Epidemiologic Notes and Reports Use of Supplements Containing High-Dose Vitamin A -- New York State, 1983-1984

As part of an epidemiologic study of the risk for birth defects associated with maternal use of 13-cis retinoic acid (AccutaneR) during pregnancy, the Reproductive Health Section of the Bureau of Environmental Epidemiology and Occupational Health in the New York State Department of Health interviewed 492 women who had delivered live-born infants without birth defects during the period from April 1983 through February 1984. The interviews, which were conducted from August 1985 through August 1986, included questions concerning maternal use of drugs and vitamin supplements just before and during pregnancy. Dietary habits were not ascertained.

Of this group, 90.7% (446/492) took some prescription or over-the-counter medication. These medications represented 48 drug classes. A supplement containing vitamin A was taken by 81.1% (399/492). Of all the women interviewed, 0.6% (3/492) had taken supplements containing greater than or equal to 25,000 international units (IU) of vitamin A daily, and 2.6% (13/492) had taken supplements containing 15,000-24,999 IU of vitamin A daily. Reported by K Costas, R Davis, N Kim, PhD, AS Stark, DrPH, S Thompson, HL Vallet, MD, MPH, DL Morse, MD, State Epidemiologist, New York Dept of Health; Div of Birth Defects and Developmental Disabilities, Center for Environmental Health, CDC.

Editorial Note

Editorial Note: These observations show that some pregnant women take supplements containing high doses of vitamin A. Because of the potential teratogenicity of excessive vitamin A when taken during early pregnancy (the embryonic period of organogenesis), this finding raises a public health concern. Retinol, the form of vitamin A usually found in supplements, is a member of a group of biochemically related compounds called retinoids. Evidence about the teratogenicity of retinoids comes from three sources: 1) animal experiments, 2) case reports of defects among children born to women who used high-dose vitamin A supplements during early pregnancy, and 3) prospective studies of women who took a synthetic retinoid, 13-cis retinoic acid, during early pregnancy (1,2).

The pattern of malformations associated with 13-cis retinoic acid, which is prescribed for treatment of chronic cystic acne, parallels those found in animals exposed in utero to high doses of retinoic acid. A relative risk of 25.6 (95% confidence interval = 11.4-57.5) was estimated for the association between 13-cis retinoic acid and selected defects (external ear malformations, cleft palate, micrognathia, conotruncal heart defects, ventricular septal defects, aortic arch malformations, and brain malformations) in infants who were exposed during early pregnancy (1). Defects have also been observed among children born to women who took etretinate (TigasanR), a retinoid prescribed for treatment of psoriasis, during pregnancy (2). Although the range of malformations potentially associated with maternal use of high-dose vitamin A supplements has not been well defined, defects observed among children born to women who took greater than or equal to 25,000 IU of vitamin A per day during pregnancy include craniofacial, central nervous system, cardiac, urinary, and vertebral and other skeletal malformations (2).

13-cis retinoic acid is the only retinoid for which the teratogenic risk has been quantified in an epidemiologic study. The risk, if any, that may be associated with use of high-dose vitamin A during human pregnancy is not known.

The National Research Council's Committee on Dietary Allowances advocates a Recommended Dietary Allowance (RDA) of 1,000 retinol equivalents (RE) per day of vitamin A during pregnancy. This is equivalent to 3,300 IU of vitamin A obtained from a supplement as retinol or 5,000 IU of vitamin A obtained from the typical American diet in the forms of retinol and its metabolic precursors, beta-carotene and related compounds (3). The Committee on Dietary Allowances based its RDAs on the amounts that are adequate for maintenance of good nutrition in healthy persons. The Food and Drug Administration's (FDA) U.S. Recommended Daily Allowance (U.S. RDA) for vitamin A is 8,000 IU per day during pregnancy (4). This recommendation was developed as a standard for food labeling and composition regulations. In the United States, nearly all multivitamin supplements that are labeled for prenatal use contain no more than the U.S. RDA for vitamin A during pregnancy. However, multivitamin supplements intended for general adult use may contain much more than 8,000 IU of vitamin A.

Organogenesis often occurs before a woman is aware that she is pregnant. Because of this, women who are at risk for pregnancy should avoid taking supplements containing more than 8,000 IU of vitamin A per day (the U.S. RDA for pregnant women). Women who have questions about the use of vitamin supplements should consult their physicians.

To learn more about the possible risks of using high-dose vitamin A during pregnancy, investigators at FDA are seeking to identify women who are currently pregnant and have taken high-dose vitamin A supplements just before or during early pregnancy. Health care workers are urged to report such women to the Epidemiological Operations Branch, Office of Regulatory Affairs, FDA, by calling (301)443-4667.

References

1. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. New Engl J Med 1985;313:837-41.

2. Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986;33:355-64.

3. Committee on Dietary Allowances, Food and Nutrition Board, National Research Council, National Academy of Sciences. Recommended dietary allowances. 9th ed. Washington, DC: National Academy Press, 1980:58-9.

4. Food and Drug Administration. Vitamin and mineral products: labeling and composition regulations. Federal Register 1976; 41(203):46156-76.

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