Vitamin A in pregnancy: requirements and safety limits13

Vronique Azas-Braesco and Grard Pascal

KEY WORDS
Pregnancy, lactation, development, teratogenesis, immunity, supplementation, developing countries, women,
vitamin A

INTRODUCTION
Vitamin A is an essential micronutrient whose role in visual
function has been known for thousands of years. The role vitamin A plays in other basic physiologic processes, such as
growth, reproduction, immunity, and epithelial tissue maintenance, has been known for a long time but is only partially
understood. Vitamin A is essential throughout the entire life
span, yet its influence is particularly critical during periods
when cells proliferate rapidly and differentiate, such as during
pregnancy and early childhood. This review focuses on the
metabolism and functions of vitamin A during the periconceptional period, pregnancy, and early childhood. The consequences on health of inadequate vitamin A status or supply are
also discussed.

MECHANISMS OF VITAMIN ADEPENDENT FUNCTIONS

Vitamin A exerts its functions through oxidized metabolites of
retinol. The first metabolite, retinaldehyde, constitutes the heme
of the visual pigment, the rhodopsin, whose light-induced isomerization triggers a phototransduction cascade that ends with a
signal transmission to neurons of the optical nerves (1). The second metabolite, retinoic acid, is a lipid-soluble hormone that
controls gene transcription through receptor-mediated events.
The first human retinoic acid receptor (RARa) was isolated in
1987 (2, 3) and was subsequently shown to activate the transcription of target genes after binding to all-trans-retinoic acid. Other
subtypes (RARb and RARg) that bind to the same ligand were
isolated shortly after. A second class of receptors, retinoid X
receptor (RXR)a, -b, and -g, was characterized in 1990 (4); these
receptors may bind all-trans-retinoic acid, yet their ligand was
identified as 9-cis-retinoic acid. The preferred RAR and RXR
subtypes have multiple isoforms that are expressed differently in
various cell types and during the various stages of development.
Moreover, RXRs can form heterodimers with a variety of receptors belonging to the same superfamily, including RARs. All
these possible interactions may be related to the pleiotropic
effects of retinoids, which regulate the expression of numerous
genes involved in many physiologic events (5).
Although most vitamin Adependent functions, except for
vision, can be mediated by retinoic acid, direct involvement of
retinoic acid in the immune system has not been definitely determined. A third oxidized metabolite of retinol, 14-hydroxy-4,14retro retinol, is suggested to be the active molecule in the
immune system, but its mechanism of action is not known (6).
The various modes of response of the immune system are
affected by vitamin A, as discussed by Ross (7).

RETINOIC ACID AND EMBRYONIC DEVELOPMENT

Over the past 10 y, considerable work has addressed the
mechanisms whereby retinoic acid affects cell differentiation
and, as a direct consequence, embryonic development. For obvi1
From the INRA, Human Nutrition and Food Safety Scientific Division,
the Metabolic Diseases and Micronutrients Unit, Vitamin Research Group,
Paris and Clermont-Ferrand, France.
2
Presented at the symposium Maternal Nutrition: New Developments and
Implications, held in Paris, June 1112, 1998.
3
Address reprint requests to V Azas-Braesco, INRA, UMMM, CRNH, Centre
de Theix, 63122 Saint-Gens, Champanelle, France. E-mail: braesco@clermont.
inra.fr.

Am J Clin Nutr 2000;71(suppl):1325S33S. Printed in USA. 2000 American Society for Clinical Nutrition

1325S

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ABSTRACT
Most of the functions of vitamin A are mediated through the binding of retinoic acid to specific nuclear
receptors that regulate genomic expression. Recent experimental
work in transgenic mice showed clearly that normal embryonic
development depends on the correct spatial and temporal expression of the receptors in the differentiating cells and on the
binding of specific forms of retinoic acid. This implies that the
parent compound, vitamin A, is available in adequate forms and
quantities. Excessive dietary intake of vitamin A has been associated with teratogenicity in humans in < 20 reported cases over
30 y. However, caution must be exercised to avoid unnecessary
supplementation of women of childbearing age. Hypovitaminosis A affects millions of women and children worldwide.
The main consequence of a poor vitamin A supply during pregnancy is a low vitamin A status at birth and in the next few
months. Vitamin A deficiency is strongly associated with
depressed immune function and higher morbidity and mortality
due to infectious diseases such as diarrhea, measles, and respiratory infections. Vitamin A deficiency is often associated with an
increased mother-to-child transmission of HIV-1. The initiation
of vitamin A supplementation should be carefully examined in
each case according to the risk-to-benefit ratio. The final decision should take into account the estimated vitamin A status of
the woman, the availability of vitamin Arich foods in her diet,
and whether supplementation can be supervised.
Am J Clin
Nutr 2000;71(suppl):1325S33S.

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AZAS-BRAESCO AND PASCAL

TABLE 1
Abnormalities described during fetal vitamin A deficiency reproduced in
retinoic acid receptor (RAR) or retinoid X receptor (RXR) null mutant
mice1
Knocked-out receptors
in null mutant mice
RARa1
RARg2
RARb2
RARa (all isoforms)
RARg (all isoforms)
RARa, RARb-RXRa, RARa
RARa, RARg
RARb, RARg-RARa, RARb
RARb, RARg-RXRa, RARa
RXRa, RARb-RXRa, RARg
RARa, RARg-RXRa, RARa
RARa, RARb-RXRa, RARg
RARa, RARg-RARb, RARg

None
None
Retrolenticular eye membrane
High neonatal mortality, growth
retardation, male sterility
High neonatal mortality, growth
retardation, male sterility
Lung hypoplasia
Myocardial hypoplasia
Anomalies of aortic arches
Anomalies of aortic arches
Anomalies of aortic arches
Renal hypoplasia
Uterine agenesia
Skeletal abnormalities (not occurring
during fetal vitamin A deficiency)
Skeletal abnormalities (not occurring
during fetal vitamin A deficiency)

From reference 10, 11.

