Society Position Paper:
Recommendations For Vitamin A Use During Pregnancy
© 1987 ALAN R. LISS, INC.
is well known that vitamin A is an essential nutrient for normal
cellular function, including reproduction and development. Vitamin
A deficiency is a worldwide problem of great magnitude. It should
be noted that "vitamin A" is a term used often ambiguously.
The total indicated vitamin A content of foods usually includes
vitamin A derived from carotene,1 a vitamin A precursor, as well
as retinol. Carotene, e.g., beta-carotene, has not been associated
with vitamin A toxic effects; accordingly the warning contained
in this paper is intended for countries and their citizens that
have high-potency vitamin A preparations (as retinol or retinyl
esters) readily available. Supplements that contain 25,000 International
Units (IU) or more of vitamin A per capsule are available as over-the-counter
preparations in many areas. The risk of birth defects owing to synthetic
vitamin A analogs has already been documented in humans, and recently
the ingestion of excess vitamin A (25,000 IU or more) as retinol/retinyl
esters during pregnancy has been associated with some birth defects
in a small number of case reports, although it is not known that
the relationship is causal. It is with this caution that the following
recommendations concerning the use of vitamin A supplements as retinol/retinyl
esters during pregnancy are presented to all interested individualsparents,
health care-providers, manufacturers, regulators, legislators, and
scientists in our world community.
Women in their reproductive years should be informed that the excessive
use of vitamin A shortly before and during pregnancy could be harmful
to their babies. The National Research Council's recommended dietary
allowance for vitamin A during pregnancy is 1,000 retinol equivalents
(RE)/day, which is equivalent to 3,300 IU as retinol or 5,000 IU
of vitamin A obtained from the typical American diet as a combination
of retinol and carotenoids, e.g., beta-carotene. An average balanced
diet contains approximately 7,000-8,000 IU of vitamin A derived
from different sources. Therefore, women who are at risk for becoming
pregnant should consider their dietary intake of vitamin A before
taking supplements. The USRDA (recommended daily allowance) established
by the Food and Drug Administration is 8,000 IU/day. Supplementation
of 8,000 IU vitamin A (as retinol/retinyl esters) per day should
be considered the recommended maximum prior to or during pregnancy
until further evaluations can be performed in the human population.
It is important to determine the type of vitamin A consumed, since
beta-carotene has not been associated with vitamin A toxicity in
animals or man.
Manufacturers of vitamin A (as retinol or retinyl esters) should
lower the maximum amount of vitamin A per unit dosage to 5,000-8,000
IU (1,500-2,400 RE) and identify the source of the vitamin A. High
dosages of vitamin A as retinol/retinyl esters (25,000 IU or more)
are not recommended, since these dosages are not necessary as a
nutrient supplement and may be teratogenic at some as yet undetermined
dose. With over-the-counter preparations, a major concern is the
use of multiple doses daily. The public perception of "one
dose is good, two are better" must be addressed by the manufacturers
concerning recommended daily intake of that particular preparation.
It is suggested that beta-carotene be considered the primary source
of these vitamins for women in their reproductive years to reduce
risk even further.
Labeling of products containing vitamin A supplements (as retinol/retinyl
esters) should indicate (a) that consumption of excessive amounts
of vitamin A may be hazardous to the embryo/fetus when taken during
pregnancy; and (b) that women of childbearing potential should consult
with their physicians before consuming these products.
Studies of the reproductive and developmental toxicity of vitamin
A are essential and should receive national and international priority.
Well-controlled epidemiologic and pharmacologic studies in humans
are essential. In addition, studies of dose-response relationships,
metabolism/distribution, mechanisms of action for induction of birth
defects, and postnatal dysfunction in animals are of critical importance.
