Vita en Lag Estacion

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original article

T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 362;19 nejm.org may 13, 20101784

Maternal Vitamin A Supplementation

and Lung Function in OffspringWilliam 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.

From the Division of Pulmonary and Crit-

ical Care, School of Medicine (W.C.,R.A.W., M.R.B.), the Program in GlobalDisease Epidemiology and Control (W.C.,

J.K., J.M.T.) and the Center for HumanNutrition (K.P.W., L.W., S.C.L., P.C., J.K.,

J.M.T.), Department of InternationalHealth, and the Department of Epidemi-ology (A.S.), Bloomberg School of PublicHealth, Johns Hopkins University, Balti-more; and the Nepal Nutrition Interven-tion Project Sarlahi, National Society forthe Prevention of Blindness, Kathmandu,Nepal (S.C.L., S.K.). Address reprint re-quests to Dr. Checkley at Johns HopkinsUniversity School of Medicine, Divisionof Pulmonary and Critical Care, 1830Monument St., 5th Fl., Baltimore, MD21205, or at [email protected].

This article (10.1056/NEJMoa0907441) waslast updated on December 29, 2010, atNEJM.org.

N Engl J Med 2010;362:1784-94.Copyright 2010 Massachusetts Medical Society.

A b s t ra c t

Background

Vitamin A is important in regulating early lung development and alveolar forma-

tion. Maternal vitamin A status may be an important determinant of embryonicalveolar 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 hy-

pothesis 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 caro-

tene had adjusted FEV1and FVC values that were similar to those of children whose

mothers had received placebo (FEV1, 14 ml higher with beta carotene; 95% CI, 24 to54; 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 func-

tion in offspring. This public health benefit was apparent in the preadolescent years.

The New England Journal of Medicine

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Maternal Vitamin A Supplementation and Lung Function in Offspring

n engl j med 362;19 nejm.org may 13, 2010 1785

Vitamin A deficiency affects 190 mil-

lion preschool-aged children and 19 mil-

lion pregnant women worldwide.1 It is the

underlying cause of 650,000 early childhood

deaths2 and has become recognized as an impor-

tant problem among women of reproductive age

in many developing countries. Chronic vitamin A

deficiency may increase the risks of complicationsand death during pregnancy and in the postpar-

tum period3-9 and, on the basis of evidence from

studies in animals, may also adversely affect the

embryonic and postnatal development of the off-

spring.10-14

The importance of vitamin A in regulating

growth through cell proliferation and differentia-

tion 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 mul-

tiple organ systems, including the respiratory sys-tem.14-20 Depletion of vitamin A from the diet of

female rats before and during pregnancy is associ-

ated 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 dose-

dependent 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. Al-

though results from studies in animals have

shown that vitamin A is an important determi-

nant of early lung development and size, data are

lacking on the long-term consequences of vita-

min A deficiency on lung health in human popu-

lations. We studied the effect of antenatal vita-

min A supplementation on the lung function of

preadolescent children in a chronically undernour-

ished population in rural Nepal. The study co-

hort consisted of children, 9 to 13 years of age,whose mothers had participated in a randomized,

placebo-controlled trial of vitamin A or beta-car-

otene supplementation before, during, and after

pregnancy.

Methods

Study Setting

We conducted the original vitamin A trial and this

follow-up study in the Sarlahi District of south-

ern Nepal, in the densely populated, low-lying

southern plains (Terai). The weather is usually

warm and humid in this region, with tempera-

tures 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 andvitamin A deficiency.22,23 Rice is the staple of the

diet. It is supplemented with small amounts of

seasonal fruits, vegetables, lentil soup, and occa-

sionally meat, fish, and eggs.

Original Vitamin A Trial

The original study, which was conducted between

April 1994 and September 1997, was a double-

blind, placebo-controlled, cluster-randomized tri-

al involving married women of childbearing age.

The study was designed to determine the effects

of weekly supplementation with a low dose ofvitamin A or beta carotene on the rates of mater-

nal death related to pregnancy.7 We invited all

eligible women from 30 village development com-

munities (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 retinol-

equivalents of vitamin A, 7000-g retinol-equiv-

alents of beta carotene, or placebo. Both supple-

ments, 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 identif ied

all pregnant women and followed the mothers

and their infants for an assessment of vital status

and health outcomes. Supplementation with vita-

min 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 com-

bined 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

their live-born infants from three VDCs (27 of the

270 wards) in a substudy with a more detailed

protocol that involved interviews about illnesses,

diet, and other exposures; collection of blood





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Th e n e w e n g l a n d j o u r n a l o f medicine


samples at mid-pregnancy and at 3 months post

partum; clinical examinations; and anthropomet-

ric 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 moder-

ately higher in the beta-carotene group than in the

placebo group.7,24 A total of 2055 children wereborn alive to mothers in the subsample who com-

pleted the pregnancy-to-postpartum dosing pro-

tocols. 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 orig-

inal study. We used a household list derived from

the original trial to generate an updated list ofchildren 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 fol-

low-up study was approved by the institutional re-

view board at the Johns Hopkins University in

Baltimore and at the Institute of Medicine, Trib-

huvan 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 deter-

mine 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 super-

visors in the performance of spirometry. We num-

bered all our spirometers and asked technicians

to use a different spirometer each day. Techni-

cians visited the study children at their homes to

perform spirometry. Each child underwent spirom-

etry while in a sitting position and wearing a

nose clip, until three acceptable and reproducible

maneuvers, of a maximum of eight, had been per-

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 di-

rect supervision and in-person review of all flow-

volume 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 differ-

ent spirometers, we also adjusted for the specific

spirometer that was used for the measurement.

