Vit A

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
original article
Maternal Vitamin A Supplementation

and Lung Function in Offspring
William Checkley, M.D., Ph.D., Keith P. West, Jr., Dr.P.H., Robert A. Wise, M.D.,
Matthew R. Baldwin, M.D., Lee Wu, M.H.S., Steven C. LeClerq, M.H.S.,
Parul Christian, Dr.P.H., Joanne Katz, Sc.D., James M. Tielsch, Ph.D.,
Subarna Khatry, M.D., and Alfred Sommer, M.D., M.H.S.
A bs t r ac t
Background
From the Division of Pulmonary and Critical Care, School of Medicine (W.C.,
R.A.W., M.R.B.), the Program in Global
Disease Epidemiology and Control (W.C.,
J.K., J.M.T.) and the Center for Human
Nutrition (K.P.W., L.W., S.C.L., P.C., J.K.,
J.M.T.), Department of International
Health, and the Department of Epidemiology (A.S.), Bloomberg School of Public
Health, Johns Hopkins University, Baltimore; and the Nepal Nutrition Intervention Project Sarlahi, National Society for
the Prevention of Blindness, Kathmandu,
Nepal (S.C.L., S.K.). Address reprint requests to Dr. Checkley at Johns Hopkins
University School of Medicine, Division
of Pulmonary and Critical Care, 1830
Monument St., 5th Fl., Baltimore, MD
21205, or at wcheckl1@jhmi.edu.
This article (10.1056/NEJMoa0907441) was
last updated on December 29, 2010, at
NEJM.org.
N Engl J Med 2010;362:1784-94.
Copyright 2010 Massachusetts Medical Society.
Vitamin A is important in regulating early lung development and alveolar formation. Maternal vitamin A status may be an important determinant of embryonic
alveolar formation, and vitamin A deficiency in a mother during pregnancy could
have lasting adverse effects on the lung health of her offspring. We tested this hypothesis by examining the long-term effects of supplementation with vitamin A or
beta carotene in women before, during, and after pregnancy on the lung function
of their offspring, in a population with chronic vitamin A deficiency.
Methods
We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers

had participated in a placebo-controlled, double-blind, cluster-randomized trial of
vitamin A or beta-carotene supplementation between 1994 and 1997.
Results
Of 1894 children who were alive at the end of the original trial, 1658 (88%) were
eligible to participate in the follow-up trial. We performed spirometry in 1371 of the
children (83% of those eligible) between October 2006 and March 2008. Children
whose mothers had received vitamin A had a forced expiratory volume in 1 second
(FEV1) and a forced vital capacity (FVC) that were significantly higher than those of
children whose mothers had received placebo (FEV1, 46 ml higher with vitamin A;
95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to
84), after adjustment for height, age, sex, body-mass index, calendar month, caste,
and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV1 and FVC values that were similar to those of children whose
mothers had received placebo (FEV1, 14 ml higher with beta carotene; 95% CI, 24 to
54; FVC, 17 ml higher with beta carotene, 95% CI, 21 to 55).
Conclusions
In a chronically undernourished population, maternal repletion with vitamin A at

