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 Vitamin A

Overview

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.

Description of Vitamin A

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.

Vitamin A toxicity during pregnancy

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.

Vitamin A regulations and recommendations

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 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.

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).


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