All analyses were performed according to the in-

tention-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 mul-tilevel 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 relation-

ship between the postpartum levels of these mi-

cronutrients in the mothers and the lung func-

tion 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.

Results

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 avail-

able for eight children (


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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), chil-

dren who could not be contacted during the study

period (P = 0.99), or children who declined to par-

ticipate or whose mothers did not want them toparticipate in the study (P = 0.78). As compared

with the 684 children from the original birth co-

hort 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


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Table 1. Demographic, Anthropometric, and Socioeconomic Characteristics and Early Exposures among Childrenin Whom Adequate Spirometric Measurements Were Obtained, According to the Group Assignment of the Mothers.*

Variable Maternal Study-Group Assignment P Value

Beta Carotene Placebo Vitamin A

Sample size

No. of wards 9 9 9

No. of children 463 419 440

No. of children per ward

Median 45 48 37

Range 2691 1678 11125

Demographic characteristics

Age (yr)

Overall mean 11.10.77 11.20.75 11.20.75

Average of ward means 11.10.21 11.30.21 11.10.19 0.17

Male sex (%)

Overall mean 55 48 51

Average of ward means 55 48 51 0.10

Anthropometric measurements

Height (cm)

Overall mean 130.47.3 130.87.2 130.97.1


Weight (kg)

Overall mean 25.14.3 24.83.8 24.74.0


Body-mass index

Overall mean 14.71.4 14.41.1 14.41.3


Socioeconomic status (average of ward pro-

portions)

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 dur-

ing pregnancy

25 27 26 0.96

* Plusminus values are means SD. The average of ward means for specific variables was calculated by adding thegroup-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 lit-

eracy were missing for 183 children (59 in the beta carotene group, 54 in the placebo group, and 70 in the vitamin Agroup), and data on paternal occupation were missing for 189 children (62 in the beta carotene group, 55 in the place-bo 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).





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calendar month, caste, and spirometer were sig-

nificant predictors of FEV1or 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 signif icant differences in FEV1or 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 populationwere 1.54 liters and 1.74 liters, respectively. Chil-

dren whose mothers had received vitamin A sup-

plementation had higher values of FEV1than chil-

dren whose mothers had received placebo (Fig. 2).

The FEV1of 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, af-

ter 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 aver-

age, 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 chil-

dren 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 hadreceived 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 caro-

tene was 17 ml higher (95% CI, 21 to 55) than

that of children whose mothers had received pla-

cebo (P = 0.36). The effects of the mothers study-

group assignment on the lung function of the

child was not confounded by the mothers socio-

economic status, the presence or absence of a his-

FEV1

(liters)

1.4

1.5

1.6

1.7

1.8

0.0


A Unadjusted

ResidualsofFEV1

(m

l)

40

20

0

20

40

60

80


B Adjusted

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, orplacebo 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 inPanel A, according to the group assignment of the mothers (nine wards were randomly assigned to each group). Be-

cause of the variability in FEV1according to the childrens anthropometric characteristics, we also show adjusted val-ues 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, calendarmonth, 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 FEV1for the nine wards in each study group.





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tory of pneumonia during the childs infancy, or

the presence or absence of a 7-day history of to-

bacco use by the mother during her pregnancy (see

the table in the Supplementary Appendix, avail-

able with the full text of this article at NEJM.org).

We did not find significant between-group differ-

ences in the ratio of FEV1

to FVC (P = 0.44), sug-

gesting 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 re-

lated to the postpartum serum retinol levels of

their mothers, after adjustment for height, body-

mass index, age, sex, caste, calendar month, and

spirometer (Fig. 4B and 4C). On average, FEV1

in-

creased by 19 ml (95% CI, 3 to 35) and FVC in-

creased 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-car-

otene levels were measured in 594 mothers. We

did not find a significant association between post-

partum serum beta-carotene levels in the moth-ers and either FEV1

or FVC in their children.

Discussion

In a population with chronic vitamin A deficien-

cy, maternal supplementation with vitamin A at

recommended dietary levels before, during, and

after pregnancy resulted in improved lung func-

tion in the offspring 9 to 13 years later. Improve-

FVC(liters)

1.6

1.7

1.8

1.9

2.0

2.1

2.2

0.0


A Unadjusted

ResidualsofFVC(m

l)

40

20

0

20

40

60

80


B Adjusted

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. Unad-

justed mean values of FVC in each ward within a village development community are shown in Panel A, according tothe 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 spirome-

ter. In the second stage, we calculated ward-level means of the residuals. We centered these ward-level summarieson the median value in the placebo group. Shown are the adjusted mean values of FVC for the nine wards in each

study group.





