Background: In March 2018, the European Medicines Agency (EMA) updated the pregnancy prevention programme (PPP) for oral retinoids as part of their risk minimisation measures (RMMs), emphasising their contraindication in pregnant women due to their teratogenic effects. Congenital anomalies are a significant cause of infant mortality, with medications being a preventable contributing factor in 2–3% of cases. Retinoids are among the most severe teratogens since thalidomide. Despite known risks and implementation of PPPs, such as the EU’s 2003 measures and the aforementioned 2018 revision, pregnancies exposed to oral retinoids (acitretin, alitretinoin, isotretinoin) continue to occur, revealing potential shortcomings in the implementation of PPPs by the EMA. The Pharmacovigilance Risk Assessment Committee of the EMA, in June 2018, required a post-authorisation safety study to assess the effectiveness of revised additional RMMs on oral retinoids use in women of childbearing potential (WOCBP). _x000D_
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Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing and the occurrence of pregnancy temporally related to retinoid use. _x000D_
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Methods: A population-based cohort study was conducted to compare utilisation level and trend changes after the RMMs implementation on a cohort of WOCBP (12–55 years of age) from January 2010 to December 2020, using six electronic health data sources from four European countries: DK-DNR from Denmark, NL-PHARMO from the Netherlands, IT-ARS and IT-Caserta from Italy, and ES-VID and ES-BIFAP from Spain. Interrupted time-series analyses (ITSA) were used for hypothesis testing. Monthly utilisation figures (incidence rates, prevalence rates, and proportions) of oral retinoids were calculated, as well as duration of treatment, discontinuation proportions, switching proportions to retinoid alternative medicines, contraception coverage while retinoid exposure and 90 days prior retinoid start, pregnancy testing, pregnancy occurrence during retinoid treatment episodes, and retinoid initiation during a pregnancy, before and after the 2018 RMMs. Sensitivity analyses were conducted on the definition of discontinuation; the identification of pregnancy and in relation to the COVID-19 lockdown period. _x000D_
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Results: From over 10.7 million WOCBP, 88,992 used oral retinoids, mainly young users (12–21 years) and primarily isotretinoin (94.6%). Most were new users (95.8%), and usage rates were low, with seasonal dips in summer, especially in southern Europe. Overall, RMMs had no significant impact on retinoid use trends, though IT-Caserta saw a small increase in prevalence, and IT-ARS had a significant drop in acitretin use for psoriasis. Most retinoid users were short-term (<6 months). Discontinuation rates ranged from 1.9% to 39.0%, mainly among short-term users, with seasonal trends and stable post-RMMs. Reasons for stopping were largely unknown (>95%). About 32% switched to other treatments, more common in acne and eczema than psoriasis, with no clear post-RMMs change. Contraceptive use during retinoid therapy rose notably post-RMMs (e.g., 5% to 29% in NL-PHARMO, 1% to 24% in ES-VID), though the impact weakened when excluding COVID-19 data. A significant increase in retinoids initiation during contraception episodes was observed in ES-BIFAP. Pregnancies during retinoid use decreased in several databases (e.g., NL-PHARMO, ES-VID), with significant reductions in some regions. Yet, concurrent use and pregnancy cases still occurred. Manual validation confirmed high accuracy of pregnancy identification, but pregnancy testing records were poor. _x000D_
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Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use.
| Date of Award | 18 Dec 2025 |
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| Original language | English |
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| Awarding Institution | - Universitat Autònoma de Barcelona (UAB)
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| Supervisor | Mònica Sabate Gallego (Director), Carlos Duran Salinas (Director) & Shahab Abtahi (Director) |
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