ous ethical reasons, these studies have been performed in animal

models, most often rodents, which sometimes makes it difficult
to extrapolate the results to humans.
From the first cell division, a complicated set of interrelated
processes allows tissue organization to take place through specific
pathways, leading to first a developed embryo and then a mature
fetus. These events include the establishment of axial polarity and
cell differentiation in response to signaling molecules whose concentrations vary according to the region of the embryo (8). Several
signaling molecules, including retinoic acid, have been identified.
In several experiments, retinoic acid was applied directly to chick
embryo limb buds and modified their development in a dose- and
zone-dependent manner (9). It is hypothesized that, depending on
its position, a cell is exposed to various concentrations of retinoic
acid, which binds its nuclear receptors and elicits a specific pattern
of gene expression that directs the cell to its correct phenotype.
Comparable findings suggested that retinoic acid is involved
directly in establishing this specific pattern of gene expression
along the anteroposterior body axis.
Other authors have shown that RARs and RXRs are involved in
morphogenesis. When the embryonic development of RAR or RXR
null mutant mice is monitored (10, 11), the abnormalities vary according to the receptor or receptors suppressed (Table 1). A significant
number of the observed alterations are consistent with observations
made in the offspring of wild type mice maintained on a vitamin
Adeficient diet (12). When the mutation affects only one receptor,
the mice survive and the abnormalities are limited, suggesting a functional redundancy between the various subtypes and isoforms of the
receptors (1315). In double-mutant mice lacking either 2 RAR subtypes or both an RAR and an RXRa, the animals do not survive and
the abnormalities are more pronounced and concern some specific
ontogenic events (16, 17). It is likely that RAR-RXRa heterodimers
are the functional entities governing the retinoid-mediated signaling
pathway during embryonic development.
The spatial and temporal expression of the various subtypes
and isoforms of RARs and RXRs in wild type organisms is

VITAMIN A METABOLISM
Although retinoic acid circulates in the blood bound to albumin at concentrations close to 10 nmol/L (20), most retinoic
acid is produced in the target cells. Vitamin A occurs in the
human diet either preformed, as retinyl esters in animal products, or as provitamin carotenoids, mainly b-carotene, which
are partly cleaved to produce vitamin A in the enterocyte. After
intestinal absorption, vitamin A is packed into chylomicrons as
retinyl esters. The chylomicron remnants are then taken up by
hepatocytes, in which the retinyl esters are hydrolyzed into
retinol (Figure 1). When vitamin A status is insufficient, ie,
when extrahepatic organs urgently need vitamin A, the newly
formed retinol is bound to retinol binding protein (RBP), a specific retinol carrier, and secreted into the blood. The overall
process from ingestion to secretion takes <5 h. When vitamin A
status is satisfactory, the newly formed retinol is transferred in
the form of retinyl esters to a specific cell type: the hepatic stellate cells (HSCs). These cells are also known as Ito cells or
perisinusoidal liver cells and can store large quantities of vitamin A in characteristic lipid droplets. The lipid droplets are subsequently mobilized to maintain the homeostatic concentration
of retinol at 2 mmol/L to meet the requirements of the organism
(see reference 21 for a review).
RBP-bound retinol is taken up by cells via a mechanism
thought to involve a membranous receptor specific for RBP.
Such a receptor has been characterized in the retinal pigment
epithelium (22) and in the placenta (23). Its existence is still controversial, however, and some investigators believe that the
specificity of uptake would be ensured by a particular lipid composition of the cellular membrane (24, 25).
Vitamin A metabolism does not seem to be considerably
affected during pregnancy. However, RBP is found in urine during normal pregnancies, whereas its excretion outside of pregnancy is considered to be a clinical symptom of renal failure
(26). Vitamin A is transferred from the mother to the embryo
across the placenta; vitamin A concentrations in fetal blood are
approximately half of those in the mother. RBP is involved in
this transfer from mother to embryo; nevertheless, its specific
metabolism and the existence of other yet unknown binding proteins in maternal blood, the placenta, and fetal blood require further study (2729).
After it is internalized, retinol is bound to a cellular RBP
(CRBP) and is oxidized to retinal and then retinoic acid. This

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RARa, RARg

Fetal abnormality

important because this expression directs the correct phenotype

of the future differentiated cell. Numerous studies have shown
that the expression of RARa and RXRb is widespread, whereas
the expression of the other subtypes and isoforms is restricted to
specific tissues and specific periods of embryonic development
(18, 19). Such patterns of expression are also observed in the
genes coding for the proteins involved in retinol metabolism.
These studies clearly illustrate the fundamental role of
retinoic acid and its receptors in embryonic development. To
achieve harmonious tissue organization, a given quantity of
retinoic acid, in its all-trans or 9-cis form, should bind specific
receptors in due course. This implies that retinoic acid is available in the considered cell in an adequate amount and at the
specific time. These spatial and temporal requirements imply a
precise regulation of retinoic acid production, the mechanism of
which is still largely unknown.

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FIGURE 1. Schematic representation of vitamin A metabolism. RBP, retinol binding protein; CRBP, cellular RBP; TTR, transthyretin; RA, retinoic
acid. In the enlarged area: 1, binding of retinoic acid to its nuclear receptor; 2, activation of this receptor; 3, binding of the receptor to a retinoic acid
response element (RARE); and 4, regulation of the expression of genes downstream.

biochemical pathway is similar to the oxidation of ethanol to

acetaldehyde and acetic acid. Enzymes such as alcohol dehydrogenase and short-chain dehydrogenase or reductase can catalyze
the first step, which is reversible, whereas aldehyde dehydrogenase and cytochrome P-450 can catalyze the irreversible oxidation of retinaldehyde to retinoic acid (30). This involvement of
the enzymes belonging to the pathway of ethanol oxidation suggests that fetal alcohol syndrome, a teratogenic manifestation,
may be due to the inhibition of aldehyde-catalyzed retinoic acid

synthesis (31). Other authors characterized a pathway for retinol

oxidation that seems to be more specific to retinol. Retinol can
be dehydrogenated in the cytosol by 2 enzymes that differ by
their cofactors or by a third enzyme localized in the microsomal
fraction that accepts CRBP-bound retinol as its substrate. The
second step, retinaldehyde oxidation, also seems to be mediated
by several isozymes (32).
These studies concern primarily the biogenesis of all-transretinoic acid, although the 9-cis isomer of retinoic acid appears

