dextrose gel and probiotic supplementation for prevention of morbidity and mortality during infancy in low and middle-income countries. Methods: We included randomized trials. Primary outcome was all-cause mortality. We conducted electronic searches on multiple databases. Data were meta-analyzed to obtain relative risk (RR) and 95% confidence interval (CI). Studies for vitamin A and Probiotics were analyzed separately. No studies were found for dextrose gel supplementation during neonatal period. The overall rating of evidence was determined by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Sixteen studies assessed the effect of vitamin A supplementation during the neonatal period. Based on pooled data from community-based studies only, there was no significant effect of vitamin A on all-cause mortality at age 1 month (RR 0.99, 95% CI 0.90, 1.08), 6 months (RR 0.98; 95% CI 0.89–1.08) and 12 months (RR 1.04, 95% CI 0.94, 1.14) but increased risk of bulging fontanelle (RR 1.53, 95% CI 1.12, 2.09). The overall quality of evidence was high for the above outcomes. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period and were mostly conducted in the hospital setting. Probiotics reduced the risk of all-cause mortality (RR 0.80, 95% CI 0.66, 0.96), necrotizing enterocolitis (RR 0.46, 95% CI 0.35, 0.59) and neonatal sepsis (RR 0.78, 95% CI 0.70, 0.86). The grade ratings for the above three outcomes were high. Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in low and middle-income countries in the community setting. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born low birth weight and/or preterm in the hospital setting.
... Following a randomized trial from Indonesia, showing a beneficial effect of neonatal vitamin A supplementation (NVAS) [4], several other NVAS trials were carried out in Asia and Africa. By 2008, six trials had been conducted [4][5][6][7][8][9][10], showing mixed results. Three trials, in Indonesia [4], India [7], and Bangladesh [8], showed reduction in mortality. ...
... Three trials, in Indonesia [4], India [7], and Bangladesh [8], showed reduction in mortality. Three other trials conducted in Nepal [10], Zimbabwe [5,6] and Guinea-Bissau [9] found no effect or a tendency for negative effects. ...
... Individual or cluster randomized trials assessing the effect of early NVAS (25,000-50,000 IU intended to be given within the first 2-3 days of life) compared with placebo, with follow-up through at least 6 months of age, were eligible. In addition, we included the Nepal trial [10], which provided NVAS within the first month of life and followed children for 4 months, and which was one of the original six trials assessed at the technical consultation in 2008 [11]. ...
Article
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A total of 12 trials have tested the effect of neonatal vitamin A supplementation (NVAS) on mortality. Overall, NVAS had no effect on mortality, but results were heterogeneous. Two competing hypotheses have been put forward to explain the divergent effects: A) NVAS works by preventing vitamin A deficiency (VAD) and not all countries have VAD; B) NVAS interacts negatively with subsequent diphtheria-tetanus-pertussis (DTP) vaccine, increasing mortality in females; in countries with low DTP coverage NVAS may have a beneficial effect. Only hypothesis A was tested in a recent meta-analysis; there is no strong empirical support for hypothesis A and it would not explain observed negative effects in some settings. Hypothesis B accounts for most observations. However, so far it has only been tested properly in a few trials. If hypothesis B is correct, it has major consequences for the understanding of the effects of vitamin A, and for the VAS policy in older children. As a WHO priority, the DTP coverage is bound to increase, and therefore hypothesis B urgently needs to be tested.
... Sixteen studies reported in 45 publications assessed the effect of neonatal vitamin A supplementation Basu et al., 2019;Benn et al., 2008Benn et al., , 2010Benn et al., , 2014Edmond et al., 2015;Giridhar et al., 2019;Humphrey et al., 1996;Klemm et al., 2008;Malaba et al., 2005;Masanja et al., 2015;Mazumder et al., 2015;Rahmathullah et al., 2003;Soofi et al., 2017;Sun et al., 2019;West et al., 1995). These studies included a total of about 16,366 participants. ...