recommended dietary levels before, during, and after pregnancy improved lung function in offspring. This public health benefit was apparent in the preadolescent years.
1784
n engl j med 362;19 nejm.org may 13, 2010
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Maternal Vitamin A Supplementation and Lung Function in Offspring
itamin A deficiency affects 190 million preschool-aged children and 19 million pregnant women worldwide.1 It is the
underlying cause of 650,000 early childhood
deaths2 and has become recognized as an important problem among women of reproductive age
in many developing countries. Chronic vitamin A
deficiency may increase the risks of complications
and death during pregnancy and in the postpartum period3-9 and, on the basis of evidence from
studies in animals, may also adversely affect the
embryonic and postnatal development of the offspring.10-14
The importance of vitamin A in regulating
growth through cell proliferation and differentiation was recognized early in the 20th century.10-12
Results from animal research have since shown
that vitamin A plays a key role in mediating fetal
growth, morphogenesis, and maturation of multiple organ systems, including the respiratory system.14-20 Depletion of vitamin A from the diet of
female rats before and during pregnancy is associated with agenesis or hypoplasia of the lungs in
offspring, conditions that can be prevented with
vitamin A supplementation in early, but not late,
pregnancy.14 Furthermore, vitamin A depletion
in pregnant rats has been associated with dosedependent decreases in DNA content in the lung
tissue of their offspring.17,18
Since alveolarization begins in utero at about
the 36th week of gestation,21 maternal vitamin
A deficiency during pregnancy may have lasting
effects on the lung maturation of progeny. Although results from studies in animals have
shown that vitamin A is an important determinant of early lung development and size, data are
lacking on the long-term consequences of vitamin A deficiency on lung health in human populations. We studied the effect of antenatal vitamin A supplementation on the lung function of
preadolescent children in a chronically undernourished population in rural Nepal. The study cohort consisted of children, 9 to 13 years of age,
whose mothers had participated in a randomized,
placebo-controlled trial of vitamin A or beta-carotene supplementation before, during, and after
pregnancy.
ern Nepal, in the densely populated, low-lying

southern plains (Terai). The weather is usually
warm and humid in this region, with temperatures exceeding 40C in the hot, dry season (April
through June), followed by a season of monsoon
rains (July through October), and thereafter by a
cooler, dry season (November through March).
The Terai is an area of chronic undernutrition and
vitamin A deficiency.22,23 Rice is the staple of the
diet. It is supplemented with small amounts of
seasonal fruits, vegetables, lentil soup, and occasionally meat, fish, and eggs.
Original Vitamin A Trial
The original study, which was conducted between

April 1994 and September 1997, was a doubleblind, placebo-controlled, cluster-randomized trial involving married women of childbearing age.
The study was designed to determine the effects
of weekly supplementation with a low dose of
vitamin A or beta carotene on the rates of maternal death related to pregnancy.7 We invited all
eligible women from 30 village development communities (VDCs) to participate in the trial. Each
VDC is composed of 9 wards (for a total of 270
wards). The unit of block randomization was the
ward, and each ward within a VDC was randomly
assigned to one of the three study groups. A total
of 44,646 women were enrolled and received
weekly supplementation with 7000-g retinolequivalents of vitamin A, 7000-g retinol-equivalents of beta carotene, or placebo. Both supplements, as well as the placebo, were given in the
form of gelatinous capsules taken orally. A total
of 75% of the pregnant women received at least
half the allowable dose (i.e., 50% of a dietary
allowance in the case of those receiving vitamin
A or beta carotene).7 We prospectively identified
all pregnant women and followed the mothers
and their infants for an assessment of vital status
and health outcomes. Supplementation with vitamin A or beta carotene resulted in a reduction in
the rates of maternal death related to pregnancy,
from 704 per 100,000 pregnancies in the placebo
group to 395 per 100,000 pregnancies in the combined vitamin Abeta-carotene groups (a 44%
relative reduction with the supplements).7 Neither
supplement had an effect on infant mortality.24
We enrolled a subgroup of pregnant women and
Me thods
their live-born infants from three VDCs (27 of the
Study Setting
270 wards) in a substudy with a more detailed
We conducted the original vitamin A trial and this protocol that involved interviews about illnesses,
follow-up study in the Sarlahi District of south- diet, and other exposures; collection of blood

1785
The
samples at mid-pregnancy and at 3 months post

partum; clinical examinations; and anthropometric measurements. Serum retinol levels, assessed
in the women post partum and in their infants at
3 months of age, were higher in the vitamin A
group than in the placebo group and were moderately higher in the beta-carotene group than in the
placebo group.7,24 A total of 2055 children were
born alive to mothers in the subsample who completed the pregnancy-to-postpartum dosing protocols. Of these children, 1894 (92%) were alive at
the end of the trial (September 30, 1997).
Enrollment in the Follow-up Study
In 2006, we revisited the households of children