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CONSEQUENCES OF EXCESSIVE VITAMIN A INTAKE
DURING PREGNANCY AND EARLY CHILDHOOD
Acute hypervitaminosis A
Acute hypervitaminosis A occurs after the administration of
very high amounts of the vitamin, usually in a single dose. The
prescription of supplemental vitamin A has been reported to
induce intracranial hypertension (53). A bulging fontanelle is
often reported in infants and young children (54), yet such an
outcome remains limited and should not prevent the administration of doses 50 000 IU [15 000 retinol equivalents (RE)] to
neonates when vitamin A status is critically low at birth or later
(55). The situation is different when the need for vitamin A is not
clearly established. In this case, the prescription of supplemental
vitamin A to young children should be considered with extreme
caution. Other symptoms related to chronic hypervitaminosis A
are observed after supplementation with low to moderate doses
of vitamin A on a regular basis over a long period of time. This
may induce severe, yet usually reversible liver damage (56).
Teratogenesis
Teratogenesis of high vitamin A intakes has been reported in
several animal species, as reviewed by Hathcock et al (57). The
pattern of birth defects sometimes called retinoic acid syndrome
includes central nervous system, craniofacial, cardiovascular,
and thymus malformations. Similar abnormalities were observed
in humans when pregnancies occurred during therapeutic treatment with retinoic acid, especially 13-cis-retinoic acid (43).
Up to 20 case reports of the relation between a high vitamin A
intake and an adverse pregnancy outcome in humans were published in the past 30 y (58). These reports are of limited use for
establishing a quantitative link between vitamin A intake and teratogenic events, however. Furthermore, the pattern of the observed
malformations is not always consistent with the retinoic acid syndrome, thus calling into question the origin of these malformations.
Five case-control studies have been published since 1990 in
which the intake of vitamin A was estimated retrospectively in
both control subjects and mothers of malformed babies (5963).
These data are summarized in Table 2. The design of these studies varied, especially regarding the classification of the observed
malformations, the statistical power, and the data on vitamin A
consumption. In most cases, no association was found between
moderate doses of vitamin A (<10 000 IU, or 3000 RE) and fetal
malformations. However, in all of these studies, the number of
women consuming high amounts of vitamin A was too limited to
reach statistical significance and the information available is
insufficient for assessing the potential teratogenic effect of such
high doses.
Only one prospective study has been conducted to date (64) and
the results of this study are clearly inconsistent with those of the
retrospective studies. The prospective study showed that an intake
exceeding 10 000 IU (3000 RE) vitamin A significantly increased
the risk of malformations (prevalence ratio: 4.8; 95% CI: 2.2,
10.5). This paper has been largely criticized (65), particularly in
relation to a suspected misclassification of the malformations, yet
its conclusion should not be ignored. A clinical trial was carried
out in Hungary in which a supplement of 6000 IU (1800 RE) vitamin A did not increase the incidence of fetal malformations. However, only limited conclusions can be drawn from this study
regarding the incidence of neural tube defects because folic acid
was administered simultaneously with vitamin A (66).

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to be of at least equal importance. This isomer could be derived

from a nonenzymatic isomerization of the all-trans form (33),
or from a 2-step oxidation of 9-cis-retinol (34). Retinoic acid,
in its all-trans or 9-cis form, can also be produced directly
from b-carotene after cleavage into retinal via b-carotene
dioxygenase (35). However, this seems to remain limited in
vivo: in one study, feeding humans 120 mg b-carotene led to a
small increase in circulating all-trans-retinoic acid from 5 to
7 nmol/L, whereas concentrations of 3-cis-retinoic acid were
unchanged (36). However, circulating values do not necessarily
reflect tissue concentrations.
Retinoic acid biogenesis is a complex process involving several biochemical pathways, the interactions and regulations of
which are not yet completely understood. Two points should be
stressed here, which will not be developed further. The first is
related to the yet undetermined role of 2 specific intracellular
binding proteins for retinoic acid: cellular retinoic acid binding
proteins (CRABP) I and II. Although they have an apparently
well regulated pattern of expression in the developing embryo
(37) and determine the rate of retinoic acid metabolism in in
vitro systems (38), the CRABPs have been shown to be dispensable. Mice in which the CRABP genes are disrupted have
a normal phenotype (39). The second point concerns the large
number of retinoic acid metabolites and isomers that have been
detected in human blood. Some of these clearly have a function, such as 4-oxoretinoic acid (40), or are considered to be a
sink for active molecules, such as the glucuronidated derivatives of retinoic acid (41). Others are thought to be elimination
metabolites, yet might have a physiologic role. For example,
13-cis-retinoic acid is usually considered as a degradation
product; however, its administration in monkeys or humans
leads to teratogenic events (42, 43).
Little information is available about the biogenesis of retinoic
acid in pregnancy or in the embryo. During organogenesis, the
retinoic acid concentration in the rat placenta is 0.06 nmol/g. The
concentration increases to 2 nmol/g in the fetus during organogenesis and then decreases to 0.01 nmol/g after organogenesis
(44). In the rat conceptus, the latter of the 2 pathways of retinol
oxidation described above seems to occur preferentially; the role
of aldehyde dehydrogenase is unclear, however, and there seems
to be no involvement of cytochrome P-450 (45). Studies in
humans are scarce; nevertheless, some authors have shown an
increase in circulating concentrations of retinoic acid and of
4-oxoretinoic acid (in their all-trans and 13-cis form) after the
intake of vitamin A (4649). The results of these experiments are
difficult to compare, however, because the experimental designs
varied. Furthermore, the half-life of the compounds measured is
usually very short (50) and thus serum concentrations may not
reflect cellular concentrations, as shown in animal models (51).
Moreover, the teratogenic threshold of circulating retinoic acid is
not known, nor is the nature of the specific teratogenic metabolite in humans. Uncertainty also remains concerning the extent of
transplacental transfer of vitamin A, retinoic acid, and their
derivatives, as well as concerning the embryonic or fetal metabolism of these compounds in humans. For example, the main
compound found in the human placenta and embryo 72 h after
13-cis-retinoic acid exposure is all-trans-retinoic acid, whereas
maternal serum concentrations of both isomers remain low (52).
A better understanding of retinoic acid metabolism in human tissue is a prerequisite for estimating potentially teratogenic doses
of vitamin A during human pregnancy.

