Abstract
Background: In three previous studies, we have shown that pregnant women were still being exposed to isotretinoin and that compliance with recommendations was incomplete. The relaxation of these recommendations (summary of product characteristics 2004), combined with the release of generic brands, encouraged us to carry out a fourth study.
Objective: To assess isotretinoin exposure during pregnancy following the application of less stringent recommendations and the marketing of generic isotretinoin brands.
Methods: All cases of isotretinoin exposure during pregnancy, between 1 January 2003 and 31 December 2006, spontaneously reported to pharmacovigilance centres, the Teratogenic Agent Information Centre, and pharmaceutical companies in France were assessed. Cases were classified for analysis into the following groups: ‘conception <1 month after isotretinoin discontinuation’, ‘conception during isotretinoin treatment’ and ‘patient already pregnant when isotretinoin was started’. The rate of spontaneously reported isotretinoin exposure during pregnancy was estimated by dividing the number of isotretinoin-exposed pregnancies by the number of women of child-bearing age treated with isotretinoin.
Results:Over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. ‘conception <1 month after isotretinoin discontinuation’ (23%), ‘conception during isotretinoin treatment’ (61%), and ‘patient already pregnant when isotretinoin was started’ (16%). Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The rate of spontaneously reported isotretinoin exposure during pregnancy has increased by approximately 30%, from 0.32 (95% CI 0.26, 0.38) to 0.41 (95% CI 0.34, 0.49) per 1000 women of childbearing age treated since 1999–2002.
Conclusions:We suggest that recommendations be tightened, with specific information regarding the most effective contraceptive method combined with compulsory monthly pregnancy testing during treatment. The French Drug Agency has informed the European Medicines Agency of the need for measures aimed at improving compliance.
This is a preview of subscription content, log in via an institution to check access.
References
Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837–41
Robertson R, MacLeod PM. Acutane-induced teratogenesis. CMAJ 1985; 133: 1147–8
Autret E, Radal M, Jonville-Béra AP, et al. Isotrétoïne (Roaccutane®) chez la femme en âge de procréer: insuffisance de suivi des recommandations de prescription. Ann Dermatol Venereol 1997; 124: 518–22
Autret-Leca E, Jonville-Béra AP, Szafir D, et al. Roaccutane® chez la femme en âge de procréer: étude de l’impact du renforcement des recommandations de prescription. Ann Dermatol Venereol 2000; 127: 808–13
Bensouda-Grimaldi L, Jonville-Béra AP, Mouret E, et al. Isotrétinoïne: suivi de l’application des recommandations des prescripteurs chez les femmes en âge de procréer. Ann Dermatol Venereol 2005; 132: 415–23
Dictionnaire Vidal®. 81st ed. Paris: Editions Vidal, 2005
Cheetham TC, Wagner RA, Chiu G, et al. A risk management program aimed at preventing fetal exposure to isotretinoin: retrospective cohort study. J Am Acad Dermatol 2006; 55: 442–8
Strauss JS, Leyden JJ, Lucky AW, et al. Safety of a new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol 2001; 45: 196–207
Mitchell AA, Van Bennekom CM. Accutane and pregnancy. J Am Acad Dermatol 2003; 49: 1201–2
Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. N Engl J Med 1995; 333: 101–6
Mitchell AA, Van Bennekom CM, Louik C. An assessment of the Acutane (isotretinoine) pregnancy program. FDA Dermatologic Drugs Advisory Committee Meeting; 2000 Sep 18; Gaithersburg (MD) [online]. Available from URL: www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1c_03.pdf[Accessed 2010 May 17]
Bérard A, Azoulay L, Koren G, et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br J Clin Pharmacol 2007; 63: 196–205
Koren G, Avner M, Shear N. Generic isotretinoin: a new risk for unborn children. CMAJ 2004; 170: 1567–8
Mendelsohn AB, Governale L, Trontell A, et al. Changes in isotretinoin prescribing before and after implementation of the System to Manage Accutane Related Teratogenicity™ (SMART™) risk management program. Pharmacoepidemiol Drug Saf 2005; 14: 615–8
Boucher N, Beaulac-Baillargeon L. Pregnancy prevention among women taking isotretinoin: failure to comply with the recommendations. Can Fam Physician 2006; 52: 338–9
Brinker A, Kornegay C, Nourjah P. Trends in adherence to a revised risk management program designed to decrease or eliminate isotretinoin-exposed pregnancies. Arch Dermatol 2005; 141: 563–9
Robertson J, Polifka JE, Avner M, et al. A survey of pregnant women using isotretinoin. Birth Defects Res A Clin Mol Teratol 2005; 73: 881–7
Garcia-Bournissen F, Tsur L, Goldstein LH, et al. Fetal exposure to isotretinoin: an international problem. Reprod Toxicol 2008; 25: 124–8
Honein MA, Lindstrom JA, Kweder SL. Can we ensure the safe use of known human teratogens? The iPLEDGE™ test case. Drug Saf 2007; 30: 5–15
De Santis M, Straface G, Cavaliere AF, et al. The need for restricted prescription of retinoic acid derivative isotretinoin to prevent retinoid teratogenicity. Prev Med 2007; 45: 243–4
Kanelleas AI, Thornton S, Berth-Jones J. Suggestions for effective contraception in isotretinoin therapy. Br J Clin Pharmacol 2008; 67: 137–8
Acknowledgements
We wish to thank the 31 French pharmacovigilance centres, the French Teratogenic Agent Information Centre, as well as Roche, Pierre Fabre, Biorga and Expanscience.
No sources of funding were used to assist in the preparation of this study. All authors have no conflicts of interest to declare that are directly relevant to the content of this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Autret-Leca, E., Kreft-Jais, C., Elefant, E. et al. Isotretinoin Exposure during Pregnancy. Drug-Safety 33, 659–665 (2010). https://doi.org/10.2165/11536250-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11536250-000000000-00000