whose mothers had participated in the original
subsample study. Fieldworkers were unaware of
the group assignments of the mothers in the original study. We used a household list derived from
the original trial to generate an updated list of
children who were eligible to participate in the
follow-up study. Households in which the children
were absent at the time of the visit were visited up
to three times to maximize enrollment. The follow-up study was approved by the institutional review board at the Johns Hopkins University in
Baltimore and at the Institute of Medicine, Tribhuvan University, in Kathmandu. We obtained oral
or written informed consent from the mothers
and assent from the children.
Spirometric Assessments
The objective of the follow-up trial was to determine whether there were differences in the forced
expiratory volume in 1 second (FEV1) and forced
vital capacity (FVC) among children according to
the group assignment of their mothers in the
original trial. We used 20 SpiroPro (JAEGER)
spirometers during the study period. SpiroPro is
a lightweight, battery-operated, portable pneumo
tachometer with factory-precalibrated pneumo
tachometer tubes. We used only one pneumotach
ometer tube per participant.
During a 6-month period before the start of
the study, we trained 11 technicians and 3 supervisors in the performance of spirometry. We numbered all our spirometers and asked technicians
to use a different spirometer each day. Technicians visited the study children at their homes to
perform spirometry. Each child underwent spirometry while in a sitting position and wearing a
nose clip, until three acceptable and reproducible
maneuvers, of a maximum of eight, had been per1786
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m e dic i n e
formed.25 Technicians reviewed with a supervisor

all the flow-volume curves that were obtained each
day. Flow-volume curves were transmitted weekly
to Johns Hopkins University for additional review.
Approximately every 3 months, we performed direct supervision and in-person review of all flowvolume curves with each technician.
Statistical Analysis
The values for FEV1 and FVC were adjusted for

height, age, sex, body-mass index, calendar month,
and caste. Because biases can occur among different spirometers, we also adjusted for the specific
spirometer that was used for the measurement.
All analyses were performed according to the intention-to-treat principle. Because clustering by
ward or VDC may have affected the estimation of
standard errors, we used a linear mixed-effects
model26 with two levels of random effects VDC
and ward within VDC to account for the multilevel design of the trial. In subgroup analyses,
we examined whether socioeconomic indicators
or early exposures confounded the effects of the
mothers original study-group assignment on lung
function.
In a subgroup of mothers in whom serum
retinol levels or serum beta-carotene levels were
measured post partum, we examined the relationship between the postpartum levels of these micronutrients in the mothers and the lung function of their preadolescent children. We compared
proportions across study groups and according to
enrollment status, using standard methods.27
P values of less than 0.05 were considered to
indicate statistical significance. We used the
R statistical package (www.r-project.org) for
analyses.
R e sult s
Characteristics of the Study Population
The status of the 2055 live-born children from the

original subsample is summarized in Figure 1.
Of the 1894 children who were alive at the end of
the original trial, 118 (6%) were no longer living
in the study area at the time of the follow-up study,
and 110 (6%) had died. No information was available for eight children (<1%). A total of 1658 children were eligible to participate, and 1371 (83%
of those eligible) underwent spirometry between
October 2006 and March 2008. We did not find
significant differences between study groups in
the mean proportions of children who died be-

5819 Women in 27 wards were recruited

and underwent randomization
2031 Women (885 pregnancies)

in 9 wards were assigned
to receive beta carotene

to receive placebo

to receive vitamin A
738 Live-born children
57 Died on or before
Sept. 30, 1997
43 Died after Sept. 30,
1997
46 Moved
1 Vital status unknown
591 Were living in study area

at time of follow-up study
Sept. 30, 1997
1997
28 Moved

103 Could not be

contacted
2 Status unknown
5 Declined
481 Underwent spirometry
Sept. 30, 1997
1997
44 Moved

63 Could not be
contacted
10 Status unknown
7 Declined
72 Could not be
contacted
20 Status unknown
5 Declined
Figure 1. Recruitment and Enrollment of Study Participants.