VITAMIN A IN PREGNANCY

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TABLE 2
Epidemiologic case-control studies of the association between vitamin A intake and fetal malformations in humans1
Population

Results

Number
of cases

Number
of controls

11 193

11 293

2658

Characteristics of
exposure to vitamin A

Odds ratio
(95% CI)

Comments

Reference

1.1 (0.5, 2.5)

2.7 (0.8, 11.7)

Only 11 cases, 4 controls

at high exposure level

(58)

2609

During the 1st month

2nd month
3rd month

2.5 (1.0, 6.2)

2.3 (0.9, 5.8)
1.6 (0.6, 4.5)

No information on the vitamin A

doses; well-characterized neural
crestderived malformations

(59)

158

3026

Use of multivitamin
supplement

0.57 (0.33, 1.00)

Focus on conotruncal
defects only

(60)

548 (NTDs)

573

> 8000 IU/d

from supplements
> 10 000 IU/d from
food and supplements

Consumption of liver did

not increase risk

(61)

426

432

09999 IU/d

1.0 (reference)

NTDs only; vitamin A from

food and supplements

(62)

16
6

12
7

10 00014 999 IU/d

>15 000 IU/d

1.4 (0.6, 2.8)

0.9 (0.3, 2.5)

387(other defects)

NTDs: 0.91 (0.31, 3.68)

Other defects: 1.05 (0.51, 2.18)
NTDs: 0.73 (0.40, 1.53)
Other defects: 0.92 (0.40, 2.11)

NTD, neural tube defect. To convert from IU to retinol equivalents, multiply by 0.3.

Thus, the teratogenicity of high vitamin A intakes during

pregnancy remains unclear and it is unlikely that new findings
will shed light on this issue over the next few years. Human
clinical trials are not ethically possible, so we must rely on
those already performed, on forthcoming epidemiologic trials,
and on our knowledge of vitamin A metabolism and functions,
which is largely derived from animal studies. This information
clearly shows that the teratogenicity of vitamin A is biologically and physiologically possible, yet its real occurrence in
humans seems limited. One drawback in all human studies is
that the specific effects of vitamin A intake cannot be determined. Most of the information comes from the use of supplements or, at best, supplemented foods, that are taken on a regular basis and in moderate doses. However, data from animal
studies clearly show that one single, high dose of vitamin A can
be teratogenic, provided it is given at a critical period of embryonic development. Such information is not available today in
humans; thus, any attempt to establish a safe threshold of vitamin A consumption during the early period of human pregnancy would be hazardous.

CONSEQUENCES OF A DEFICIENT VITAMIN A STATUS

DURING PREGNANCY AND EARLY CHILDHOOD
Liver vitamin A stores are usually sufficiently high to withstand low or no vitamin A supply for a limited period, provided that usual intake is adequate. Therefore, more emphasis
should be placed on vitamin A status than on vitamin A intake,
yet this is difficult to do because of the lack of a satisfactory
biomarker for assessing the vitamin A status of individuals or
population except in the case of extreme hypovitaminosis A
(67). Unfortunately, extreme hypovitaminosis A is sufficiently
frequent to be ascertained in wide areas of the world. At the

last International Nutrition Conference, it was stated that not

only are <250 million children under 5 y of age at risk, but
2.8 million are currently vitamin A deficient and have reached
the xerophthalmia stage (68).
Low vitamin A status and embryonic development
Up until the 1950s, a relatively large number of studies
showed that laboratory animals (pigs, rabbits, chickens, rats,
and mice) fed vitamin Adeficient diets gave birth to malformed
offspring, mostly affected by microphthalmia and anophthalmia
associated with abnormalities of the cardiac, lung, and urogenital systems (12). Because of the lack of appropriate analytic
techniques at that time, maternal vitamin A concentrations were
not recorded. More recent studies in RAR and RXR null mutant
mice clearly confirm the role of vitamin A in embryonic development. Interestingly, a study in rats showed that retinol is
required during midgestation for neonatal survival. In the
absence of retinol, the pups exhibited a lethal failure in lung
development (69). This seems similar to the respiratory distress
syndrome observed in premature infants whose vitamin A status
is often deficient. Severe vitamin A deficiency is also responsible for abnormal spermatogenesis in animals (70). Zootechnicians have found a positive association between b-carotene
intake and fertility of cattle, but no similar relation for vitamin
A intake (71).
In light of these findings, a higher incidence of malformed
babies would be expected in areas of endemic vitamin A deficiency, but this is not the case. Although this apparent discrepancy may arise from the failure to report birth defects in these
countries, the number of reported cases remains surprisingly
low. The few cases reported occurred in India. One study
reported 15 cases of microphthalmia or anophthalmia over a
10-y period, which is not considerably excessive (72).

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> 10 000 IU/d

> 40 000 IU/d

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AZAS-BRAESCO AND PASCAL

TABLE 3
Recommendations and safety limits of vitamin A intake during pregnancy and early childhood1
Women
Source

Recommendation

Pregnant women
Safety
limit

Recommendation

Lactating women

Safety
limit

Recommendation

Safety
limit

Infants
Recommendation

Safety
limit

IU/d
WHO/FAO (94)

500

Low: 270,
high: 10 0002

600

Low: 450,
high: 10 000

850

Low: 450,
high:10 0002

350

United States (95)

United Kingdom (96)
France (97)
European Union (98)

900
600
800
600

3
3
3000
Low: 250,
high: 40004

900
700
900
700

8000
3
3000
5

1350
950
1300
950

3
3
3000
3

375
400
350
400

Low: 180,
high: 50 000 in
one single dose
3
3
3000
1700

To convert from IU to retinol equivalents, multiply by 0.3.

If infertility can be ensured, a single supplement of 200 000 IU is possible.
3
An official quantitative recommendation is not available.
4
For nonpregnant or women not likely to be pregnant.
5
It is stated that pregnant women on a good diet should not take supplementary vitamin A except under medical advice.
2

These have been more extensively studied although no link

has been established between vitamin Adeficient status and partial molar pregnancy (73), premature rupture of membranes (74),
or eclampsia (75). One study reported lower vitamin A concentrations in placental abruption pregnancies than in normal pregnancies, but no cause-and-effect relation was established (76). It
is possible that the requirements of the embryo are met first, as
suggested by a 1962 study in which serum vitamin A values in
the mother were deficient, whereas cord blood values were
within the normal range (77). Such studies should be carried out
again with use of better analytic techniques.
Low vitamin A status does not seem to be related to a higher
incidence of intrauterine growth retardation (7880), although
one British study reported a significant correlation between birth
weight and anthropometric indexes in a low-income area of London (81). More worrying is the link consistently established
between low vitamin A status and high mother-to-child transmission of HIV. Several clinical trials are under way in Africa that
should definitively establish whether a causal link exists (82).
Circulating retinol values in mature newborns are always 50%
lower than those in the mother, and concentrations of <1 mmol/L
are frequent and should not be considered indicative of a deficient status at this stage (83, 84). The situation is more critical
for premature deliveries, because both serum and hepatic vitamin A concentrations can be very low and may pose a direct
threat to the childs health. Although vitamin A supplementation
can be used, its ability to prevent and reduce lung injury such as
bronchopulmonary dysplasia is still controversial (85, 86).
The fetus starts to accumulate vitamin A during the third
trimester of pregnancy, and needs several months of sufficient
intake after birth to build up an adequate hepatic store. In many
countries, babies are breast-fed, in which case the vitamin A content of the breast milk is of primary importance. The composition
of breast milk is influenced by the vitamin A status and serum concentrations of the mother during the last trimester of pregnancy
(87). Colostrum and early milk are extremely rich in vitamin A, and
even the milk of a mildly undernourished woman may meet the
physiologic needs of the newborn during the first weeks (8891).

