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ISOTRETINOIN

Fetal Risk Summary

Isotretinoin (Accutane) is a vitamin A isomer used for the treatment of severe, recalcitrant cystic acne. The animal teratogenicity of this drug was well documented before its approval for human use in 1982 (1,2). The mechanism of isotretinoin teratogenicity in animals may involve cytotoxic peroxyl free radical generation by metabolism with prostaglandin synthase (3). Newborn mice exposed in utero to isotretinoin at a critical point in gestation had characteristic craniofacial and limb malformations, but concurrent treatment with aspirin, a prostaglandin synthase inhibitor, resulted in a dose-dependent decrease in the overall incidence of abnormalities, the number of anomalies per fetus, and the incidence of specific craniofacial and limb defects (3).

Shortly after its approval, several publications appeared warning of the human teratogenic potential if isotretinoin were administered to women who were pregnant or who may become pregnant (4,5,6,7,8 and 9). In the 22 months following its introduction (September 1982-July 5, 1984), the manufacturer, the U.S. Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC), received reports on 154 isotretinoin-exposed pregnancies (10). Some of these cases had been described in earlier reports (11,12,13,14,15,16,17,18,19 and 20). Of the 154 pregnancies, 95 were electively aborted, 12 aborted spontaneously, 26 infants were born without major defects (some may not have been exposed during the critical gestational period), and 21 had major malformations (10). Three of the 21 infants were stillborn and 9 died after birth. A characteristic pattern of defects was observed in the 21 infants that closely resembled that seen in animal experiments (10). The syndrome of defects observed in these infants and in other reported cases (21,22,23,24,25,26,27,28,29,30,31,32,33 and 34) consists of all or part of the following:   Central nervous system:   Hydrocephalus Facial (VII nerve) palsy Posterior fossa structure defects Cortical and cerebellar defects Cortical blindness Optic nerve hypoplasia Retinal defects Microphthalmia Craniofacial: Microtia or anotia Low-set ears Agenesis or marked stenosis of external ear canals Micrognathia Small mouth Microcephaly Triangular skull Facial dysmorphism Depressed nasal bridge Cleft palate Hypertelorism Cardiovascular:      Conotruncal malformations: Transposition of great vessels Tetralogy of Fallot Double-outlet right ventricle Truncus arteriosus communis Ventricular septal defect Atrial septal defect Branchial-arch mesenchymal-tissue defects Interrupted or hypoplastic aortic arch Retroesophageal right subclavianartery Thymic defects: Ectopia, hypoplasia, or aplasia Miscellaneous defects      (sporadic occurrence): Spina bifida Nystagmus Hepatic abnormality Hydroureter Decreased muscle tone Large scrotal sac Simian crease Limb reduction Other defects have been reported with isotretinoin, but in these cases exposure had either been terminated before conception or was outside the critical period for the defect (33). These defects are thought to be nonteratogenic or have occurred by chance (33). Similarly, three reports of anomalies in children in which only the father was exposed (biliary atresia and ventricular septal defect; four-limb ectromelia and hydrocephalus; anencephaly) also probably occurred by chance (33).

A 1985 case report proposed that reduction deformities observed in all four limbs of a male infant were induced by isotretinoin (35,36). Other evidence suggested that these defects may have been secondary to amniotic bands (37). However, a 1991 Reference described an infant and a fetus with limb reduction deformities after 1st trimester exposure to isotretinoin (38). A 17-year-old mother took 50 mg/day of isotretinoin for 10 days during the 2nd month of gestation. Abnormalities present in the infant were absence of the right clavicle and nearly absent right scapula, a short humerus, and a short, broad, completely synostotic right radius and ulna (38). Other defects present were asymmetrical ventriculomegaly, minor dysmorphic facial features, a short sternum with a sterno-umbilical raphe, and developmental delay (38). The second case involved an 18-year-old woman who took 60 mg/day of isotretinoin during the first 62 days of gestation (38). The pregnancy was terminated at 22 weeks' gestation because of fetal hydrocephalus and cystic kidney. Multiple defects were noted in the fetus, including an absent left thumb but with normal proximal bony structures, a single umbilical artery, anal and vaginal atresia, urethral agenesis with dysplastic, multicystic kidneys, and other malformations consistent with isotretinoin exposure (38).