There were 2055 live-born offspring of a well-defined subgroup of mothers from the original study of vitamin A supplementation, which
was conducted between April 1994 and September 1997. A total of 1658 of those children were alive and living in the study area at the
time of the follow-up study; 1371 of them underwent spirometry. Children were 9 to 13 years of age at the time they were enrolled in the
follow-up study.
fore September 30, 1997 (P=0.09), children who

died after September 30, 1997 (P=0.62), children
who moved out of the study area (P=0.78), children who could not be contacted during the study
period (P=0.99), or children who declined to participate or whose mothers did not want them to
participate in the study (P=0.78). As compared
with the 684 children from the original birth cohort who were not included in the follow-up study,
children who were contacted and who underwent
spirometry were less likely to be members of a
low caste (P=0.003), less likely to live in a thatch
or bamboo house (P<0.001), more likely to live in
a household that owned land or livestock (P<0.001
for both comparisons), and more likely to have a
father who was a farmer (P=0.04).
In 1322 (96%) of the 1371 children who underwent spirometry, the quality of the spirometry
data met American Thoracic Society standards.
We did not find significant differences between
the study groups in demographic characteristics,
anthropometric measurements, socioeconomic
indicators, or early exposures (Table 1). We also
did not find significant between-group differences in the age-adjusted mean height of the
children (P=0.51) or in the proportion of children with a history of pneumonia during infancy
(P=0.96).
Predictors of Lung Function
In an exploratory analysis, FEV1 and FVC were normally distributed. Height, sex, body-mass index,

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The
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Table 1. Demographic, Anthropometric, and Socioeconomic Characteristics and Early Exposures among Children
in Whom Adequate Spirometric Measurements Were Obtained, According to the Group Assignment of the Mothers.*
Variable
Maternal Study-Group Assignment

Beta Carotene
Placebo
P Value
Vitamin A
Sample size
No. of wards
No. of children
463
419
440
No. of children per ward

Median
45
48
37
Range
2691
1678
11125
Overall mean
11.10.77
11.20.75
11.20.75
Average of ward means
11.10.21
11.30.21
11.10.19
Demographic characteristics
Age (yr)
0.17
Male sex (%)

Overall mean
55
48
51
55
48
51
0.10
Anthropometric measurements
Height (cm)
Overall mean
130.47.3
130.87.2
130.97.1
130.62.0
131.51.8
131.31.8
0.62
Weight (kg)
Overall mean
25.14.3
24.83.8
24.74.0
25.21.3
25.31.4
25.11.7
0.97
Body-mass index
Overall mean
14.71.4
14.41.1
14.41.3
14.70.4
14.60.5
14.50.6
0.73
Socioeconomic status (average of ward proportions)

Low caste
86
92
83
0.65
Low-quality house
89
95
92
0.22
Family owns land
60
66
62
0.72
Family owns livestock
85
82
90
0.32
Family owns radio
32
28
30
0.67
Mother is literate
21
10
17
0.17
Father is farmer
50
53
46
0.61
Early exposures (% in ward)

History of infantile pneumonia
64
67
63
0.93
7-day history of maternal tobacco use during pregnancy
25
27
26
0.96
* Plusminus values are means SD. The average of ward means for specific variables was calculated by adding the
group-specific ward means for that variable and dividing the sum by the number of group-specific wards.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
Data in all categories of socioeconomic status were missing for 1 child in the beta carotene group, data on maternal literacy were missing for 183 children (59 in the beta carotene group, 54 in the placebo group, and 70 in the vitamin A
group), and data on paternal occupation were missing for 189 children (62 in the beta carotene group, 55 in the placebo group, and 72 in the vitamin A group).
Low-quality houses were those minimally constructed with either bamboo or thatch.
Data on infant pneumonia were missing for 66 children (21 in the beta carotene group, 19 in the placebo group, and 26
in the vitamin A group), and data on the use of tobacco during the mothers pregnancy were missing for 123 children
(44 in the beta carotene group, 44 in the placebo group, and 35 in the vitamin A group).
1788