A .is important in maintaining normal growth, regulating proliferation
and differentiation of epithelial tissues, and maintaining visual
and reproductive functions (Goodman, '84). Vitamin A analogs (retinoids)
are used in the clinical management of dermatologic diseases such
as acne, psoriasis, icthyosis and in oncology. More than 1,500 retinoids
have been synthesized in an attempt to separate side effects from
clinically desirable therapeutic efficacy (Bollag and Matter, '81;
Bollag, '83). The use of vitamin A and retinoids in the United States
and other developed countries is increasing. Ingestion of excess
nutrients, including "megadose" supplements, is being
encouraged by popular writers such as Linus Pauling ('86), Adele
Davis ('70), and others. The purpose of this paper is to express
concern that indiscriminate use of vitamin A during pregnancy could
lead to an increased risk of congenital anomalies. A large volume
of literature documents the experimental use of these compounds
as teratogens in animal models and as cellular modifiers in other
biologic systems. Case reports of malformed children of mothers
who have taken excess vitamin A are accumulating. Isotretinoin (13-cis-retinoic
acid, Accutane®) has been established as a human teratogen;
and etretinate (Tigason®), an aromatic retinoid, has also been
implicated in such effects.
A (retinol and retinyl esters) and its naturally occurring congeners,
retinaldehyde and all-trans retinoic acid (tretinoin), are part
of a large class of chemical compounds, the retinoids. Retinoids
include both naturally occurring compounds with vitamin A activity
and synthetic analogs of retinoic acid. Comprehensive reviews of
the biology and function of vitamin A and retinoids have appeared
recently (Bauernfeind, '83; Olsen et al., '83; Wolf, '84; Goodman,
'84) including a two-volume treatise (Sporn et al., '84) and an
issue of the New York Academy of Sciences (DeLuca and Shapiro, '81).
intake of vitamin A that greatly exceeds the recommended daily allowance
leads to clinical manifestations of hypervitaminosis A with toxic
effects to the central nervous system, liver, bone, and skin (Goodman,
'84). The toxicity of retinoids has been reviewed (Underwood, '84;
Howard and Willhite, '86).
as retinol and beta-carotene are widely used as vitamin A supplements.
To determine the source which provides the retinol, one must define
the unit activity of each compound by its effectiveness. It is important
to determine the type of vitamin A consumed, since beta-carotene
is not metabolized or stored in the same way as vitamin A. Beta-carotene
also has not been associated with vitamin A toxicity in animals
or humans (Underwood, '84). Thus, such lack of vitamin A toxicity
associated with beta-carotene suggests that beta-carotene is not
a human teratogen, even though there are no data at the present
time on which to confirm this conclusion.
understand the biologic effectiveness of vitamin A, its synthetic
analogs, and provitamin (carotenoids), a definition of unit activity
must be appreciated. One international unit (IU) of vitamin A is
equivalent to 0.3 mcg of all-trans-retinol. A retinol equivalent
(RE) is used to convert all sources of vitamin A and carotenoids
in the diet to a single unit. Thus, 1 mcg of all-trans-retinol equals
1 RE. For comparison by readers accustomed to international units,
25,000 IU of vitamin A is equivalent to 7.5 mg of all-trans-retinol.
Generally, 1 mcg of retinol is assumed to be biologically equivalent
to 6 mcg of beta-carotene or 12 mcg of mixed dietary carotenoids.
RE is becoming a more accepted term because it reflects the different
activities of chemicals as noted for dietary cartenoids, e.g., beta-carotene.
This position paper uses international units since it is the most
common expression of daily dosage in the market place.
metabolism of retinol and its derivatives/esters differ, especially
transport and binding. Retinoic acid is absorbed through the portal
system and transported in plasma, bound to serum albumin; it does
not accumulate appreciably in liver and other tissues. Retinyl esters,
on the other hand, are usually hydrolyzed in the intestinal lumen.
The luminal retinol is absorbed into the mucosal cells where it
is reesterified and absorbed into the lymphatic system. The retinyl
esters in the form of chylomicron remnants are removed from the
circulation and stored by the liver. Ingestion of high-retinol doses
by humans yields high plasma retinyl ester concentrations without
appreciably altering plasma retinol levels (Goodman et al., '83).
