{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:44:43Z","timestamp":1792669483333,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"Pregnant and breastfeeding individuals are routinely excluded from clinical drug development, creating persistent evidence gaps in pharmacology, safety, and dosing. Despite mandatory contraception and pregnancy testing, unintended pregnancies occur, particularly during the development of central nervous system (CNS) medicines used by women of reproductive age. Once exposure to an investigational medicinal product (IMP) has occurred, these pregnancies may provide valuable prospective human data; however, treatment or trial participation is often discontinued and follow\u2010up may be incomplete. This study assessed how unintended pregnancies and breastfeeding data were reported, managed, and evaluated in clinical trials supporting marketing authorization applications (MAAs) for CNS products. We reviewed 35 MAAs for centrally authorized CNS products submitted to the European Medicines Agency between 2012 and 2022. Pregnancy frequency, IMP exposure, pregnancy outcomes, breastfeeding data and regulatory comments were extracted from MAA dossiers, Day 120 Lists of Questions and Summaries of Product Characteristics. Overall, 451 pregnancies were identified, including 343 with IMP exposure. Of these, 108 occurred in pivotal phase 3 trials, resulting in 39 live births, 23 elective terminations, 17 spontaneous pregnancy losses, and 29 unknown or ongoing outcomes. Regulators raised 19 pregnancy\u2010related and six breastfeeding\u2010related concerns. Only one dossier included a dedicated human lactation study. Pregnancy reporting varied substantially in location, format and case\u2010level detail, while 27% of pivotal IMP\u2010exposed pregnancies had unknown or ongoing outcomes at assessment. More structured reporting and follow\u2010up, including relevant exposure and pharmacokinetic data where feasible, could strengthen clinical pharmacology and regulatory evidence and support more informative product information.<\/jats:p>","DOI":"10.1002\/cpt.70529","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:29:41Z","timestamp":1792668581000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unintended Pregnancies and Breastfeeding Studies during Central Nervous System Drug Development: How Are they Handled, Is There Room for Improvement?"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-6159","authenticated-orcid":false,"given":"Sam","family":"Schoenmakers","sequence":"first","affiliation":[{"name":"European Medicines Agency Amsterdam the Netherlands"},{"name":"Department of Obstetrics and Gynaecology Erasmus MC University Medical Center Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9822-2354","authenticated-orcid":false,"given":"Charlotte","family":"Bakker","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4700-1839","authenticated-orcid":false,"given":"Alexandra","family":"Ganev","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8305-2089","authenticated-orcid":false,"given":"Florence","family":"Butlen\u2010Ducuing","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam the Netherlands"},{"name":"Psycho\u2010Oncology Unit, Interdisciplinary Department for the Organization of Patient Pathways Gustave Roussy, Cancer Campus Grand Paris Villejuif France"},{"name":"MOODS Team Universit\u00e9 Paris\u2010Saclay, UVSQ, Inserm Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0236-8816","authenticated-orcid":false,"given":"Corinne S.","family":"de Vries","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"crossref","first-page":"e100","DOI":"10.1097\/AOG.0000000000001150","article-title":"Ethical considerations for including women as research participants","volume":"126","author":"Committee on E. 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Gynecol."},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s43856-022-00198-1","article-title":"Clinical trials and pregnancy","volume":"2","author":"Waitt C.","year":"2022","journal-title":"Commun. Med. (Lond.)"},{"key":"e_1_2_10_24_1","unstructured":"ICH.E21 Guideline on inclusion of pregnant and breastfeeding individuals in clinical trials(2025)."},{"key":"e_1_2_10_25_1","unstructured":"Clinical Trials Coordination G Heads of Medicines A.Recommendations related to contraception and pregnancy testing in clinical trials(2024) ."},{"key":"e_1_2_10_26_1","unstructured":"European Medicines A.Guideline on strategies to identify and mitigate risks for first\u2010in\u2010human and early clinical trials with investigational medicinal products(2017) ."},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1363\/psrh.12017","article-title":"Contraceptive failure in the United States: estimates from the 2006\u20132010 National Survey of family growth","volume":"49","author":"Sundaram A.","year":"2017","journal-title":"Perspect. Sex. Reprod. 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Sex Differ."},{"key":"e_1_2_10_45_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13006-022-00494-5","article-title":"Breastfeeding, pregnancy, medicines, neurodevelopment, and population databases: the information desert","volume":"17","author":"Jordan S.","year":"2022","journal-title":"Int. Breastfeed. J."},{"key":"e_1_2_10_46_1","unstructured":"ICH E21 Guideline on inclusion of pregnant and breastfeeding individuals in clinical trials \u2013 Scientific guideline(2025) ."},{"key":"e_1_2_10_47_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/d41573-021-00115-6","article-title":"Implications of sex\u2010related differences in central nervous system disorders for drug research and development","volume":"20","author":"Butlen\u2010Ducuing F.","year":"2021","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Clinical Pharmacology & Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70529","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70529","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70529","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:29:47Z","timestamp":1792668587000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70529"}},"subtitle":["Maintaining the Gap: Pregnancy and Breastfeeding in CNS Clinical Trials"],"short-title":[],"issued":{"date-parts":[[2026,10,22]]},"references-count":47,"alternative-id":["10.1002\/cpt.70529"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70529","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,22]]},"assertion":[{"value":"2026-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70529"}}