Because isotretinoin causes central nervous system abnormalities, concern has been raised over the potential for adverse behavioral effects in infants who seemingly are normal at birth (39). Long-term studies are in progress to evaluate behavioral toxicities, such as mental retardation and learning disabilities, but have not been concluded because the exposed children are still too young for tests to produce meaningful results (40).

The teratogenic mechanism of isotretinoin and its main metabolite, 4-oxo-isotretinoin, is thought to result from an adverse effect on the initial differentiation and migration of cephalic neural crest cells (10,41). Daily doses in the range of 0.5–1.5 mg/kg were usually ingested in cases with adverse outcome (10), but doses as low as 0.2 mg/kg or lower may also have caused teratogenicity (34,42). The critical period of exposure is believed to be 2–5 weeks after conception, but clinically it is difficult to establish the exact dating in many cases (33). Because of the high proportion of spontaneous abortions in prospectively identified exposed women, the CDC commented that fetotoxicity may be a more common adverse outcome than liveborn infants with abnormalities (11).

The lack of reports of isotretinoin-induced abnormalities from areas other than the United States and Canada caused speculation that this was caused by the use of lower doses, more restricted use in women, or later marketing of the drug (43). Several groups of investigators have responded to this, and although underdiagnosis and underreporting may contribute, the reasons are still unclear (42,45,46 and 47).

An autosomal or X-linked recessive syndrome with features of isotretinoin-induced defects has been described in three male siblings (48). Although the mother had no history of isotretinoin or vitamin A use, the authors did not rule out a defect in vitamin A metabolism.

In a follow-up to a previous report involving 36 pregnancies, investigators noted the outcome of an additional 21 pregnancies exposed in the 1st trimester to isotretinoin (49). The outcomes of the 57 pregnancies were 9 spontaneous abortions, 1 malformed stillborn, 10 malformed live births, and 37 normal live births. In this population, the absolute risk for a major defect in pregnancies extending to 20 weeks' gestation or longer was 23% (11 of 48) (49).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 6 newborns had been exposed to isotretinoin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (16.7%) major birth defect was observed (0.3 expected). Specific data was not available for the anomaly, but it was not one of six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.

The outcome of pregnancies occurring after the discontinuation of isotretinoin was described in a 1989 article (50). Of 88 prospectively ascertained pregnancies, conception occurred in 77 within 60 days of the last dose of the drug. In 10 cases, the date of conception (defined as 14 days after the last menstrual period) occurred within 2–5 days after the last dose of isotretinoin. These 10 pregnancies ended in 2 spontaneous abortions and 8 normal infants. Three women who had taken their last dose within 2 days of the estimated date of conception delivered normal infants. The outcomes of all 88 pregnancies were as follows: 8 (9.1%) spontaneous abortions, 1 abnormal birth (details not provided), 75 (85.3%) normal infants, and 4 (4.5%) infants with congenital malformations. The defects observed were small anterior fontanelle (1 case), congenital cataract with premature hypertrophic vitreous membrane (1 case), congenital cataract (1 case), and hypospadias (1 case). The mothers had taken their last dose of isotretinoin 33, 22, 17, and 55 days before conception, respectively. These anomalies are not characteristic of those reported with in utero exposure to isotretinoin. In an additional 13 cases obtained retrospectively, 5 ended in spontaneous abortions, 4 normal infants were delivered, and 4 infants had congenital defects: syndactyly (1 case), Down's syndrome (1 case), hypoplasia of left side of heart (1 case), and unknown defects (1 case). In the cases of known defects, the mothers had stopped isotretinoin at least 9 months before conception. As with the prospective cases, the defects described in the 3 infants were not those typical of isotretinoin-induced anomalies. Moreover, retrospective reports are probably more likely to report abnormal outcomes and to underreport normal infants (50).