Retinol is released from the liver bound to retinol-binding protein
in the plasma and does not manifest its toxic effect unless the
binding capacity is exceeded. Doses of retinol which yield high
plasma retinyl ester concentrations are of principle concern.
A deficiency is a worldwide problem of much greater magnitude than
hypervitaminosis A; accordingly, the warning contained in this paper
is intended for countries which have high-potency vitamin A preparations
readily available to the public
teratogenicity of excess vitamin A in laboratory animals was first
reported more than 30 years ago by Cohlan ('53). He fed pregnant
rats 35,000 IU vitamin A per day on days 2-16 of gestation and noticed
a number of fetal anomalies such as exencephaly, cleft lip and/or
palate, brachygnathia, and various eye defects. Subsequently, other
animal speciesincluding mice, guinea pigs, hamsters, and rabbitswere
found to be similarly susceptible to hypervitaminosis A (Geelen,
teratologists began studying synthetic retinoids in the mid' sixties
(Kochhar, '67) because unlike natural vitamin A compounds, they
accumulate minimally in body tissues, and more quantitative dosing
could be achieved. Subsequently, these retinoids were found to affect
almost every developing tissue and organ (Geelen, '79). Shenefelt
('72) documented almost 70 types of fetal anomalies after exposure
of pregnant hamsters to all-trans-retinoic acid. The anomalies were
developmentally stage-dependent; treatment during the immediate
postimplantation period resulted in anomalies of the head, sensory
organs, and the cardiovascular system, whereas exposure later in
gestation resulted in limb and genitourinary defects (Kochhar, '73;
Geelen, '79; Willhite and Balogh-Nair, '85; Webster et al., '86).
investigators have used a single high dose of retinoids given to
pregnant animals on selected days of gestation to elicit stage-dependent
developmental effects. The literature on the minimal teratogenic
doses of retinoids is not extensive. Such information is important
to estimate safe or no-effect levels in humans from animal data
(Table 1). The doses of retinoids in this table are those commonly
used in studies during organogenesis in which the animals are treated
daily for about 10 days (e.g., days 6-15 of gestation in the rat).
Single doses range between 25 and 100 mg/kg during organogenesis
and affect virtually every exposed embryo.
Lowest teratogenic dose (mg/kg/day) of vitamin A1 and synthetic
retinoids in animals and man
1 Retinol or retinyl esters.
2 Rosa et al., '86.
3 Kamm, '82; Kamm et al., '84.
4 Kochhar and McBride, '86.
5 Zbinden, '75a.
6 Howard and Willhite, '86 (from single dose experiments).
7 ND = not determined.
8 Agnish, Roche, Inc. (personal communication).
pattern of malformations induced by retinoid analogs is similar
to that induced by naturally occurring forms of vitamin A if given
during the same period of embryogenesis(Geelen, '79; Lammer et al.,
'85; Rosa et al., '86; Willhite et al., '86).
reports have documented functional and behavioral deficits in the
offspring of animals exposed to maternal hypervitaminosis A. Cognitive
and behavioral abnormalities were detected in rat offspring (Hutchings
et al., '73; Vorhees et al., '78; Mooney et al., '81).
does vitamin A or the retinoid molecule interfere with embryonic
organ formation or cellular function? No definite answers are available.
Early studies considered pathologic changes in the embryonic mesoderm
(Marin-Padilla and Ferm, '65), but the combination of ear, thymus,
great vessel, and brain abnormalities in isotretinoin-exposed human
infants has raised speculation that a specific effect on cranial
neural crest cells may be involved. Experimental studies on mouse
and hamster embryos have strengthened this notion (Webster et al.,
'86; Goulding and Pratt., '86; Irving et al., '86). Thorogood et
al. ('82) indicated that not only neural crest cells but also other
migratory cells are susceptible to retinoic acid. Other experimental
studies lend support to this hypothesis (Kwasigroch and Kochhar,
'75; Morriss, '76).