A Unadjusted
B Adjusted
80
1.8
60
Residuals of FEV1 (ml)
FEV1 (liters)
1.7
1.6
1.5
1.4
0.0
40
20
0
20
40
Beta Carotene
Placebo
Vitamin A
Beta Carotene
Placebo
Vitamin A
Figure 2. FEV1 in Children Whose Mothers Received Beta Carotene, Vitamin A, or Placebo before, during,
and after Pregnancy.
Results for forced expiratory volume in 1 second (FEV1) are shown for children 9 to 13 years of age whose mothers
had been randomly assigned to receive supplementation with beta carotene, supplementation with vitamin A, or
placebo before, during, and after pregnancy. Bars indicate wards; the wide bars indicate the wards that represent the
median values. Unadjusted mean values of FEV1 in each ward within a village development community are shown in
Panel A, according to the group assignment of the mothers (nine wards were randomly assigned to each group). Because of the variability in FEV1 according to the childrens anthropometric characteristics, we also show adjusted values of FEV1 (Panel B). We used a two-stage process to calculate adjusted values of FEV1. In the first stage, we used
ordinary least squares to calculate the residuals of FEV1 regressed on height, age, sex, body-mass index, calendar
month, caste, and spirometer. In the second stage, we calculated ward-level means of the residuals. We centered
these ward-level summaries on the median value in the placebo group. Shown are the adjusted mean values of FEV1
for the nine wards in each study group.
calendar month, caste, and spirometer were significant predictors of FEV1 or FVC. We did not find
significant differences in FEV1 or FVC according
to the technician who performed the test or the
pneumotachometer calibration code, nor did we
find significant differences in FEV1 or FVC values
over the course of the study.
Effects of Maternal Supplementation
on the Lung Function of Offspring
The mean FEV1 and FVC in our study population

were 1.54 liters and 1.74 liters, respectively. Children whose mothers had received vitamin A supplementation had higher values of FEV1 than children whose mothers had received placebo (Fig. 2).
The FEV1 of children whose mothers had received
vitamin A was, on average, 46 ml higher (95%
confidence interval [CI], 6 to 86) than that of
children whose mothers had received placebo, after adjustment for age, height, sex, body-mass
index, caste, calendar month, and spirometer
(P=0.03). The adjusted FEV1 of children whose

mothers had received beta carotene was, on average, 14 ml higher (95% CI, 24 to 54) than that
of children whose mothers had received placebo
(P=0.47).
A similar comparison for FVC shows that children whose mothers had received vitamin A had
higher values than children whose mothers had
received placebo (Fig. 3). After adjustment for the
same factors as those adjusted for in the FEV1
analysis, the FVC of children whose mothers had
received vitamin A was 46 ml higher (95% CI,
8 to 84) than that of children whose mothers
had received placebo (P=0.02). The adjusted FVC
of children whose mothers had received beta carotene was 17 ml higher (95% CI, 21 to 55) than
that of children whose mothers had received placebo (P=0.36). The effects of the mothers studygroup assignment on the lung function of the
child was not confounded by the mothers socioeconomic status, the presence or absence of a his-

1789
The
A Unadjusted
m e dic i n e
B Adjusted
2.2
80
2.1
60
Residuals of FVC (ml)
2.0
FVC (liters)
of
1.9
1.8
40
20
0
20
1.7
40
1.6
0.0
Beta Carotene
Placebo
Vitamin A
Beta Carotene
Placebo
Vitamin A
Figure 3. FVC in Children Whose Mothers Received Beta Carotene, Vitamin A, or Placebo before, during,
and after Pregnancy.
Results for forced vital capacity (FVC) are shown for children 9 to 13 years of age whose mothers had been randomly
assigned to receive supplementation with beta carotene, supplementation with vitamin A, or placebo before, during,
and after pregnancy. Bars indicate wards; the wide bars indicate the wards that represent the median values. Unadjusted mean values of FVC in each ward within a village development community are shown in Panel A, according to
the group assignment of the mothers (nine wards were randomly assigned to each group). Because of the variability
in FVC according to the childrens anthropometric characteristics, we also show adjusted values of FVC (Panel B).
We used a two-stage process to calculate adjusted values of FVC. In the first stage, we used ordinary least squares to
calculate the residuals of FVC regressed on height, age, sex, body-mass index, calendar month, caste, and spirometer. In the second stage, we calculated ward-level means of the residuals. We centered these ward-level summaries
on the median value in the placebo group. Shown are the adjusted mean values of FVC for the nine wards in each
study group.
tory of pneumonia during the childs infancy, or