In summary, isotretinoin is a potent human teratogen. Critically important is the fact that a high percentage of the recipients of this drug are women in their childbearing years. Estimates have appeared indicating that 38% of isotretinoin users are women aged 13–19 years (14). Pregnancy must be excluded and prevented in these and other female patients before isotretinoin is prescribed.

Fortunately, in one study the drug did not interfere with the action of oral contraceptive steroids (51). Initially, recommendations included stopping therapy at least 1 month before conception (14), but others indicated that shorter intervals between the last dose of isotretinoin and conception were apparently safe (50). Labeling by the manufacturer currently states that a negative serum pregnancy 2 weeks before beginning therapy is required (52,53). A recent statement by the Teratology Society supplemented the manufacturer's recommendations, for treatment of women of childbearing potential with isotretinoin, with additional recommendations and reviewed the animal and human teratogenicity of this agent (53).

Breast Feeding Summary

It is not known whether isotretinoin or its metabolite, 4-oxo-isotretinoin, is excreted into human milk. The closely related retinoid, vitamin A, is excreted (see Vitamin A), and the presence of isotretinoin in breast milk should be expected.

References

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2. Kamm JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 1982;6:652–9.
3. Kubow S. Inhibition of isotretinoin teratogenicity by acetylsalicylic acid pretreatment in mice. Teratology 1992;45:55–63.
4. Perry MD, McEvoy GK. Isotretinoin: new therapy for severe acne. Clin Pharm 1983;2:12–9.
5. Henderson IWD, Rice WB. Accutane. Can Med Assoc J 1983;129:682.
6. Shalita AR, Cunningham WJ, Leyden JJ, Pochi PE, Strauss JS. Isotretinoin treatment of acne and related disorders: an update. J Am Acad Dermatol 1983;9:629–38.
7. Anonymous. Update on isotretinoin (Accutane) for acne. Med Lett Drugs Ther 1983;25:105–6.
8. Conner CS. Isotretinoin: a reappraisal. Drug Intell Clin Pharm 1984;18:308–9.
9. Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Isotretinoin. A review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders. Drugs 1984;28:6–37.
10. Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT, Richard JM, Sun SC. Retinoic acid embryopathy. N Engl J Med 1985;313:837–41.
11. Anonymous. Isotretinoin—a newly recognized human teratogen. MMWR 1984;33:171–3.
12. Anonymous. Update on birth defects with isotretinoin. FDA Drug Bull 1984;14:15–6.
13. Rosa FW. Teratogenicity of isotretinoin. Lancet 1983;2:513.
14. Anonymous. Adverse effects with isotretinoin. FDA Drug Bull 1983;13:21–3.
15. Braun JT, Franciosi RA, Mastri AR, Drake RM, O'Neil BL. Isotretinoin dysmorphic syndrome. Lancet 1984;1:506–7.
16. Hill RM. Isotretinoin teratogenicity. Lancet 1984;1:1465.
17. Benke PJ. The isotretinoin teratogen syndrome. JAMA 1984;251:3267–9.
18. Fernhoff PM, Lammer EJ. Craniofacial features of isotretinoin embryopathy. J Pediatr 1984;105:595–7.
19. Lott IT, Bocian M, Pribram HW, Leitner M. Fetal hydrocephalus and ear anomalies associated with maternal use of isotretinoin. J Pediatr 1984;105:597–600.
20. De La Cruz E, Sun S, Vangvanichyakorn K, Desposito F. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 1984;74:428–30.
21. Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol 1984;10:851–4.
22. Marwick C. More cautionary labeling appears on isotretinoin. JAMA 1984;251:3208–9.
