Vitamin A is a chemical that is essential to sustain human life and must be provided in
adequate amounts through food or other dietary supplements. However, excessive consumption
of vitamin A can cause birth defects. Recently, birth defects have been observed in
children born to mothers taking synthetic vitamin A drugs used to treat acne. These
observations raised concerns that high vitamin A intake during pregnancy could cause birth
defects in unborn children. Initial studies comparing levels of vitamin A intake during
pregnancy in women who had healthy infants to woman who gave birth to infants with birth
defects were contradictory. However, birth defects were observed in the young of animals
fed high concentrations of vitamin A during pregnancy. The California Environmental
Protection Agency (CAL/EPA) has identified retinol or retinyl esters (types of pre-formed
vitamin A) as developmental toxins when administered at doses greater than 10,000
International Units (IU). The Food and Drug Administration has established a daily
recommended allowance (RDA) of 5,000 IU for vitamin A. Because vitamin A is required to
ensure reproductive health, it has been recommended that pregnant woman maintain their
intake around 8,000 IU and that vitamin A be taken in the form of beta-carotene, which is
not considered toxic. Women can take vitamin A in many forms. Pre-formed vitamin A
(retinol or retinyl esters) is found in liver, vitamin tablets, and fortified cereals.
Beta-carotene is found in fruits and vegetables and is converted to vitamin A in the body.
Vitamin A occurs in several different forms. Pre-formed vitamin A is a family of
substances called retinol or retinyl esters (Teratology
Society; 1987). Retinyl palmitate and retinyl acetate are examples of retinyl esters
that are commonly used in vitamins (Illinois Teratogen Information Service). Pre-formed vitamin A is also found in animal products like liver and in
fortified cereals and vitamin tablets (Illinois Teratogen Information Service). Beta-carotene, found in fruits and vegetables, is a vitamin A precursor, which
means that it is converted to vitamin A in the body.
Concentrations of vitamin A are expressed in terms of International Units (IU) or
retinol equivalents (RE) (Teratology Society; 1987).
An IU is equivalent to 0.3 microgram (mc) of a vitamin A compound called
all-trans-retinol. Units of RE are used to standardize different forms of dietary vitamin
A and 1 RE is equal to 1 mg of all-trans-retinol.
Some women who used the synthetic vitamin A drug Accutane® while pregnant gave birth
to babies with birth defects, according to the March of Dimes (http://www.marchofdimes.com/pregnancy/alcohol_accutane.html).
Examples of birth defects were "hydrocephaly (enlargement of the fluid-filled spaces
in the brain); microcephaly (small head); mental retardation; ear and eye abnormalities,
cleft lip and palate, and other facial abnormalities and heart defects." Women who
took the drug also had a higher risk of miscarriage. The active ingredient in Accutane®,
isotretinoin, is produced in the body in small amounts after eating vitamin A. Therefore,
concerns were raised that a high intake of vitamin A by pregnant women could cause birth
defects in infants.
Contradictory results have been obtained in studies that examined vitamin A intake
during pregnancy and birth defects in humans. A study sponsored by the National Institute
of Child Health and Human Development (NICHD) compared vitamin A intake during pregnancy
in women who had given birth to infants who were healthy, who had a neural tube defect
(defects in the brain and spinal cord), and who had a cranial-neural-crest defect
(malformation of cleft palate, face, or heart) (NIH News Alert; July 22, 1997).
It was concluded, "When compared to women in the control group, neither the women in
the neural tube defect group nor those in the group pregnant with children having other
major malformations were found to have been more likely to have consumed between 8,000 and
10,000 IU of vitamin A."
A similar study conducted at the Boston University School of Medicine compared vitamin
A intake during pregnancy in women who had given birth to healthy infants or who had
cranial-neural-crest defects (defects of the head, face, nervous system excluding the
neural tubes, thymus, and heart), neural tube defects (defects in brain or spinal cord),
or defects of the bones, muscles, or urinary tract (New England Journal of Medicine Journal
Club; 333:1369-73; 11/23/95). The study found that women who took about 10,000 IU or
more vitamin A during pregnancy were more likely to give birth to a child with a
cranial-neural-crest defect. It was estimated that intakes of greater than 10,000 IU of
vitamin A by pregnant women could result in a defect in one of every 57 infants.
According to the Teratology Society, there are several reports of malformations in
humans following a vitamin A intake of 25,000 IU/day or more during pregnancy
(Teratology Society; 1987). Some of the defects were
similar to those caused by isotretinoin.
Animal studies have demonstrated birth defects similar to those produced by Accutane®.
Cleft palates and defects of the head, face, and eye were seen in the young of pregnant
rats fed 35,000 IU of vitamin A (Teratology Society;
1987). Similar defects were also observed following vitamin A administration to
pregnant mice, guinea pigs, hamsters, and rabbits.
Retinol/retinyl esters (pre-formed vitamin A) in doses greater than 10,000 IU, or 3,000
retinol equivalents are listed on the CAL/EPA Proposition 65 list of developmental toxins (Cal/EPA Proposition 65 List). This means that
an expert group of scientists found sufficient evidence that the compounds can be harmful
to unborn children. The following statement is included with the listing, "NOTE:
Retinol/retinyl esters are required and essential for maintenance of normal reproductive
function. The recommended daily level during pregnancy is 8,000 IU".
Several recommendations have been made for vitamin A intake by pregnant women. The FDA
has recommended that pregnant women obtain vitamin A in the form of beta-carotene whenever
possible (Illinois Teratogen Information Service). According to the FDA, "beta-carotene is a substance found
naturally in plants, and it can be converted to vitamin A in the body. It is considerably
less toxic than the pre-formed vitamin A. Therefore, women of child-bearing age are
advised to choose fortified foods that contain vitamin A in the form of beta-carotene
rather than pre-formed vitamin A, whenever possible. The vitamin A in fruits and
vegetables is naturally in the form of beta-carotene, and high intakes of vitamin A from
these sources are generally not of concern. Taking too little vitamin A can result in
adverse effects just as can taking in too much. The key is in finding the 'right amount'
through carefully reading product nutrition labeling."
The following list contains recommendations from the Teratology Society (Teratology Society; 1987):
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
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.
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.
Dr. Larry Gilstrap of the American College of Obstetricians and Gynecologists was
quoted as saying (USA Today), "We want to reassure women that the amount (of vitamin
A) in their prenatal vitamin is safe, and so is the amount they're likely getting from
their diet.'' Gilstrap went on to say that vitamins given to pregnant women usually
contain 4,000-5,000 IU. Dr. Gilstrap considered this amount of vitamin A to be sufficient
because it leaves room for dietary sources of vitamin A such as meat and dairy products.
G. Oakley and J. Erickson from the Centers for Disease Control and Prevention (CDC)
stated that pregnant women should take supplements containing less than 8,000 IU vitamin A
and limit the amount of liver they eat (New
England Journal of Medicine Journal Club; 333:1369-73; 11/23/95).