After this time, however, a rapidly-growing infant may exhibit negative vitamin A balance, with severe consequences for health.
Young children who are vitamin A deficient are at greater risk
of morbidity and mortality than vitamin Asufficient children
(89). Diarrhea, respiratory infections, and measles are the diseases most frequently associated with a deficient vitamin A status
(90, 91). There are still some discrepancies in the results observed
in various community trials: vitamin A supplementation does not
always result in the expected decrease in morbidity, although
mortality is usually reduced (92, 93). Infants born to HIVinfected mothers are more vulnerable to disease, possibly, at least
partly, because of the impairment of their immune system.

PRACTICAL RECOMMENDATIONS: HOW CAN

ADEQUATE VITAMIN A STATUS DURING PREGNANCY
AND EARLY CHILDHOOD BE REACHED?
An adequate vitamin A status, one that is neither too low nor
too high, is needed for harmonious fetal and child development. In practice, practical recommendations vary greatly
according to the endemicity of inadequate vitamin A status,
vitamin A availability, and the socioeconomic constraints of the
country being considered. This is illustrated by the relatively
wide range of recommended daily allowances for vitamin A
(Table 3). Useful specific guidelines were published recently
by the World Health Organization (94).
In industrialized countries, there is no endemicity of low
vitamin A status, and consequently no need for vitamin A supplementation of pregnant women or women of childbearing
age. Such a measure could even be harmful because of the
potential risk of teratogenesis with high doses of vitamin A.
For the same reasons, over-the-counter supplements should
contain low amounts of vitamin A (less than one times the recommended daily amount) and caution should be taken regarding vitamin Arich foods. Certain authorities, such as the
World Health Organization, have taken an official stance. The
World Health Organization recommends that a daily vitamin A
supplement taking during any part of the fertile period be limited to 10 000 IU (3000 RE) (94). The Teratology Society of the

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Pregnancy outcomes in women with low vitamin A status

VITAMIN A IN PREGNANCY
REFERENCES

1. Saari JC. Retinoids in photosensitive systems. In: Sporn MB,

Roberts AB, Goodman DS, eds. The retinoids: biology, chemistry
and medicine. New York: Raven Press, 1994:35185.
2. Petkovitch M, Brand NJ, Krust A, Chambon P. A human retinoic
acid receptor which belongs to the family of nuclear receptors.
Nature 1987;330:44450.
3. Gigure V, Yang N, Segui P, Evans RM. Identification of a new class
of steroid hormone receptors. Nature 1987;330:6249.
4. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor
that identifies a novel retinoic acid-response pathway. Nature 1990;
345:2249.
5. Pemrick SM, Lucas DA, Grippo JF. The retinoid receptors.
Leukemia 1994;8:1797806.
6. Buck J, Ritter G, Dannecker L, et al. Intracellular signaling by 14hydroxy-4,14-retro retinol. Science 1991;254:16545.
7. Ross AC. Vitamin A status: relationship to immunity and the antibody response. Proc Soc Exp Biol Med 1992;200:30320.
8. Melton DA. Pattern formation during animal development. Science
1991;252:23441.
9. Brickell PM, Tickle C. Morphogens in chick limb development.
Bioassays 1989;11:1459.
10. Kastner P, Mark M, Chambon P. Non-steroid nuclear receptors:
what are genetic studies telling us about their role in real life? Cell
1995;83:85969.
11. Ghyselinck NB, Dup V, Dierich A, et al. Role of the retinoic acid
receptor beta (RAR beta) during mouse development. Int J Dev Biol
1997;41:42547.
12. Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of
malformations induced by maternal vitamin A-deficiency. Effects of
restoration of vitamin A at various times during gestation. Am J
Anat 1953;92:189217.
13. Li E, Sucov HM, Lee KF, Evans RM, Jeanisch R. Normal development
and growth of mice carrying a targeted disruption of the alpha 1 retinoic
acid receptor gene. Proc Natl Acad Sci U S A 1993;90:15904.
14. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P.
Function of retinoic acid receptor gamma in the mouse. Cell 1993;
73:64358.
15. Lufkin T, Lohnes D, Mark M, et al. High postnatal lethality and
testis degeneration in retinoic acid receptor alpha mutant mice. Proc
Natl Acad Sci U S A 1993;90:72259.
16. Lohnes D, Mark M, Mendelsohn C, et al. Function of the retinoic
acid receptors (RARs) during development (I). Cranofacial and
skeletal abnormalities in RAR double mutants. Development 1994;
120:272348.
17. Mendelsohn C, Lohnes D, Dcimo D, et al. Function of the retinoic
acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants.
Development 1994;120:274971.
18. Doll P, Ruberte E, Leroy P, Morriss-Kay G, Chambon P. Retinoic
acid receptors and cellular retinoid binding proteins. I. A systematic
study of their differential pattern of transcription during mouse
organogenesis. Development 1990;110:113351.
19. Mangelsdorf DJ, Borgmeyer U, Heyman RA, et al. Characterization
of three RXR genes that mediate the action of 9cis retinoic acid.
Genes Dev 1992;6:32944.
20. Eckhoff C, Nau H. Identification and quantitation of all-trans- and
13-cis-retinoic acid, and 13-cis-4-oxoretinoic acid in human
plasma. J Lipid Res 1990;31:144554.
21. Blaner WS, Olson JA. Retinol and retinoic acid metabolism. In:
Sporn MB, Roberts AB, Goodman DS, eds. The retinoids: biology,
chemistry and medicine. New York: Raven Press, 1994:22955.
22. Bavik CO, Busch C, Ericksson U. Characterization of a plasma
retinol-binding protein membrane receptor expressed in the retinal
pigment epithelium. J Biol Chem 1992;267:2303542.
23. Johansson S, Gustafsson AL, Donovan M, Romert A, Ericksson U,
Dencker L. Retinoid binding protein in mouse yolk sac and chorioallantoic placentas. Anat Embryol (Berl) 1997;195:48390.