perturbation of cellular events, which is common to most developing
organs, is a logical assumption for one possible mechanism of retinoid
action. Cell death, interference with some aspect of cell multiplication
pattern, cell differentiation, extra-cellular matrix synthesis,
or an alteration in overall pattern formation are additional mechanisms
that have been advanced. Changes in pattern formation have been
observed by developmental biologists working on retinoid-treated
chick and amphibian embryos (Maden and Summerbell, '86).
cell types, both normal and transformed, are responsive to retinoids,
pointing to some fundamental molecular and cellular mechanisms of
action (Sporn and Roberts, '83). Some evidence suggests that the
retinoid enters the cell, binds to a specific cytoplasmic binding
protein, and may be transported to the nucleus, where it may alter
the pattern of gene action. Two cellular binding proteins, one specific
for retinol and the other for retinoic acidcalled cellular
retinol binding protein (CRBP) and cellular retinoic acid binding
protein (CRABP), respectivelyare present in various tissues
(Chytil and Ong, '84). The presence of CRABP has been detected in
mouse and chick embryos (Kwarta et al., '85; Maden and Summerbell,
'86). The role of these binding proteins or of changes in gene transcription
which mediate the teratogenic action of vitamin A is not well defined.
recommended dietary allowance (RDA) of vitamin A during pregnancy
is 1,000 RE, which is equal to 3,300 IU of retinol or retinyl esters
or 5,000 U in an average U.S. diet containing a mixture of retinol
and carotenoids (Food and Nutrition Board, 1980) (Table 2). The
RDA of vitamin A during pregnancy was established by extrapolating
from that recommended for the nonpregnant adult (800 RE/day or 4,000
IU/day). The International Vitamin A Consultative Group (IVACG)
recommended a daily intake of 9.3 RE/kg plus 100 RE during pregnancy
(Underwood, '86); this is approximately 620 RE/day (1,800 IU/day)
of vitamin A for a 55-kg woman. The World Health Organization (WHO)
and IVACG state that a daily supplemental dose of 3,000 RE (10,000
IU) of vitamin A is appropriate in geographical areas or under conditions
where vitamin A intake is known to be inadequate and when diet cannot
be improved. The USRDA (U.S. recommended daily allowance) of 8,000
IU/day during pregnancy has been established by the U.S. Food and
Drug Administration (FDA) as a standard for nutrition labeling,
including the labeling of nutritional supplements. Most prenatal
vitamin preparations contain 8,000 IU/capsule of vitamin A as a
daily supplement. Dietary surveys in the U.S., however, have defined
that the average unsupplemented adult diet contains 7,0008,000
IU/day of vitamin A (Russell-Briefel et al., '85). Therefore, women
who are at risk for pregnancy should consider their total dietary
intake of vitamin A before taking supplements.
Vitamin A1 and synthetic retinoids in humans
and retinyl esters
for nonpregnant women2
for pregnant women2
adult3 adverse levels
lowest teratogenic level
lowest teratogenic level4
Retinol or retinyl esters
2 See Food and Nutrition Board: National Academy of Sciences,
3 Kamm, '82; Kamm et al, '84.
4 Rosa et al., '86
least seven case reports of adverse pregnancy outcome associated
with a daily intake of vitamin A of 25,000 IU or more have been
published (Rosa et al., '86). These authors have also presented
unpublished information from eleven Adverse Drug Reaction Reports
associated with the use of vitamin A during pregnancy that were
filed with the FDA. Almost all of the FDA cases are brief, retrospective
reports of malformed infants or fetuses exposed to supplements of
25,000 IU/day or more of vitamin A during pregnancy. The biases
that contributed to the decision to report or publish these cases
of malformed vitamin A-exposed infants are unknown but are probably
substantial. Some of these infants have malformations similar to
those found among isotretinoin-exposed infants; the malformations
of the others were quite different. At best, it can be said that
the malformations of some of the vitamin A-exposed infants fit the
pattern of malformation seen among infants exposed to isotretinoin.