... All the included studies were RCTs. Thirteen studies were individually randomized Basu et al., 2019;Benn et al., 2008Benn et al., , 2010Benn et al., , 2014Edmond et al., 2015;Giridhar et al., 2019;Humphrey et al., 1996;Malaba et al., 2005;Masanja et al., 2015;Mazumder et al., 2015;Rahmathullah et al., 2003), and three studies were cluster-randomized (Klemm et al., 2008;Soofi et al., 2017;Sun et al., 2019;West et al., 1995). Three trials had multiple arms of interventions Malaba et al., 2005). ...
Article
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Background The last two decades have seen a significant decrease in mortality for children <5 years of age in low and middle‐income countries (LMICs); however, neonatal (age, 0–28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs. Objectives To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period. Search Methods We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019. Selection Criteria We aimed to include randomized and quasi‐experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate. Data Collection and Analysis Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all‐cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta‐analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main Results Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low‐ and middle‐income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea‐Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all‐cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90–1.08; six studies with 126,548 participants, statistical heterogeneity I² 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89–1.07; 12 studies with 154,940 participants, statistical heterogeneity I² 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94–1.14; eight studies with 118,376 participants, statistical heterogeneity I² 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12–2.09; six studies with 100,256 participants, statistical heterogeneity I² 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty‐three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born < 37 weeks gestation) and/or low birth weight (<2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all‐cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66–0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I² 0%, funnel plot symmetrical, GRADE quality high). Twenty‐nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35–0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I² 24%, funnel plot symmetrical, GRADE quality high). Twenty‐one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70–0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I² 23%, funnel plot symmetrical, GRADE quality high). Authors' Conclusions Vitamin A supplementation during the neonatal period does not reduce all‐cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi‐experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all‐cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in‐home/community setting in LMICs.
... MUAC was surprisingly less predictive of mortality than either chest or head circumference, given a low MUAC (<9.0 cm) at birth has been shown to be comparable to low birth weight in predicting neonatal mortality in India (16) and Guatemala (17). Furthermore, in Nepal, MUAC measured throughout early infancy (45) and the preschool years (46) has been strongly associated with the risk of mortality. However, none of these studies compared the predictiveness of MUAC with other concurrently assessed circumferential measurements. ...
Article
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Background: Low birth weight predicts risk of infant death. However, several birth measurements may be equally predictive, for which cutoffs and associated risks are less explored. Objectives: We assessed and optimized population cut-offs of birth length, weight, and mid-upper arm (MUAC), head (HC) and chest (CC) circumferences for predicting neonatal (≤28 days) and infant (≤365 days) mortality in northwest Bangladesh. Design: Among 28,026 singletons born in an antenatal micronutrient supplement trial, 21,174 received anthropometry ≤ 72 hours after birth, among whom 583 died in infancy. Optimization for predicting mortality for each measurement was guided by the Youden Index (sensivity + specificity-1). Relative Risk Ratios (RRR) and positive predictive values (PPV) were calculated across cut-off ranges for individual, and any pair of, measurements. Results: Optimal cutoffs, harmonized to 100 g or 0.5 cm readings, for neonatal and infant mortality were 44.5 cm for length, 2200 g for weight, 9.0 cm for MUAC, 31.0 cm for HC, and for 28.5 cm CC, below which all predicted mortality. However, a CC < 28.5 cm, alone and combined with HC < 31.0 cm, yielded highest RRR [9.68 (95% CI:7.84, 11.94) and 15.74 (95% CI:12.54, 19.75), respectively] and PPV (11.3% and 10.7%) for neonatal mortality and highest RRR [6.02 (95% CI:5.15, 7.02) and 9.19 (95% CI:7.72, 10.95)] and PPV (16.3% and 14.5%) for infant mortality. Pairs of measurements revealed higher RRR for neonatal and infant mortality than individual measurements of any one pair, although the ranges of PPV remained comparable. Conclusions: In Bangladesh, multiple birth measurements alone or in combination, and particularly, chest circumference, predict neonatal and infant mortality.