Downloaded from ajcn.nutrition.org by guest on February 8, 2016

United States recommends that vitamin A supplements or total

intake not exceed 8000 IU/d (2400 RE/d) (99). These recommendations should be taken into account by both individuals
and practitioners. In France, the vitamin A content of a
supplement for the general population cannot exceed 3000 IU
(900 RE) (100), but a practitioner may prescribe higher doses
in medically designed preparations.
Most countries recommend that vitamin A supplementation
be avoided without medical advice. Physicians and gynecologists should be aware of all aspects of the vitamin Apregnancy
issue. They can then prescribe either a well-balanced diet rich in
b-carotenecontaining vegetables or vitamin A supplementation
to women with suspected low vitamin A status. Such status is
particularly difficult to assess. Indicators of low vitamin A status include a low serum retinol concentration (< 0.7 mmol/L)
and poor dietary habits.
In areas of endemic vitamin A deficiency, the problem and its
solutions are quite different. The benefit that pregnant women or
women of childbearing age and their children may derive from
vitamin A supplementation outweighs the potential risk. However,
extra caution should be taken to minimize this risk, especially
because for practical reasons supplementation is administered at
high doses. The recommendations of the World Health Organization can be summarized as follows:
1) During pregnancy, a daily supplement should not exceed
10 000 IU (3000 RE) and a weekly supplement should not
exceed 25 000 IU (7500 RE).
2) During the first 6 mo postpartum, supplementation is safer if
the mother is breast-feeding, which reduces fertility. Otherwise, the supplement given after 6 wk postpartum should not
exceed 10 000 IU (3000 RE).
3) During the first 6 mo of age, the infant can receive a direct
supplement of 50 000 IU (15 000 RE) or, preferably, 2 doses
of 25 000 IU (7500 RE) or more if he or she is not breast-fed.
Today, vitamin A supplementation is the most efficient way of
correcting vitamin A deficiency. Its only drawback is the potential risk of teratogenesis. Interesting attempts have been made to
replace vitamin A with the provitamin b-carotene, which has
never been associated with any teratogenic risk. When b-carotene
was provided as a synthetic supplement, it was as efficient as
vitamin A in reversing abnormal eye cytology, a clinical marker
of vitamin A deficiency (101). Other authors found that the
b-carotene of orange fruit (S de Pee, CE West, D Permaesih,
S Maruti, Muhilal, JGAJ Hautvast, unpublished observations,
1997) was a more efficient source of vitamin A than dark-green
leafy vegetables (102), probably because of the lower bioavailability of b-carotene in the latter. Fostering the local production
and utilization of sources of vitamin A is promising, yet the
problem lies not only in the availability of vitamin A sources, but
also in the economic status of the population.
Such a distinction between areas where vitamin A deficiency is
endemic (ie, some low-income countries) and those where it is not
(ie, industrialized countries) is convenient, but may not reflect the
real situation. It is quite possible, and in our opinion rather likely,
that a significant portion of the low-income population in some of
the most industrialized countries suffers from undiagnosed low
vitamin A status (103). Women in these populations, who often do
not undergo prenatal examinations, would benefit from a safely
designed vitamin A supplementation protocol. However, to our
knowledge, there has been no attempt to identify these women or
to correct their nutritional deficiencies.

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46. Eckhoff C, Collins MD, Nau H. Human plasma all-trans-, 13-cisand 13-cis-4-oxoretinoic acid profiles during subchronic vitamin A
supplementation: comparison to retinol and retinyl plasma levels.
J Nutr 1991;121:101625.
47. Buss NE, Tembe EA, Prendergast BD, Renwick AG, George CF.
The teratogenic metabolites of vitamin A in women following supplements and liver. Hum Exp Toxicol 1994;13:3343.
48. Chen C, Mistry G, Jensen B, et al. Pharmacokinetics of retinoids in
women after meal consumption or vitamin A supplementation.
J Clin Pharmacol 1996;36:799808.
49. Miller RK, Hendrickx AG, Mills JL, Hummler H, Wiegand UW.
Perioconceptional vitamin A use: how much is teratogenic? Reprod
Toxicol 1998;12:7588.
50. Brazzell RJ, Vane FM, Ehmann CW, Colburn WA. Pharmacokinetics of isotretinoin during repetitive dosing to patients. Eur J Clin
Pharmacol 1983;24:692702.
51. Tzimas G, Collins MD, Brgin H, Hummler H, Nau H. Embryotoxic doses of vitamin A to rabbits result in low plasma but high
embryonic concentrations af all-trans-retinoic acid: risk for vitamin
A exposure to humans. J Nutr 1996;126:215971.
52. Creech-Kraft J, Nau H, Lammer E, Olney A. Embryonic retinoid
concentration after maternal intake of isotretinoin. N Engl J Med
1989;321:262 (letter).
53. Gangemi M, Di Martino L, Maiuri F, Pettoello M. Intracranial
hypertension due to acute vitamin A intoxication. Acta Neurol
1985;7:2731.
54. Bacqui AH, De Francisco A, Arifeen SE, Siddique AK, Sack RB.
Bulging fontanelle after supplementation with 25 000 IU of vitamin A
in infancy using immunization contacts. Acta Paediatr 1995;84:8636.
55. Agoestina T, Humphrey JH, Taylor GA, et al. Safety of one 52-mmol
(50 000 IU) oral dose of vitamin A administered to neonates. WHO
Bulletin OMS 1994;72:85968.
56. Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage
caused by therapeutic vitamin A administration: estimates of doserelated toxicity in 41 cases. Gastroenterology 1991;100:17019.
57. Hathcock JN, Hattan DG, Jenkins MY, et al. Evaluation of vitamin
A toxicity. Am J Clin Nutr 1990;52:183202.
58. Biesalski HK. Comparative assessment of the toxicology of vitamin
A and retinoids in man. Toxicology 1989;57:11761.
59. Martines-Frias ML, Salvador J. Epidemiological aspects of prenatal
exposure to high doses of vitamin A in Spain. Eur J Epidemiol
1990;6:11823.
60. Werler MM, Lammer EJ, Rosenberg L, Mitchell AA. Maternal vitamin A supplementation in relation to selected birth defects. Teratology 1990;42:497503.
61. Botto LD, Khoury MJ, Miulinare J, Erickson JD. Periconceptional
multivitamin use and the occurrence of conotruncal heart defects:
results from a population-based, case-control study. Pediatrics
1996;98:9117.
62. Mills JL, Simpson JL, Cunningham GC, Conley MR, Rhoads GG.
Vitamin A and birth defects. Am J Obstet Gynecol 1996;177:316.
63. Shaw GM, Velie EM, Schaeffer D, Lammer EJ. Periconceptional
intake of vitamin A among women and risk of neural tube defectaffected pregnancies. Teratology 1997;55:1323.
64. Rothman KJ, Moore LL, Ringer MR, Nguyen UDT, Mannino S,
Milunsky A. Teratogenicity of high vitamin A intake. N Engl J Med
1995;333:136973.
65. Werler MM, Lammer EJ, Mitchell AA. Teratogenicity of high vitamin A intake: reply. N Engl J Med 1996;334:1195 (letter).
66. Dudas I, Czeisel AE. Use of 6000 IU vitamin A during early pregnancy without teratogenic effect. Teratology 1992;45:3356.
67. Underwood BA. Vitamin in human nutrition. Public health considerations. In: Sporn MB, Roberts AB, Goodman DS, eds. The
retinoids: biology, chemistry and medicine. New York: Raven Press,
1994:21127.
68. WHO/OMS. Highlights of recent activities in the context of the
world declaration and plan for action for nutrition. Geneva: World
Health Organization, 1995. (WHO/OMS/95.2.)