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ment in lung function was probably due to sup-

plementation 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-cover-

age, 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 pre-

formed 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 re-

ported that supplementation with preformed vi-

tamin A, but not beta carotene, corrected abnor-mal dark-adaptation thresholds in pregnant and

lactating women32 and reduced the rate of death

among infants born to mothers with night blind-

ness.33 The greater bioefficacy of preformed vita-

min 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

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 caro-

tene is less well absorbed than the preformed es-

ter and must be cleaved and hydrolyzed to retinol

in the intestines before becoming available as vi-

tamin A.29 Beta carotene can also be directly ab-

sorbed and may be converted to vitamin A in tis-

sues other than the intestine,31 including the

Figure 4. Association between Maternal PostpartumLevels of Serum Retinol and Lung Function in Offspring.

Shown are maternal postpartum levels of serum retinoland 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 serumretinol levels, according to maternal group assignment,

are shown in Panel A. The lower and upper bounds ofthe boxes represent the 25th and 75th percentiles, re-

spectively, and the heavy horizontal lines representmeans. The I bars represent 1.5 times the interquartile

range outside the 25th and 75th percentiles. The opencircles represent values outside the I bars. Panel B

shows a smoothing spline fit (solid line) and corre-sponding 95% confidence band (dashed lines) of the

association between postpartum serum retinol levelsin the mothers and FEV

1in their offspring, as estimat-

ed from a generalized additive model after adjustment

for height, age, sex, body-mass index, caste, calendarmonth, and spirometer. The notches on the x axis rep-

resent 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, asestimated from a generalized additive model after ad-

justment for height, age, sex, body-mass index, caste,calendar month, and spirometer. The notches on the

x axis represent the distribution of values for postpar-

tum retinol.

B

A

C

PostpartumR

etinol

(m

ol/liter)

2.5

1.5

0.5

0.0

Beta Carotene(N=244)

Placebo(N=201)

Postpartum Retinol (mol/liter)

Vitamin A(N=233)

PostpartumR

etin

olComponent

ofEstimatedFEV1

(liters)

0.1

0.0

0.1

0.5 1.0 1.5 2.0 2.5

Postpartum Retinol (mol/liter)

PostpartumR

etinolComponent

ofEstimatedFVC

(liters)

0.1

0.0

0.1

0.5 1.0 1.5 2.0 2.5





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maternalplacental interface.35 The lower bioeffi-

cacy 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 mid-

pregnancy and post partum7 and in their infants

at 3 months of age24 were lower among those in

the beta-carotene group than they were amongthose in the preformedvitamin A group.

There is a wealth of data from studies in ani-

mals13,20,36,37 and from observational studies in-

volving 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 tovitamin A deficiency, to deletions in nuclear re-

ceptors for retinoic acid, or to improper signaling

of these receptors have been associated with ab-

normalities in lung development.13,14,21 In ani-

mals, prenatal vitamin A supplementation after

induced maternal deficiency prevents abnormal

lung development in offspring.14 Postnatal treat-

ment with retinoic acid, even in the presence of

inhibitors of alveolar formation, induces alveolar-

ization.20,37 However, retinoic acid is an intracel-

lular 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 chil-

dren in an undernourished population whose

mothers were assigned at random to receive an-

tenatal 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 confound-ers or imbalances across maternal supplement

groups in predictors of lung function strength-

ens 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 his-

tory with respect to pneumonia after infancy were

not available.

The effects of enhanced vitamin A status early

in human life extend beyond the pulmonary sys-

tem. Vitamin A supplementation in early child-

hood prevents xerophthalmia, a condition at-

tributable to keratinization and necrosis of the

corneal epithelium.46 Routine administration of

vitamin A strengthens host defenses against in-

fection, which can favor child survival in under-nourished 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 reduc-

tions were in diarrhea-related deaths.50

It is important to recognize that a mean in-

crease 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 distributionof values in this study population of children and

does not predict the level of benefit that is ex-

pected in an individual child. However, the mag-

nitude of the effect observed in this study is

slightly greater than that associated with pre-

venting exposure to parental smoking in school-

aged children.51 Because FEV1

correlates with

overall longevity in the general adult popula-

tion,52-54 any improvement in the distribution of

values of FEV1

in a population may provide long-

term health benefits.

In summary, in an area in which there was

chronic vitamin A deficiency, maternal supplemen-

tation 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 supple-

mentation in communities where undernutrition

is highly prevalent may have long-lasting conse-

quences for lung health.

Supported by a grant (no. 614) from the Bill and Melinda GatesFoundation and by a grant from the Sight and Life Research Insti-

tute, Baltimore. The original maternal vitamin A or beta-carotene

supplementation trial (19941997) was conducted under the Vita-min A for Health Cooperat ive Agreement (HRN-A-0097-00015-00)

between Johns Hopkins University and the Office of Health, In-fectious Diseases and Nutrition of the U.S. Agency for Interna-

tional Development, with additional support from Task ForceSight 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) fromthe 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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