... The WHO therefore recommend largescale VA supplementation for children under 5 years of age to improve child survival (22). However, the outcomes for VA supplementation in children younger than 6 months range from no benefit to potentially beneficial or even potentially harmful in previous studies (31)(32)(33)(34). There is wide disagreement throughout the world on the appropriate policy for neonatal VA supplementation (19). ...
Article
Full-text available
Objectives: This study aimed to explore the changes in infant vitamin A (VA) status and the effect of early VA supplementation on VA level throughout the first 6 months of life. Methods: A prospective cohort study was conducted in Chongqing, China. A total of 1,016 healthy infants were enrolled at birth. Then, 930, 882, 854 and 822 healthy infants were followed up at postnatal day 7 and postnatal months 1, 3, and 6, respectively. Blood samples and dietary survey and physical development data were collected. Serum VA was measured by chromatography tandem-mass spectrometry and was classified according to the VA deficiency (VAD) criteria for older children aged 6–70 months (<0.70, 0.70–1.05, ≥1.05 μmol/L). Normally distributed continuous variables are presented as the mean ± standard deviation. The categorical variables are described by the frequency and percentage (%). The reference interval for the VA level was the 2.5th−97.5th percentile. Changes in VA status with age and the relationship of VA supplementation with VA level were investigated by generalized estimating equations followed by Bonferroni post hoc test, controlling for the effects of feeding pattern and sex. Results: Infant VA levels increased significantly from 0.499 ± 0.146 to 1.061 ± 0.414 μmol/L with age at 6 months, even without VA supplementation ( P < 0.05). From birth to 6 months, the percentage of infants with a VA level <0.70 μmol/L decreased from 88.6 to 19.5%. During follow-up, no infant demonstrated clinical VAD conditions, such as night blindness, conjunctival xerosis or Bitot's spots. Less than 7.0% of infants were underdeveloped in terms of weight, length and head circumference. The VA status of infants with VA≥0.588 μmol/L at birth gradually increased to adequate VA (VA ≥ 1.05 μmol/L) at 6 months. For these infants, there was no significant difference in VA level between the VA supplementation and non-supplementation groups ( P > 0.05). Infants with VA <0.430 μmol/L at birth still had VA <0.70 μmol/L at 6 months; in this group, VA levels increased by 0.08 μmol/L more among supplemented infants than among non-supplemented infants ( P < 0.05). Conclusions: A low VA level among neonates at birth may be a normal physiological state and may increase with age; thus, not all neonates may need early VA supplementation. More multicenter studies are needed to determine a new cutoff point for the diagnosis of neonatal VAD and the administration of nutritional intervention.
... However, there have been contrasting results of NVAS on infant mortality. Trials in Indonesia (23), India (24), and Bangladesh (25) demonstrated a reduction in infant mortality (15-64%), yet trials in Nepal (26), Zimbabwe (27), and Guinea-Bissau (28,29) had no effect on infant mortality (8). Three additional trials were carried out in India (30), Ghana (31), and Tanzania (32) that demonstrated no impact on infant mortality, but in India there was a borderline significant reduction in mortality at 6 mo with NVAS (RR: 0.90, 95% CI: 0.81-1.00, ...