the presence or absence of a 7-day history of tobacco use by the mother during her pregnancy (see
the table in the Supplementary Appendix, available with the full text of this article at NEJM.org).
We did not find significant between-group differences in the ratio of FEV1 to FVC (P=0.44), suggesting that lung size and airway caliber were
influenced proportionally by maternal vitamin A
supplementation.
Postpartum Serum Retinol Levels and Lung
Function of Offspring
We measured postpartum serum retinol levels in

678 mothers. Supplementation with vitamin A or
beta carotene was associated with significantly
higher serum retinol levels post partum (Fig. 4A).
Without consideration of the mothers original
group assignments, we found that the FEV1 and
FVC levels of the study children were linearly re1790
lated to the postpartum serum retinol levels of

their mothers, after adjustment for height, bodymass index, age, sex, caste, calendar month, and
spirometer (Fig. 4B and 4C). On average, FEV1 increased by 19 ml (95% CI, 3 to 35) and FVC increased by 16 ml (95% CI, 1 to 32) for every 1-SD
increase in postpartum serum retinol level (1 SD =
0.510 mol per liter). Postpartum serum beta-carotene levels were measured in 594 mothers. We
did not find a significant association between postpartum serum beta-carotene levels in the mothers and either FEV1 or FVC in their children.
Discussion
In a population with chronic vitamin A deficiency, maternal supplementation with vitamin A at
recommended dietary levels before, during, and
after pregnancy resulted in improved lung function in the offspring 9 to 13 years later. Improve-

Postpartum Retinol
(mol/liter)
2.5
1.5
0.5
0.0
Beta Carotene
(N=244)
Placebo
(N=201)
Vitamin A
(N=233)
B
Postpartum Retinol Component
of Estimated FEV1 (liters)
Figure 4. Association between Maternal Postpartum

Levels of Serum Retinol and Lung Function in Offspring.
Shown are maternal postpartum levels of serum retinol
and their association with forced expiratory volume in
1 second (FEV1) and forced vital capacity (FVC) in the
offspring 9 to 13 years later. Box plots of maternal serum
retinol levels, according to maternal group assignment,
are shown in Panel A. The lower and upper bounds of
the boxes represent the 25th and 75th percentiles, respectively, and the heavy horizontal lines represent
means. The I bars represent 1.5 times the interquartile
range outside the 25th and 75th percentiles. The open
circles represent values outside the I bars. Panel B
shows a smoothing spline fit (solid line) and corresponding 95% confidence band (dashed lines) of the
association between postpartum serum retinol levels
in the mothers and FEV1 in their offspring, as estimated from a generalized additive model after adjustment
for height, age, sex, body-mass index, caste, calendar
month, and spirometer. The notches on the x axis represent the distribution of values for postpartum retinol.
Panel C shows a smoothing spline fit (solid line) and
corresponding 95% confidence band (dashed lines)
of the association between postpartum serum retinol
levels in the mothers and FVC in their offspring, as
estimated from a generalized additive model after adjustment for height, age, sex, body-mass index, caste,
calendar month, and spirometer. The notches on the
x axis represent the distribution of values for postpartum retinol.
0.1
0.0
0.1
0.5
1.0
1.5
2.0
2.5
Postpartum Retinol (mol/liter)
ment in lung function was probably due to supplementation received in utero because this
population of children was subsequently exposed
starting at 6 months of age and extending
through their preschool years to high-coverage, semiannual vitamin A supplementation as
part of a national program.28 The benefit from
maternal supplementation with vitamin A was
limited to children whose mothers received preformed vitamin A and was not seen in those whose
mothers received beta carotene, possibly because
beta carotene is a less efficient source of vitamin A
than the preformed ester.29-31 We previously reported that supplementation with preformed vitamin A, but not beta carotene, corrected abnormal dark-adaptation thresholds in pregnant and
lactating women32 and reduced the rate of death
among infants born to mothers with night blindness.33 The greater bioefficacy of preformed vitamin A as compared with beta carotene may stem
from differences in absorption and metabolism.
In the gut, the preformed ester is hydrolyzed to
retinol and efficiently absorbed, re-esterified, and
delivered through circulating chylomicrons to the
Postpartum Retinol Component

