Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy

In this Canadian study of pregnancies on oral isotretinoin, the finding of 3.1 pregnancies per 1000 female isotretinoin users between 1996 -2011 is cause for concern for all prescribers of this medication. The authors proffer potential reasons for inadvertent fetal exposure to oral isotretinoin including marketing of generic versions that may have lesser consumer educational resources than the original; online availability without prescription or appropriate risk information; and increased utilization for milder forms of acne.1 The latter requires response from a dermatological perspective.

The designation of clinical severity is problematic. As an illness, acne severity is multidimensional comprising primary acne lesions (type, lesion intensity, extent and distribution), scarring and psychosocial impact. However, acne guidelines typically refer to clinician assessments based on a static evaluation of primary acne lesions.2 Furthermore, acne is a chronic condition with a potential for adverse psychosocial consequences - an impact not directly correlated with clinical severity as judged by clinicians.3 Psychosocial impact may be severe despite acne being mild or moderate on clinical examination while severe acne increases the risk of attempted suicide. In patients requiring oral isotretinoin for severe acne, increased suicide risk was observed even before institution of this medication.4 Furthermore, post acne scarring is not included as a dimension in current acne severity scales. Scarring has been observed in those clinically assessed with mild-to-moderate as well as severe acne. This reflects severity fluctuation and intense inflammation leading to dermal damage. Post acne scarring is a marker for more severe acne with its own psychosocial effects and treatment consequences, typically invasive and costly.

While oral isotretinoin has been the standard of care for severe acne,2 the management of moderate acne has evolved with increasing recognition of the public health consequences of prolonged antibiotic use. Current guidelines, recommend limiting the use of oral antibiotics to 3-4 months to mitigate this risk.5 As these agents are unlikely to lead to remssion, their discontinuation generally leads to acne recurrence and consequently, need for an alternative systemic option such as oral isotretinoin. The latter remains the sole agent with the potential for inducing remission in acne.6

Pregnancy prevention programs have developed in parallel with the availability of oral isotretinoin in the US and Canada over the past 3 decades. In the United States, these have evolved through warning on labels; addition of red label stickers to pharmacies; addition of "avoid pregnancy" icons, patient consent forms, pregnancy testing prior to start of treatment, selection of 2 forms of birth control (Pregnancy Prevention Program or PPP, 1988); 2 pregnancy tests prior to starting treatment and pharmacist provision of a medication guide with prescriptions, dispensing limited to 30 day supply with no refills (SMART, 2001); monthly pregnancy tests, registration database for patients, prescribers, pharmacists and wholesalers, plus qualifying questions for patients and monthly identification of contraceptive methods by patients and doctors (iPLEDGE, 2006).7 Despite these increasingly stringent pregnancy risk management approaches, no significant reduction in pregnancies have been demonstrated with SMART8 or iPLEDGE9. A consequence of each, however, has been a sequential reduction in number of isotretinoin treatment courses and number of patients treated, with females being disproportionately impacted. In Canada, the current program is like PPP described above with the addition of 2 pregnancy tests prior to starting treatment and monthly pregnancy tests including one month after discontinuation.

The conclusion of stated by the authors, that medical practitioners and female patients must be reminded of fetal risks of this medication - including adherence to pregnancy prevention program measures,1 is well founded and timely for all stakeholders. Additional considerations are the multidimensional nature of acne severity and the potential for morbidity and mortality in a subgroup of patients. The ongoing challenge with oral isotretinoin in Canada is safe and appropriate use while not limiting access to those who need it.

References 1.Henry D, Dormuth C, Winquist B, et al. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ 2016;188:723-30. 2. Asai Y, Baibergenova A, Dutil M, et al. Management of acne: Canadian clinical practice guideline. CMAJ 2016;188:118-26. 3. Tan JK, Li Y, Fung K, et al. Divergence of demographic factors associated with clinical severity compared with quality of life impact in acne. J Cutan Med Surg 2008;12:235-42. 4. Sundstrom A, Alfredsson L, Sjolin-Forsberg G, et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 2010;341:c5812. 5. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 2016;74:945-73. 6. Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol 2013;149:1392-8. 7. Abroms L, Maibach E, Lyon-Daniel K, et al. What is the best approach to reducing birth defects associated with isotretinoin? PLoS Med 2006;3:e483. 8. Brinker A, Kornegay C, Nourjah P. Trends in adherence to a revised risk management program designed to decrease or eliminate isotretinoin-exposed pregnancies: evaluation of the Accutane SMART program. Arch Dermatol 2005;141:563-9. 9. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol 2011;65:1117-25.

Conflict of Interest:

Dr. Jerry Tan has been an advisor, consultant and/or speaker for Cipher and Roche. Dr. Neil Shear has been an advisor, consultant and/or speaker for Cipher.