Downloaded from ajcn.nutrition.org by guest on February 8, 2016

24. Noy N, Slosberg E, Scarlata S. Interactions of retinol with binding

proteins: studies with retinol-binding protein and with transthyretin.
Biochemistry 1992;31:1111824.
25. Hodam JR, Creek KE. Comparison of the metabolism of retinol
delivered to human keratinocytes either bound to serum retinolbinding protein or added directly to the cell culture medium. Exp
Cell Res 1998;238:25764.
26. Ger G, Anthony F, Rowe DJF, Dennis KJ. Increased urinary excretion of retinol-binding protein during normal pregnancies. Clin
Chem 1986;32:9167.
27. Sklan D, Shalit I, Lasebnik N, Spirer Z, Weisman Y. Retinol transport proteins and concentrations in human amniotic fluid, placenta,
and fetal and maternal sera. Br J Nutr 1985;54:57783.
28. Dancis J, Levitz M, Katz J, et al. Transfer and metabolism of retinol
by the perfused human placenta. Pediatr Res 1992;32:1959.
29. Trma H, Vahlquist A. Uptake of vitamin A and retinol-binding protein by human placenta in vitro. Placenta 1986;7:295305.
30. Duester G. Involvement of alcohol dehydrogenase, short-chain
dehydrogenase/reductase, aldehyde dehydrogenase, and cytochrome
P-450 in the control of retinoid signaling by activation of retinoic
acid synthesis. Biochemistry 1996;35:122217.
31. Deltour L, Ang HL, Duester G. Ethanol inhibition of retinoic acid
synthesis as a potential mechanism for fetal alcohol syndrome.
FASEB J 1996;10:10507.
32. Boerman MHEM, Napoli JL. Cellular-binding protein-supported
retinoic acid synthesis. Relative roles of microsomes and cytosol.
J Biol Chem 1996;271:56106.
33. Urbach J, Rando RR. Isomerization of all-trans-retinoic acid to
9-cis-retinoic acid. Biochem J 1995;299:45965.
34. Mertz JR, Shang E, Piantedosi R, Wei S, Wolgemuth DJ, Blaner
WS. Identification of a stereospecific human enzyme that catalyzes
9-cis-retinol oxidation. J Biol Chem 1997;272:117449.
35. Wang XD, Krinsky NI. Identification and quantification of retinoic
acid and other metabolites from beta-carotene excentric cleavage.
Methods Enzymol 1997;282:11730.
36. Borel P, Grolier P, Mekki N, et al. Low and high responders to pharmacological doses of b-carotene: proportion in the population,
mechanisms involved and consequences on b-carotene metabolism.
J Lipid Res 1998;39:225060.
37. Sapin V, Ward S, Bronner S, Chambon P, Doll P. Differential
expression of transcripts encoding retinoid binding proteins and
retinoic acid receptors during placentation of the mouse Dev Dyn
1997;208:199210.
38. Boylan JF, Gudas LJ. The level of CRABP-I expression influences
the amounts and types of all-trans-retinoic acid metabolites in F9
teratocarcinoma stem cells. J Biol Chem 1992;267:2148691.
39. Lampron C, Rochette-Egly C, Gorry P. Mice deficient in cellular
retinoic acid binding protein II (CRABP II) or in both CRABP I and
II are essentially normal. Development 1995;121:53948.
40. Nikawa T, Schulz WA, VandenBrink CE, et al. Efficacy of all-transbeta-carotene, canthaxanthin, and all-trans, 9-cis-, and 4-oxoretinoic
acids in inducing differentiation of an F9 embryonal carcinoma
RAR beta-lacZ reporter cell line. Arch Biochem Biophys 1995;
316:66572.
41. Barua AB. Retinoyl b-glucuronide: a biologically active form of
vitamin A. Nutr Rev 1997;55:25967.
42. Tzimas G, Nau H, Hendrickx AG, Peterson PE, Hummler H.
Retinoid metabolism and transplacental pharmacokinetics in the
cynomolgus monkey following a nonteratogenic dosing regimen
with all-trans-retinoic acid. Teratology 1996;54:25565.
43. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy.
N Engl J Med 1985;313:83741.
44. Rainier S. Retinol homeostasis during organogenesis in the fetal rat.
PhD dissertation. Southwestern Medical School, Dallas, 1990.
45. Chen H, Namkung MJ, Juchau MR. Biotransformation of all-transretinol and all-trans-retinal to all-trans retinoic acid in rat conceptal homogenates. Biochem Pharmacol 1995;50:125764.