of Estimated FVC (liters)
C
0.1
0.0
0.1
0.5
1.0
1.5
2.0
2.5
Postpartum Retinol (mol/liter)
liver for storage, although extrahepatic pathways

for tissue delivery of vitamin A also exist.34 Once
hepatic retinol is bound to retinol binding protein,
it is released into the circulation to meet tissue
needs, including those of the placenta and the
developing fetus.35 On the other hand, beta carotene is less well absorbed than the preformed ester and must be cleaved and hydrolyzed to retinol
in the intestines before becoming available as vitamin A.29 Beta carotene can also be directly absorbed and may be converted to vitamin A in tissues other than the intestine,31 including the

1791
The
maternalplacental interface.35 The lower bioefficacy of the beta-carotene supplement as a source

of vitamin A in the mothers and their offspring
in our trial was also evident in the finding that
serum retinol concentrations in mothers at midpregnancy and post partum7 and in their infants
at 3 months of age24 were lower among those in
the beta-carotene group than they were among
those in the preformedvitamin A group.
There is a wealth of data from studies in animals13,20,36,37 and from observational studies involving children38,39 and adults40-43 suggesting that
there is a positive functional relationship between
vitamin A status and lung function. Studies have
shown that defects in pulmonary development
such as bronchopulmonary dysplasia may be linked
to vitamin A deficiency.44,45 Vitamin A mediates
alveolar formation and septation through the
binding of its active metabolite, retinoic acid, to
nuclear receptors.21 Thus, conditions that lead to
vitamin A deficiency, to deletions in nuclear receptors for retinoic acid, or to improper signaling
of these receptors have been associated with abnormalities in lung development.13,14,21 In animals, prenatal vitamin A supplementation after
induced maternal deficiency prevents abnormal
lung development in offspring.14 Postnatal treatment with retinoic acid, even in the presence of
inhibitors of alveolar formation, induces alveolarization.20,37 However, retinoic acid is an intracellular metabolic intermediate of retinol, and unlike
naturally occurring retinoids such as preformed
vitamin A, it is not available as a supplement for
common use.
Our study provides data from a cohort of children in an undernourished population whose
mothers were assigned at random to receive antenatal vitamin A supplementation or placebo. We
controlled for potential imbalances that may have
resulted from incomplete follow-up, since not all
of the 2055 children who were born alive to the
subsample of women enrolled in the original trial
were available for study. The absence of confounders or imbalances across maternal supplement
groups in predictors of lung function strengthens the likelihood that the observed association
between maternal vitamin A supplementation and
increased lung function in offspring was causal.
Data regarding nutrition from birth to the time
lung function was measured, retinol levels at the
time lung function was measured, and the history with respect to pneumonia after infancy were
not available.
1792
of
m e dic i n e
The effects of enhanced vitamin A status early

