with concerns about the possible teratogenicity of high vitamin A intake during pregnancy. Practitioners should be ... mide and rubella (C. Grabowski, MD: Statement onbehalfof ..... The possible teratogenic effect of megadoses of vitamin A.
78
Iie Health Sand Pxwetive Medicine U
Vitamin A-A Pregnancy Hazard Alert KENNETH W. KIZER, MD, MPH; ANNA M. FAN, PhD; JOLANTA BANKOWSKA, PhD; RICHARD J. JACKSON, MD, MPH; and DONALD 0. LYMAN, MD, Sacramento, California
This is one of a series of articles from western state public health departments.
Vitamin A is essential to human health, but concerns have arisen recently regarding its potential teratogenicity. Human and animal birth defects have been associated with the use of the vitamin A analogue, isotretinoin, or Accutane, for acne treatment, although the association of such defects with vitamin A itself is unclear. The federal Food and Drug Administration is evaluating the health issues surrounding vitamin A and, together with the manufacturer, has developed restrictions and label warnings to ensure the appropriate use of Accutane. We also have evaluated these issues, with concerns about the possible teratogenicity of high vitamin A intake during pregnancy. Practitioners should be familiar with the possible hazard of excessive dosages of vitamin A and its analogues. Vitamin A daily doses of higher than 8,000 IU for pregnant woman are not necessary for good health and are not recommended. Foods high in P-carotene can provide the necessary amounts of vitamin A and, in contrast to the synthetic analogues, their use has not been associated with vitamin A toxicity or teratogenicity in humans or animals. (Kizer KW, Fan AM, Bankowska J, et al: Vitamin A-A pregnancy hazard alert. West J Med 1990 Jan; 152:78-81)
T he essentiality of vitamin A for normal human health is well known. Likewise, problems of vitamin A deficiency and hypervitaminosis A have been recognized for many years. Concerns about the potential teratogenicity of vitamin A and its synthetic analogues have arisen only recently. Practitioners need to be aware of these concerns. Vitamin A is essential for normal cellular function and growth, the proliferation and differentiation of epithelial tissues, and to maintain visual and reproductive functions. 1 In the United States, vitamin A deficiency is rare and is usually associated with severe chronic malnutrition, especially in children. Vitamin A deficiency can result in skin lesions such as follicular hyperkeratosis; keratomalacia and visual impairment; keratinization of the bronchorespiratory tract; pathologic changes of the epithelium of the urinary tract (which can lead to urinary calculi), gastrointestinal tract, and sweat glands; faulty modeling of bone; and abnormal reproductive functions, including impaired spermatogenesis, testicular degeneration, spontaneous abortion, fetal resorption, and fetal malformations. The most notable impairment resulting from vitamin A deficiency is classic night blindness. Vitamin A deficiency is treated with vitamin A dietary supplementation as retinol or retinyl ester preparations. Similarly, various synthetic vitamin A supplements are available for use to prevent vitamin A deficiency during periods of increased physiologic demand such as during pregnancy, lactation, and infancy. Other retinoids, such as tretinoin and isotretinoin (13-cis-retinoic acid), are used to treat skin disorders such as cystic acne, pustular psoriasis, keratosis fol-
licularis (Darier's disease), and ichthyosis.I The clinical use of these compounds, however, is often limited by side effects observed at therapeutic dosages. Although the effects of hypervitaminosis A on the integumentary, skeletal, reticuloendothelial, and central nervous systems have long been recognized, the potential for adverse developmental effects of vitamin A is less well known. Concern about excess intake of vitamin A during pregnancy has increased in recent years because of its structural and metabolic relationships to other retinoids, especially 13-cisretinoic acid (isotretinoin, or Accutane), a synthetic retinoid that has a teratogenic potency in humans similar to thalidomide and rubella (C. Grabowski, MD: Statement on behalf of the Teratology Society to the US Food and Drug Administration [FDA] concerning isotretinoin, April 26, 1988). Isotretinoin (Accutane or Roaccutane) has been used since 1982, when it was first marketed as an oral agent for treating recalcitrant cystic acne.2 More recently, an evaluation of 154 pregnancies with exposure to the drug showed that 14% (21 cases) resulted in malformed infants, 17% (26 cases) in infants without major defects, 8% (12 cases) in spontaneous abortions, and 62 % (95 cases) in elective abortions.3 The risk for serious birth defects in infants of pregnant women with exposure to isotretinoin was determined to be about 25 %. Another report showed that isotretinoin administered orally to 64 women during the first trimester of pregnancy resulted in 34 cases of fetal defects and 30 cases of spontaneous abortion.4 Defects have involved pathologic changes in the central nervous system, facial malformations
From the California Department of Health Services (CDHS) (Dr Kizer); the Pesticides and Food Toxicology Unit (Drs Fan and Bankowska), Office of Environmental Health Hazard Assessment (Dr Jackson), and Preventive Medical Services Division (Dr Lyman), CDHS, Sacramento, California. Dr Kizer is Director of the CDHS. Reprint requests to Kenneth W. Kizer, MD, MPH, 714 P St, Room 1253, Sacramento, CA 95814.