Article
Full-text available
A systematic review was conducted to summarize the absorption, transport, storage, and metabolism of oral neonatal vitamin A supplementation (NVAS). This review focused specifically on the neonatal period (first 28 d of life for humans) to inform guidance by WHO on recommendations related to NVAS. A systematic search of international and regional databases was conducted. Inclusion criteria were human or animal studies that gave oral vitamin A as a single or limited number of doses to apparently healthy neonates. Studies evaluating fortification or food-based approaches, dosing with retinoic acid, or studies of neonatal models of disease were excluded. The search retrieved 8847 unique records. After screening by title and abstract, 88 were screened using the full text, and 35 records met inclusion criteria: 13 human and 22 animal studies. Studies indicate that high-dose NVAS is absorbed well by neonates, typically mirroring fat absorption. Doses were primarily stored in the liver and transiently increased in the lung, kidney, spleen, adrenal glands, brain, skin, and adipose tissue, generally with a dose-response. Serum retinol and retinyl esters also transiently increased following NVAS. Although minimal acute adverse effects are noted, there is a lack of data supporting NVAS for improving organ maturation or sustained delivery to target organs. Research gaps include the physiological effects of the short-term increase of vitamin A concentrations in extrahepatic tissues, or whether there are unknown adverse effects over time.
... 13 While the link between these immunological markers and subsequent mortality remains to be understood, the results support long-lasting interaction between NVAS, DTP and sex with respect to immune function. Table 1 summarises the key observations from the now 11 NVAS trials 5 7-9 14-21 (excluding a small trial from Nepal, which did not include children immediately after birth 22 ). ...
Article
Environmental disasters have increased in frequency and intensity as a result of climate change. Can timely intervention help protect against the health impacts of these disasters? We study this question by leveraging data from a double-blind cluster-randomized controlled trial of at-birth vitamin A supplementation, which boosts immune system functioning, in Bangladesh. During the trial, a large tornado swept through the study area, affecting both treatment and control clusters. Tornado exposure in infancy decreased physical growth and increased the incidence of severe fevers. But infants who received supplementation were protected from these negative effects.
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Micronutrient deficiencies continue to be widespread among children under-five in low- and middle-income countries (LMICs), despite the fact that several effective strategies now exist to prevent them. This kind of malnutrition can have several immediate and long-term consequences, including stunted growth, a higher risk of acquiring infections, and poor development outcomes, all of which may lead to a child not achieving his or her full potential. This review systematically synthesizes the available evidence on the strategies used to prevent micronutrient malnutrition among children under-five in LMICs, including single and multiple micronutrient (MMN) supplementation, lipid-based nutrient supplementation (LNS), targeted and large-scale fortification, and point-of-use-fortification with micronutrient powders (MNPs). We searched relevant databases and grey literature, retrieving 35,924 papers. After application of eligibility criteria, we included 197 unique studies. Of note, we examined the efficacy and effectiveness of interventions. We found that certain outcomes, such as anemia, responded to several intervention types. The risk of anemia was reduced with iron alone, iron-folic acid, MMN supplementation, MNPs, targeted fortification, and large-scale fortification. Stunting and underweight, however, were improved only among children who were provided with LNS, though MMN supplementation also slightly increased length-for-age z-scores. Vitamin A supplementation likely reduced all-cause mortality, while zinc supplementation decreased the incidence of diarrhea. Importantly, many effects of LNS and MNPs held when pooling data from effectiveness studies. Taken together, this evidence further supports the importance of these strategies for reducing the burden of micronutrient malnutrition in children. Population and context should be considered when selecting one or more appropriate interventions for programming.
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Vitamin A deficiency increases susceptibility to skin infection. However, the mechanisms by which vitamin A regulates skin immunity remain unclear. Here, we show that resistin-like molecule a (RELMa), a small secreted cysteine-rich protein, is expressed by epidermal keratinocytes and sebocytes and serves as an antimicrobial protein that is required for vitamin-A-dependent resistance to skin infection. RELMa was induced by microbiota colonization of the murine skin, was bactericidal in vitro, and was protected against bacterial infection of the skin in vivo. RELMa expression required dietary vitamin A and was induced by the therapeutic vitamin A analog isotretinoin, which protected against skin infection in a RELMa-dependent manner. The RELM family member Resistin was expressed in human skin, was induced by vitamin A analogs, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings provide insight into how vitamin A promotes resistance to skin infection.
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