in human life extend beyond the pulmonary system. Vitamin A supplementation in early childhood prevents xerophthalmia, a condition attributable to keratinization and necrosis of the
corneal epithelium.46 Routine administration of
vitamin A strengthens host defenses against infection, which can favor child survival in undernourished populations.46 Randomized trials in
Indonesia, India, and Bangladesh showed that oral
supplementation with 50,000 IU of vitamin A in
oil shortly after birth reduced the rates of death
during the first year of life by 64%,47 23%,48 and
16%,49 respectively. At sites in which specific
causes of death were analyzed, the largest reductions were in diarrhea-related deaths.50
It is important to recognize that a mean increase of 46 ml in FEV1 (3% of the mean FEV1 in
this study population) and in FVC (3% of the mean
FVC) corresponds to a change in the distribution
of values in this study population of children and
does not predict the level of benefit that is expected in an individual child. However, the magnitude of the effect observed in this study is
slightly greater than that associated with preventing exposure to parental smoking in schoolaged children.51 Because FEV1 correlates with
overall longevity in the general adult population,52-54 any improvement in the distribution of
values of FEV1 in a population may provide longterm health benefits.
In summary, in an area in which there was
chronic vitamin A deficiency, maternal supplementation with vitamin A before, during, and after
pregnancy was a critical determinant of lung
maturation among offspring 9 to 13 years later.
Early interventions involving vitamin A supplementation in communities where undernutrition
is highly prevalent may have long-lasting consequences for lung health.
Supported by a grant (no. 614) from the Bill and Melinda Gates
Foundation and by a grant from the Sight and Life Research Institute, Baltimore. The original maternal vitamin A or beta-carotene
supplementation trial (19941997) was conducted under the Vitamin A for Health Cooperative Agreement (HRN-A-0097-00015-00)
between Johns Hopkins University and the Office of Health, Infectious Diseases and Nutrition of the U.S. Agency for International Development, with additional support from Task Force
Sight and Life, Basel, Switzerland. Dr. Checkley is the recipient
of a Clinician Scientist Award from Johns Hopkins University and
a K99/R00 Pathway to Independence Award (K99HL096955) from
the National Heart, Lung, and Blood Institute, National Institutes
of Health.
No potential conflict of interest relevant to this article was
reported.
We are grateful for the dedicated contributions of Sharada
Ram Shrestha (deceased) to the field study.


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The

Maternal Vitamin A Supplementation

We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers

In a chronically undernourished population, maternal repletion with vitamin A at

n engl j med 362;19 nejm.org may 13, 2010

The New England Journal of Medicine

Maternal Vitamin A Supplementation and Lung Function in Offspring

ern Nepal, in the densely populated, low-lying

The original study, which was conducted between

The New England Journal of Medicine

samples at mid-pregnancy and at 3 months post

In 2006, we revisited the households of children

formed.25 Technicians reviewed with a supervisor

The values for FEV1 and FVC were adjusted for

The status of the 2055 live-born children from the

n engl j med 362;19 nejm.org may 13, 2010

The New England Journal of Medicine

Maternal Vitamin A Supplementation and Lung Function in Offspring

5819 Women in 27 wards were recruited

2031 Women (885 pregnancies)

1795 Women (771 pregnancies)

1993 Women (803 pregnancies)

738 Live-born children

635 Live-born children

682 Live-born children

591 Were living in study area

506 Were living in study area

103 Could not be

481 Underwent spirometry

561 Were living in study area

426 Underwent spirometry

464 Underwent spirometry

Figure 1. Recruitment and Enrollment of Study Participants.

fore September 30, 1997 (P=0.09), children who

n engl j med 362;19 nejm.org may 13, 2010

The New England Journal of Medicine

Maternal Study-Group Assignment

No. of children per ward

Average of ward means

Male sex (%)

Average of ward means

Average of ward means

Average of ward means

Average of ward means

Socioeconomic status (average of ward proportions)

Family owns land

Family owns livestock

Family owns radio

Early exposures (% in ward)

7-day history of maternal tobacco use during pregnancy

n engl j med 362;19 nejm.org may 13, 2010

The New England Journal of Medicine

Maternal Vitamin A Supplementation and Lung Function in Offspring

Residuals of FEV1 (ml)

The mean FEV1 and FVC in our study population

(P=0.03). The adjusted FEV1 of children whose

n engl j med 362;19 nejm.org may 13, 2010

The New England Journal of Medicine

Residuals of FVC (ml)

tory of pneumonia during the childs infancy, or

We measured postpartum serum retinol levels in

lated to the postpartum serum retinol levels of

n engl j med 362;19 nejm.org may 13, 2010