THE WESTERN JOURNAL OF MEDICINE
-
JANUARY 1990
o
ABBREVIATIONS USED IN TEXT CDHS = California Department of Health Services FDA = Food and Drug Administration
with small
or
absent external
ears,
and cardiovascular im-
pairments. The total number of infants with birth defects
consistent with those associated with isotretinoin use is unclear, with the estimates ranging from 62 to 1,300 (P. M. Bossey, "Maker of Drug for Acne Calls Birth-Defect Report 'Invalid,' "New York Times, April 23, 1988, p 1). Human birth defects and spontaneous abortions have been associated with the use of etretinate (Tegison, United States; Tigason, Europe), the trimethylmethoxyphenyl ethyl ester analogue of all-trans-retinoic acid (analogue of vitamin A acid) (Roche Laboratories, Division of HoffmannLaRoche, Inc: Statement made to the FDA Advisory Committee and public hearing on etretinate safety). I Etretinate is currently approved for use in the treatment of psoriasis. In Europe, seven cases of fetal malformations due to etretinate exposure during pregnancy were reported; these included meningomyeloceles, craniofacial and skeletal abnormalities, severe brain defects with anophthalmia, and low-set ears. ' A case of congenital malformation was reported in a child born to a woman from Brazil who had discontinued etretinate therapy almost a year before she conceived.5 There have been no reports of birth defects associated with its use in the United States, but it was approved only in late 1986 (FDA Consumer, October 1988, pp 27-29). The lowest human teratogenic doses for the two retinoids, isotretinoin and etretinate, are estimated to be 0.4 and 0.2 mg per kg per day, respectively.6 Etretinate is, therefore, more potent than isotretinoin, and its teratogenic effect may persist longer than isotretinoin's. Vitamin A is metabolized to the all-trans-retinoic acid, which differs from isotretinoin (13-cis-retinoic acid) only in the direction of the acid tail. All-trans-retinoic acid also produces 13-cis-retinoic acid as a metabolite. Whether vitamin A itself (as retinol or retinyl esters) is a human teratogen is unclear. There have been several isolated case reports of human birth defects with high levels of maternal vitamin A exposure.7 Some of the mnalformations are consistent with the pattern of defects produced by isotretinoin, but a causal relationship has not been established. Although poor exposure surveillance confounded by the simultaneous intake of other nutritional supplements makes the available data inconclusive, the evidence certainly raises concerns about possible human teratogenicity of high doses of vitamin A. Isotretinoin, etretinate, and vitamin A as retinol or retinyl esters have been confirmed as embryotoxic and teratogenic in studies of animals.8 These findings contrast with those related to naturally occurring carotenoids, which are biotransformed in mammals to vitamin A and have not been identified as teratogenic or embryotoxic in studies ofeither animals or humans. The many biologic effects of vitamin A and its derivatives are summarized in Table 1. The existing guidelines from the manufacturer (Hoffmann-LaRoche Inc) for the use of Accutane by women are specific and detailed.9 They stress the necessity of obtaining a negative pregnancy test two weeks before initiating therapy with Accutane and the importance of using an effective form
79
152 * 1
of contraception a month before, during, and for a month after taking Accutane. Women who become pregnant while using isotretinoin are advised to discuss with their physicians the advisability of continuing the pregnancy. Despite these restrictions and warnings to physicians and consumers, women taking Accutane continue to become pregnant and produce malformed infants (FDA Consumer, October 1988, pp 27-29 and Centers for Disease Control, unpublished data, cited by C. Grabowski). More vigilant supervision in the use ofthe medication seems necessary. To consider the isotretinoin issues, the FDA convened a meeting of its Dermatologic Drugs Advisory Committee in April 1988, with representatives from the Centers for Disease Control, the American Academy of Pediatrics, the American Academy of Dermatology, and consumer advocates (FDA Consumer, October 1988, pp 27-29). After considering advice from consumer and professional organizations, the FDA and Hoffmann-LaRoche developed further restrictions and unprecedented labeling warnings to ensure the appropriate use of the drug, with the hope of eliminating the associated birth defects. At this time, the FDA plan calls for the following: * Physician labeling providing A stronger, boxed warning statement with large print. Affirmation in the statement that the drug is not to be used for a woman of childbearing age unless her physician determines that she meets all six of the following criteria: 1. She has severe disfiguring acne. 2. She can understand and carry out instructions. 3. She is capable of complying with mandatory contra-
ceptive measures. 4. She has received oral and written warnings of the hazards of pregnancy while taking Accutane. 5. A pregnancy test within two weeks of initiating
therapy was negative. 6. The drug's use will not begin until the start of the next normal menstrual period. A prominent non-pregnancy symbol-outline of a pregnant woman inside the international crossed circle meaning "not" or "don't"-is added at the beginning of the label and in drug labeling printed in the Physicians' Desk Reference. '0 There is clear labeling that the drug should be prescribed only by physicians who have special competence in the diagnosis and treatment of severe cystic acne. * Patient labeling details the following: An extremely high risk-one chance in four, or greaterthat a deformed infant will result if a women becomes pregnant while taking Accutane. A photograph of an infant with characteristic visible external deformities incurred from exposure to Accutane. The non-pregnancy symbol on each page of the patient material and on each panel of the "blister pack." (Accutane must only be dispensed in a blister pack containing patient warnings and other information in the package, in addition to the currently used pamphlets physicians and pharmacists are asked to give patients.) A consent form, with a discussion of fetal abnormalities. A statement that each new prescription or refill should be started only on the second or third day after the start of a normal menstrual period.
PUBLIC HEALTH AND PREVENTIVE MEDICINE
80
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