There are no epidemiologic studies that provide the data necessary
to quantitate the risk for major malformation following daily fetal
exposure to supplements of any dose of vitamin A.
the initial report of three malformed infants (Roche Laboratories
'83), epidemiologic evidence began to accumulate that isotretinoin
is a human teratogen (Rosa, '83). Lammer et al. ('85) found that
isotretinoin use during early pregnancy caused major malformations
in almost 20% of exposed fetuses. The malformations involved craniofacial,
central nervous system, cardiac, and thymic structures. Isotretinoin-exposed
infants were 26 times more likely to have brain, cardiac, or ear
malformations than unexposed infants. The brain malformations included
hydrocephalus (several types), microcephaly, cerebellar micro- and
macrodysgenesis, and other abnormalities which can be via neuronal
migrational defects. Cardiac malformations included aorticopulmonary
septation abnormalities or conotruncal developmental defects (Lammer
and Opitz, '86). Craniofacial malformations included malformed external
ears, stenotic/atretic external ear canals, micrognathia, facial
asymmetry, and cleft palate. Most of the mothers of affected infants
took daily doses of isotretinoin at levels of 0.5-1.5 mg/kg (Lammer
et al., '85).
we extrapolate from the known teratogenic daily dose of isotretinoin
to an equivalent intake of vitamin A? Probably not at this time.
We know that the malformations in laboratory animals and humans
after isotretinoin treatment are strikingly similar. Yet the pharmacologic
differences between vitamin A and isotretinoin make it difficult
to estimate the amount of each compound to which an embryo is exposed
when comparable amounts have been taken orally. For example, the
relative teratogenic concentrations for various retinoids could
be determined by using whole postimplatation rodent embryo cultures;
however, there are no widely accepted procedures to extrapolate
these data to the pregnant human. Finally, in a single case, regardless
of vitamin A intake, one cannot impute the cause of birth defects
to vitamin A based upon present knowledge.
summary, the review of vitamin A has raised questions concerning
its human teratogenicity. It is essential to evaluate these concerns
in a systematic manner (Shepard '73 '86; Wilson '77; Brent '78,
'86a, '86b; Stein et al., '84; Hemminki and Vineis '85).
Do human clinical studies or epidemiological studies consistently
support the concept that high doses of vitamin A may be teratogenic
and produce a recognizable group of malformations?
human epidemiologic studies are available. Although not conclusive,
the case reports suggest that high doses of vitamin A may be teratogenic,
since some of the infants had malformations that fit the recognizable
pattern that occurred following human exposure to isotretinoin.
Do secular trends of high-dose vitamin A exposure and the birth
prevalence of malformations correlate?
is sufficient information concerning trends in exposures to high-dose
vitamin A and concerning knowledge of defects that may be induced
by use of vitamin A.
Does vitamin A induce malformations in experimental animals following
exposures to doses that are pharmacologically comparable to the
maternal use (25,000 IU or more) of one or several unit doses per
day of the vitamin A products that are available to the public?
Is the frequency of malformations dose related and in the pharmacologic
range of human toxic exposures?
are not available for the human. Yesfor animal studies
Is it biologically plausible that high doses of vitamin A may cause
birth defects in the human?
isotretinoin is a known human teratogen. Since isotretinoin and
vitamin A (retinol and retinyl esters) induce similar patterns of
malformations in animals, it is probable that similar pathogenetic
mechanisms are involved in inducing the malformations. Currently
there is no evidence to suggest that vitamin A should act differently
than isotretinoin in the human conceptus. Beta-carotene, a provitamin
A, does not produce vitamin A toxicity nor does it produce teratogenicity
in animals. All of these data are consistent with a specific vitamin
A-related teratogenic response.
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1In its provitamin A form, e.g., beta-carotene, vitamin
A is found in carrots, tomatoes, and many other "red, yellow,
and green" vegetables. As the retinol, vitamin A is found in
oil of cod and other fish, egg yolks, cheese, liver, and butter.
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