VITAMIN A IN PREGNANCY

86. ICGPD (Italian Collaborative Research Group on Preterm Delivery). Vitamin A supplementation in premature neonates with postnatal injury. Int J Clin Pharmacol Ther 1996;34:3625.
87. Ortega RM, Andres P, Martinez RM, Lopez-Sobaler AM. Vitamin A
status during the third trimester of pregnancy in Spanish women:
influence on concentrations of vitamin A in breast milk. Am J Clin
Nutr 1997;656:5648.
88. West KP Jr, Chirambo M, Katz J, Sommer A, the Malawi Survey
Group. Breast-feeding, weaning patterns, and the risk of xerophthalmia in Southern Malawi. Am J Clin Nutr 1986;44:6907.
89. Humphrey JH, West KP, Sommer A. Vitamin A deficiency and
attributable mortality among under-5-year-olds. WHO Bulletin
OMS 1992;70:22532.
90. West KP, Howard GR, Sommer A. Vitamin A and infection: public
health implications. Annu Rev Nutr 1989;9:6386.
91. Fawzi WW, Herrera MG, Willett WC, Nestel P, Amin AE, Mohamed
KA. Dietary vitamin A intake and the incidence of diarrhea and respiratory infection among Sudanese children. J Nutr 1995;125:121121.
92. Underwood BA. Was the anti-infective vitamin misnamed? Nutr
Rev 1994;52:1403.
93. Fawzi WW, Herrera MG, Willett WC, Nestel P, Amin AE, Mohamed
KA. The effect of vitamin A supplementation on the growth of preschool
children in the Sudan. Am J Public Health 1997; 87:135962.
94. WHO. Safe vitamin A dosage during pregnancy and lactation. Recommendations and report from a consultation. Micronutrient series.
Geneva: World Health Organization, 1998. (WHO.NUT/98.4.)
95. National Research Council. Vitamin A. In: Recommended dietary
allowances. 10th ed. Washington, DC: National Academy Press,
1989:7892.
96. Department of Health. Vitamin A. In: Dietary reference values for
food energy and nutrient for the United Kingdom. London: Her
Majestys Stationery Office, 1991:859. (Report on health and
social subjects 41.)
97. CNRS-CNERNA. Vitamin A. In: Dupin H, Abraham J, Giacchetti I.
Apports nutritionnels conseills pour la population Franaise. (Recommended dietary intakes for the French population.) Paris:
Lavoisier, 1992:525 (in French).
98. European Community. Nutrient and energy intake for the European
Community. In: Reports of the scientific committee for food. Brussels: European Commission, 1993:6070.
99. Anonymous. Teratology Society position paper: recommendations
for vitamin A use during pregnancy. Teratology 1987;35:26975.
100. Azas-Braesco V. Vitamin A. In: Les limites de scurit dans les
consommations alimentaires des vitamines et des minraux. (Upper
safety limits for vitamin D and mineral intakes.) Paris: Lavoisier,
1996:10114 (in French).
101. Carlier C, Coste J, Etchepare M, Priquet B, Amde-Manesme O.
A randomised controlled trial to test equivalence between retinyl
palmitate and b-carotene for vitamin A deficiency. BMJ 1993;
307:110610.
102. de Pee S, West CE, Muhilal, Karyadi D, Hautvast JGAJ. Lack of
improvement in vitamin A status with increased consumption of
dark-green leafy vegetables. Lancet 1995;346:7581.
103. Stephens D, Jackson PL, Gutierrez Y. Subclinical vitamin A deficiency: a potentially unrecognized problem in the United States.
Pediatr Nurs 1996;22:37789.

Downloaded from ajcn.nutrition.org by guest on February 8, 2016

69. Wellik DM, Norback DH, DeLuca HF. Retinol is specifically

required during midgestation for neonatal survival. Am J Physiol
1997;272:E259.
70. van Pelt AMM, van Dissel-Emiliani FMF, Gaemers IC, van den
Burg M, Tanke HJ, de Rooij DG. Characteristics of aspermatogonia
and preleptotene spermatocytes in the vitamin A-deficient rat testis.
Biol Reprod 1995;53:5708.
71. Akordor FY, Stone JB, Walton JS, Leslie KE, Buchanan-Smith JG.
Reproductive performance of lactating Holstein cows fed supplemental b-carotene. J Dairy Sci 1986;69:21738.
72. Kapoor S, Kapoor M. Congenital ocular anomalies in Pondicherry.
J Pediatr Ophthalmol 1977;14:3829.
73. Berkowitz RS, Bernstein MR, Harlow BL, et al. Case-control study
of risk factors for partial molar pregnancy. Am J Obstet Gynecol
1995;173:78894.
74. Westney OE, Westney LS, Johnson AA, et al. Nutrition, genital
tract infection, hematologic values, and premature rupture of
membranes among African American women. J Nutr 1994;124:
987S93S.
75. Ziari SA, Mireles VL, Cantu CG, et al. Serum vitamin A, vitamin E,
and b-carotene levels in preeclamptic women in northern Nigeria.
Am J Perinatol 1996;13:28791.
76. Sharma SC, Bonnar J, Dostalova L. Comparison of blood levels of
vitamin A, b-carotene and vitamin E in abruptio placentae with
normal pregnancy. Int J Vitam Nutr Res 1986;56:39.
77. Venkatachalam PS, Belavady B, Gopalan C. Studies on the vitamin
A nutritional status of mothers and infants in poor communities of
India. Trop Pediatr 1962;61:2628.
78. Rondo PHC, Abbott R, Rodrigues LC, Tomkins AM. Vitamin A,
folate, and iron concentration in cord and maternal blood of intrauterine growth retarded and appropriate birth weight babies. Eur J
Clin Invest 1995;49:3919.
79. Hasin A, Begum R, Khan MR, Ahmed F. Relationship between birth
weight and biochemical measures of maternal nutritional status at
delivery in Bangladeshi urban poors. Int J Food Sci Nutr 1996;
47:2739.
80. Tamura T, Goldenberg RL, Johnston KE, Cliver SP, Hoffman HJ.
Serum concentrations of zinc, folate, vitamins A and E, and proteins
and their relationships to pregnancy outcome. Acta Obstet Gynecol
Scand Suppl 1997;165:6370.
81. Ghebremeskel K, Burns L, Burden TJ. Vitamin A and related essential nutrients in cord blood: relationships with anthropometric measurements at birth. Early Hum Dev 1994;39:17788.
82. Semba RD. Overview of the potential role of vitamin A in motherto-child transmission of HIV-1. Acta Paediatr 1997;421(suppl):
10712.
83. Godel JC, Basu TK, Pabst HF, et al. Perinatal vitamin A (retinol)
status of northern Canadian mothers and their infants. Biol Neonate
1996;69:1339.
84. Tamai H, Mingci Z, Kawamura N, Kuno T, Ogihara T, Mino M. Fatsoluble vitamins in cord blood and colostrum in the south of China.
Int J Vitam Nutr Res 1996;66:2226.
85. Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of
vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia. J Pediatr 1987;111:26977.

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