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. 2023 Aug 17:14:1207976.
doi: 10.3389/fphar.2023.1207976. eCollection 2023.

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

Carlos E Durán  1 , Judit Riera-Arnau  1   2 , Shahab Abtahi  3 , Romin Pajouheshnia  3 , Vjola Hoxhaj  1 , Magdalena Gamba  3 , Ema Alsina  1 , Mar Martin-Perez  4 , Patricia Garcia-Poza  4 , Ana Llorente-Garcia  4 , Diana Gonzalez-Bermejo  4 , Luisa Ibánez  2 , Mònica Sabaté  2 , Xavier Vidal  2 , Elena Ballarín  2 , Gabriel Sanfélix-Gimeno  5 , Clara Rodríguez-Bernal  5 , Salvador Peiró  5 , Aníbal García-Sempere  5 , Francisco Sanchez-Saez  5 , Valentina Ientile  6 , Ylenia Ingrasciotta  7 , Claudio Guarneri  6 , Matilde Tanaglia  7 , Michele Tari  8 , Ron Herings  9 , Eline Houben  9 , Karin Swart-Polinder  9 , Emily Holthuis  9 , Consuelo Huerta  10 , Rosa Gini  11 , Giuseppe Roberto  11 , Claudia Bartolini  11 , Olga Paoletti  11 , Giorgio Limoncella  11 , Anna Girardi  11 , Giulia Hyeraci  11 , Morten Andersen  12 , Sarah Brøgger Kristiansen  12 , Christine Erikstrup Hallgreen  13 , Olaf Klungel  3 , Miriam Sturkenboom  1
Affiliations

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

Carlos E Durán et al. Front Pharmacol. .

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.

Keywords: acne; contraceptive measures; dermatologic conditions; isotretinoin; oral retinoids; pregnancy prevention programme; risk minimisation measures.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Query diagram to illustrate treatment episode construction and treatment discontinuation definition of oral retinoid and contraceptive exposures. (a) Subjects may be excluded during initial data processing if they meet the general exclusion criteria. This will help to reduce data volume. DAPs may apply these exclusion criteria during their ETL, but they must report this (it will also be detected when assessing at patient flow). Subjects with any record of male sex will be excluded. (b) Time series of cross-sectional analyses is performed over this period (monthly analyses). The final month will begin December 2020.
FIGURE 2
FIGURE 2
Interrupted time-series analyses (ITSA) on prevalence (current users/1,000 persons) and incidence (new users/1,000 person-months rates of retinoid use in female subjects of childbearing potential per database between 2010–2020, excluding COVID-19 pandemic period. (A) NL-PHARMO, Netherlands. (B) IT-ARS,Tuscany (Italy). (C) IT-Caserta region, Italy. (D) ES-VID, Valencia region (Spain). (E) ES-BIFAP, several regions (Spain).
FIGURE 3
FIGURE 3
Interrupted time-series analyses (ITSA) on the monthly percentage of oral retinoid users who start within a contraception coverage episode, in female subjects of childbearing age per database, between 2010 and 2020, excluding COVID-19 pandemic period. (A) NL-PHARMO, Netherlands. (B) ES-VID, Valencia region (Spain). (C) ES-BIFAP, several regions (Spain).
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