Epidemiologic Notes and Reports Isotretinoin -- A Newly Recognized Human Teratogen

Isotretinoin (Accutane((R))), an orally administered, retinoic acid licensed in September 1982 for treating severe, intractable cystic acne, has been associated with spontaneous abortions and congenital malformations. The manufacturer (Roche Laboratories) and the U.S. Food and Drug Administration (FDA) have received 29 case reports of adverse reproductive outcomes among women taking isotretinoin (Accutane) during the first trimester of pregnancy.

Excessive amounts of vitamin A and its congeners--which include retinoic acids--are known to be teratogenic in rodents and nonhuman primates (1). A daily dose of 10 mg/kg of retinoic acid on days 20-44 of gestation was teratogenic in studies of nonhuman primates (2). A variety of structural malformations was produced: malformed ears, cleft palates, limb reduction defects, contractures, and craniofacial bone anomalies. However, isotretinoin is normally prescribed in a dosage of 40-80 mg per day, a range of approximately 0.7-1.4 mg/kg/day for women weighing 60 kg (132 pounds).

Before the outcomes of their pregnancies were determined, 18 pregnant women exposed to this drug were prospectively identified by the manufacturer. Among this group, 13 spontaneous abortions, four normal infants, and one infant with malformations occurred. (No information is available about whether the women who had spontaneous abortions were otherwise predisposed for adverse pregnancy outcomes.) A second similar group of 16 women was identified after the outcomes of their pregnancies were determined. These pregnancies resulted in six spontaneous abortions, one normal infant, and nine infants with similar congenital malformations, which included microtia with or without agenesis of the ear canal (eight of 10 infants); structural central nervous system abnormalities (9/10), including hydrocephalus and microcephaly; and congenital heart defects (5/10) represented by conotruncal malformations, aortic arch atresia, and ventricular septal defects. Other reported malformations included facial dysmorphism, microphthalmia, micrognathia, and cleft palate. Reported by FW Rosa, MD, Epidemiology Development Br, Div of Drug and Biologics Experience, U.S. Food and Drug Administration; Birth Defects Br, Chronic Diseases Div, Center for Environmental Health, CDC.

Editorial Note

Editorial Note: Although the total number of exposed, pregnant women is unknown, the consistency of the laboratory and human experiences with isotretinoin exposure during pregnancy provides sufficient evidence to conclude that the drug is a human teratogen.

The spectrum of malformations described among these infants exposed to isotretinoin resembles that found in the animal studies. The 10 infants referred to above have an unusual characteristic pattern of malformations not consistent with any known syndromes. The occurrence by chance of these defects in 10 infants of isotretinoin-exposed pregnant women is highly unlikely. Among exposed pregnant women, the percentage of infants who will have malformations is unclear, since only five of the prospectively followed fetuses reached a viable gestational age. The large percentage of spontaneous abortions among the prospectively identified women suggests that fetotoxicity is a more common adverse outcome of exposure than malformation of a live infant. As expected, birth defects were reported more frequently among exposed women after the outcomes of their pregnancies were determined than were spontaneous abortions and normal births.

Since the drug was first marketed in the United States in September 1982, the isotretinoin package insert has carried the following warning: "Because teratogenicity has been observed in animals given isotretinoin, patients who are pregnant or intend to become pregnant while undergoing treatment should not receive Accutane. Women of childbearing potential should not be given Accutane unless an effective form of contraception is used, and they should be fully counseled on the potential risks to the fetus should they become pregnant while undergoing treatment. Should pregnancy occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy." In July 1983, after the first reports of malformed newborns, Roche Laboratories mailed letters to U.S. physicians and pharmacists reiterating important portions of the package insert and suggesting a pregnancy test before initiation of therapy.

The continuing reports of severely malformed infants born to mothers inadvertently exposed to isotretinoin emphasize the need to repeat the warnings of teratogenicity. Any woman taking isotretinoin who becomes pregnant should receive informed counseling about the risks to her fetus.

To define the teratogenic risks of isotretinoin more accurately, further information about inadvertently exposed fetuses and infants is needed. This information is most valuable when an exposed, pregnant woman is reported before the outcome is determined. Physicians are urged to report exposures to Roche Laboratories by calling collect (201) 235-3021.

Since fetotoxicity appears to be a common adverse outcome of isotretinoin exposure, studies of abortuses, either spontaneous or induced, will supplement information already accumulated on the risks to the fetus. Arrangements for analyses of abortuses can be made by contacting the Epidemiology Development Branch, Division of Drug and Biologics Experience, FDA, or the Department of Environmental and Drug-Induced Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20306, telephone (202) 576-2434.

References

1. Kochhar DM, Kuczynski-Brown BA, Tellone CI. Comparative teratogenicity of all-trans- and 13-cis-retinoic acid in mice as studied by in vivo and in vitro methods. Teratology 1983;27:58A.

2. Fantel AG, Shepard TH, Newell-Morris LL, Moffett BC. Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina).

1. General features. Teratology 1977;15:65-71.

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