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We would like to thank Satu Siiskonen for her contribution to the project management, as well as to the communications with the funding party. We would like to thank Caitlin Dodd for her contribution in the early stages of this project. We would also like to acknowledge Jennifer Smith for her contribution to the language editing of the manuscript.r The research leading to these results was conducted as part of the activities of the EU PE & amp;PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the Utrecht University, Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2017/09/PE (Lot 4). The content of this manuscript expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

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Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Publicated to:Frontiers In Pharmacology. 14 1207976- - 2023-08-17 14(), DOI: 10.3389/fphar.2023.1207976

Authors: Duran, Carlos E; Riera-Arnau, Judit; Abtahi, Shahab; Pajouheshnia, Romin; Hoxhaj, Vjola; Gamba, Magdalena; Alsina, Ema; Martin-Perez, Mar; Garcia-Poza, Patricia; Llorente-Garcia, Ana; Gonzalez-Bermejo, Diana; Ibanez, Luisa; Sabate, Monica; Vidal, Xavier; Ballarin, Elena; Sanfelix-Gimeno, Gabriel; Rodriguez-Bernal, Clara; Peiro, Salvador; Garcia-Sempere, Anibal; Sanchez-Saez, Francisco; Ientile, Valentina; Ingrasciotta, Ylenia; Guarneri, Claudio; Tanaglia, Matilde; Tari, Michele; Herings, Ron; Houben, Eline; Swart-Polinder, Karin; Holthuis, Emily; Huerta, Consuelo; Gini, Rosa; Roberto, Giuseppe; Bartolini, Claudia; Paoletti, Olga; Limoncella, Giorgio; Girardi, Anna; Hyeraci, Giulia; Andersen, Morten; Kristiansen, Sarah Brogger; Hallgreen, Christine Erikstrup; Klungel, Olaf; Sturkenboom, Miriam

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Abstract

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women.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, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription.Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs.Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively.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.

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