Current Trends Birth Defects Caused by Isotretinoin -- New Jersey

Between June 1983 and January 1987, four infants with isotretinoin embryopathy were born in New Jersey. Isotretinoin embryopathy consists of severe birth defects associated with first-trimester exposure to the synthetic retinoid isotretinoin (AccutaneTM*, Roche Laboratories, A Division of Hoffmann-La Roche, Inc.), which is used to treat severe, recalcitrant cystic acne. Two of the cases were reported to the New Jersey Birth Defects Registry. A third case was described in the pediatric literature (1). The fourth was identified through a teratologist currently investigating cases of isotretinoin embryopathy in the United States (Massachusetts General Hospital, unpublished data). These cases are similar to a larger number of cases that have been reported to the Food and Drug Administration (FDA) from all areas of the United States.

Case 1: In June 1983, a 1,260 g female infant of 30 weeks gestation was born to a 22-year-old woman with no previous pregnancies. The woman had taken isotretinoin for 8 days when she was 4 to 6 weeks pregnant. Isotretinoin treatment had been stopped when the woman learned that she was pregnant. At birth, the infant had microcephaly, bilateral microphthalmia, and bilateral rudimentary pinnae. She died on the 28th day of life. Postmortem examination revealed lissencephaly, rudimentary pinnae, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and interrupted aortic arch (1).

Case 2: In June 1985, a full-term male infant weighing 2,760 g was born to a 22-year-old woman who had taken isotretinoin during the first weeks of gestation. She had been counseled about the risk of drug-induced birth defects and had elected to carry the pregnancy to term. The infant had micrognathia, facial dysmorphism, missing ear lobes, Dandy-Walker malformation, and hearing and visual impairment. He now has severe mental retardation and developmental delay and requires institutional care.

Case 3: In September 1986, a male infant of 27 weeks gestation was born to a woman who had taken isotretinoin during the second month of gestation. The infant had dysplastic external ears and hydrocephalus, which was treated with a ventriculo- peritoneal shunt. This abnormality is thought to be secondary to an intraventricular hemorrhage during the early neonatal period.

Case 4: In January 1987, a full-term male infant weighing 3,558 g was born with dysplastic ears and hearing loss. His mother had been treated with isotretinoin during the first trimester of pregnancy. Reported by: M Knapp, MSN, RN, Special Child Health Svcs and New Jersey Birth Defects Registry; New Jersey State Dept of Health. Birth Defects and Genetic Diseases Br, Div of Birth Defects and Developmental Disabilities, Center for Environmental Health and Injury Control, CDC.

Editorial Note

Editorial Note:

Isotretinoin was recognized as an animal teratogen before it was first marketed in September 1982. It was, therefore, classified by FDA as Category X, contraindicated for use during pregnancy. A statement to that effect was included in the package insert.

In June 1983, human teratogenicity was reported to FDA and to the public (2). Subsequent reports have documented a strong association between a characteristic group of birth defects and exposure to isotretinoin during the first weeks of gestation (3,4). These defects include external ear malformations, cleft palate, micrognathia, conotruncal heart defects, ventricular septal defects, aortic-arch malformations, and certain brain malformations (3). In one prospective follow-up study, eight of 36 pregnancies that were exposed to isotretinoin resulted in spontaneous abortions during the first trimester; four resulted in live-born infants with at least one major malformation; one, in a malformed stillborn infant; and 23, in infants without major malformations (3). This study found a relative risk of 25.6 (95% confidence interval, 11.4 to 57.5) for the defects associated with isotretinoin embryopathy.

Human birth defects also have been observed after prenatal exposure to etretinate (TegisonTM**, Roche Laboratories, A Division of Hoffmann-La Roche, Inc.), a drug approved in October 1986 for treatment of severe, recalcitrant psoriasis (2). Etretinate also carries Category X labeling. Measurable serum concentrations of this drug have been documented more than 2 years after cessation of therapy (5), and the risk of teratogenicity may extend for an indefinite period of time after therapy (6).

Isotretinoin embryopathy is a preventable syndrome, and the number of infants born with these problems can be reduced by following the guidelines developed cooperatively by FDA and the manufacturer, Hoffmann-La Roche, Inc. This information is distributed in the form of package inserts and patient information leaflets. Current information for prescribing AccutaneTM and TegisonTM has been published in the 1988 Physicians' Desk Reference (7). A summary of these guidelines follows:

1. Isotretinoin and etretinate should not be used by women who are pregnant or who may become pregnant while taking the drug.

2. Pregnancy should be ruled out before treatment begins. This precaution may best be accomplished by obtaining a negative pregnancy test no more than 2 weeks prior to the beginning of therapy and starting therapy on the second or third day of the patient's next normal menstrual period.

3. An effective form of contraception should be used for at least 1 month before therapy begins.

4. Women who have received isotretinoin should continue using an effective form of contraception for 1 month after discontinuing treatment.

5. The period of time during which pregnancy must be avoided after treatment is discontinued has not been determined for women who have received etretinate.

6. Female patients should be counseled on the risk of major birth defects associated with first-trimester exposure to isotretinoin or etretinate. Should a pregnancy occur during treatment (or after treatment, in the case of etretinate), the woman should consult her physician about the management of her pregnancy. In addition, patients should be counseled not to share these prescription drugs with friends or family members.

The approach suggested by these guidelines cannot be expected to prevent all fetal exposures. It can be anticipated that infants will be born with defects caused by first-trimester exposures to the synthetic retinoids isotretinoin and etretinate as long as these drugs are available for use.

References

1. de la Cruz E, Sun S, Vangvanichyakorn K, Desposito F. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 1984;74:428-30.

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

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

4. Rosa FW. Teratogenicity of isotretinoin (Letter). Lancet 1983;2:513.

5. Food and Drug Administration. Etretinate approved. FDA Drug Bull 1986;16:16-7.

6. Roche Laboratories. Tegison brand of etretinate/Roche capsules (Package Insert). Nutley, New Jersey: Hoffmann-La Roche, Roche Laboratories, 1986.

7. Medical Economics Company. Physicians' desk reference. 42nd ed. Oradell, New Jersey: Medical Economics Company, 1988:1705,1746. *Use of trade names is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services or the Public Health Service. **Use of trade names is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services or the Public Health Service.

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