23. Zarowny DP. Accutane Roche: risk of teratogenic effects. Can Med Assoc J 1984;131:273.
24. Hall JG. Vitamin A: a newly recognized human teratogen. Harbinger of things to come? J Pediatr 1984;105:583–4.
25. Robertson R, MacLeod PM. Accutane-induced teratogenesis. Can Med Assoc J 1985;133:1147–8.
26. Willhite CC, Hill RM, Irving DW. Isotretinoin-induced craniofacial malformations in humans and hamsters. J Craniofac Genet Dev Biol 1986;2(Suppl):193–209.
27. Cohen M, Rubinstein A, Li JK, Nathenson G. Thymic hypoplasia associated with isotretinoin embryopathy. Am J Dis Child 1987;141:263–6.
28. Millan SB, Flowers FP, Sherertz EF. Isotretinoin. South Med J 1987;80:494–9.
29. Jahn AF, Ganti K. Major auricular malformations due to Accutane (isotretinoin). Laryngoscope 1987;97:832–5.
30. Bigby M, Stern RS. Adverse reactions to isotretinoin: a report from the adverse drug reaction reporting system. J Am Acad Dermatol 1988;18:543–52.
31. Anonymous. Birth defects caused by isotretinoin—New Jersey. MMWR 1988;37:171–2,177.
32. Orfanos CE, Ehlert R, Gollnick H. The retinoids: a review of their clinical pharmacology and therapeutic use. Drugs 1987;34:459–503.
33. Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986;33:355–64.
34. Rosa FW. Retinoic acid embryopathy. N Engl J Med 1986;315:262.
35. McBride WG. Limb reduction deformities in child exposed to isotretinoin in utero on gestation days 26–40 only. Lancet 1985;1:1276.
36. McBride WG. Isotretinoin and reduction deformities. Lancet 1985;2:503.
37. Lammer EJ, Flannery DB, Barr M. Does isotretinoin cause limb reduction defects? Lancet 1985;2:328.
38. Rizzo R, Lammer EJ, Parano E, Pavone L, Argyle JC. Limb reduction defects in humans associated with prenatal isotretinoin exposure. Teratology 1991;44:599–604.
39. Vorhees CV. Retinoic acid embryopathy. N Engl J Med 1986;315:262–3.
40. Lammer EJ. Retinoic acid embryopathy (in reply). N Engl J Med 1986;315:263.
41. Webster WS, Johnston MC, Lammer EJ, Sulik KK. Isotretinoin embryopathy and the cranial neural crest: an in vivo and in vitro study. J Craniofac Genet Dev Biol 1986;6:211–22.
42. Ayme S, Julian C, Gambarelli D, Mariotti B, Maurin N. Isotretinoin dose and teratogenicity. Lancet 1988;1:655.
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44. Robert E. Isotretinoin dose and teratogenicity. Lancet 1988;1:236.
45. Lammer EJ, Schunior A, Hayes AM, Holmes LB. Isotretinoin dose and teratogenicity. Lancet 1988;2:503–4.
46. Hope G, Mathias B. Teratogenicity of isotretinoin and etretinate. Lancet 1988;2:1143.
47. Lancaster PAL. Teratogenicity of isotretinoin. Lancet 1988;2:1254.
48. Kawashima H, Ohno I, Ueno Y, Nakaya S, Kato E, Taniguchi N. Syndrome of microtia and aortic arch anomalies resembling isotretinoin embryopathy. J Pediatr 1987;111:738–40.
49. Lammer EJ, Hayes AM, Schunior A, Holmes LB. Risk for major malformation among human fetuses exposed to isotretinoin (13-cis-retinoic acid). Teratology 1987;35:68A.
50. Dai WS, Hsu M-A, Itri LM. Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 1989;125:363–5.
51. Orme M, Back DJ, Shaw MA, Allen WL, Tjia J, Cunliffe WJ, Jones DH. Isotretinoin and contraception. Lancet 1984;2:752–3.
52. Product information. Accutane. Roche Dermatologics, 1993.
53. Public Affairs Committee, The Teratology Society. Recommendations for isotretinoin use in women of childbearing potential. Teratology 1991;44:1–6.
    
    

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