{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:44:56Z","timestamp":1792154696379,"version":"4.4.0"},"reference-count":29,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl J Gynecology &amp;amp; Obste"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>For six decades, pregnant women have been routinely excluded from pharmaceutical clinical trials, a practice rooted in a protectionist ethic that emerged after the thalidomide tragedy. This narrative review examines whether that exclusion remains ethically justifiable, drawing on the obstetric, pharmacological, and bioethical literature together with guidance from the Council for International Organizations of Medical Sciences, the US Food and Drug Administration, and the European Medicines Agency. Far from eliminating risk, systematic exclusion has produced a critical evidence gap: most medications used in pregnancy are prescribed off\u2010label, without adequate data on efficacy, safety, or dosing, leaving clinicians and patients to decide in an evidentiary vacuum. Using the four principles of biomedical ethics, autonomy, justice, beneficence, and nonmaleficence, this review argues that reflexive exclusion shifts risk from the monitored setting of a trial to the unmonitored setting of routine care. It further examines the medico\u2010legal counterpart of that shift: off\u2010label prescribing in pregnancy is lawful but places risk and responsibility on the individual prescriber, so that the absence of pregnancy\u2010specific evidence neither excuses nor incriminates off\u2010label use in itself, while converting a systemic regulatory failure into individual clinical liability and heightening the duty of disclosure and documentation. It outlines a risk\u2010stratified approach to trial design distinguishing early\u2010phase from late\u2010phase research and differentiating clinical scenarios from chronic maternal illness to acute obstetric conditions. Further, it analyzes Brazil's Law 14\u2009874\/2024 and its implementing Decree 12\u2009651\/2025 as a case study of regulatory modernization in a middle\u2010income country, distinguishing what is transferable to other low\u2010 and middle\u2010income countries from what depends on institutional preconditions many such settings lack. To operationalize this shift, concrete policy measures are proposed, modeled on precedents from pediatric drug regulation: mandatory ethics committee justification requirements, a pregnancy\u2010specific development plan analogous to the European Union's pediatrics investigation plan, and liability\u2010mitigation mechanisms consistent with existing United States Task Force on Research Specific to Pregnant Women and Lactating Women recommendations. The review concludes that the burden of ethical justification must shift from proving why pregnant women should be included in research to proving why they should be excluded.<\/jats:p>","DOI":"10.1002\/ijgo.71402","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T11:49:19Z","timestamp":1792151359000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic orphans no more: Revisiting the ethical justification for excluding pregnant women from pharmaceutical clinical trials"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7130-2344","authenticated-orcid":false,"given":"Camila Kruger","family":"Cabar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences Federal University of Santa Catarina  Florian\u00f3polis Santa Catarina Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8178-2136","authenticated-orcid":false,"given":"F\u00e1bio Roberto","family":"Cabar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of S\u00e3o Paulo\u2013Faculty of Medicine  S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_19_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2021.02.002"},{"key":"e_1_2_19_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2022.106806"},{"key":"e_1_2_19_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14914"},{"key":"e_1_2_19_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.whi.2012.10.003"},{"key":"e_1_2_19_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2021.02.032"},{"key":"e_1_2_19_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2021.04.227"},{"key":"e_1_2_19_8_1","volume-title":"Guideline on risk assessment of medicinal \u2010products on human reproduction and lactation: from data to labelling","author":"European Medicines Agency","year":"2008"},{"key":"e_1_2_19_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2021.03.024"},{"key":"e_1_2_19_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijgo.70076"},{"key":"e_1_2_19_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-018-2495-9"},{"key":"e_1_2_19_12_1","volume-title":"Pregnant women: scientific and ethical considerations for inclusion in clinical trials. Guidance for industry (draft)","author":"US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research","year":"2018"},{"key":"e_1_2_19_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-017-2402-9"},{"key":"e_1_2_19_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(20)30484-8"},{"key":"e_1_2_19_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.whi.2022.06.004"},{"key":"e_1_2_19_16_1","volume-title":"Principles of Biomedical Ethics","author":"Beauchamp TL","year":"2019"},{"key":"e_1_2_19_17_1","doi-asserted-by":"publisher","DOI":"10.56759\/rgxl7405"},{"key":"e_1_2_19_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2006.08.022"},{"key":"e_1_2_19_19_1","volume-title":"Parecer CFM n\u00b0 2\/2016: uso off label de medicamentos","author":"Conselho Federal de Medicina (Brazil)","year":"2016"},{"key":"e_1_2_19_20_1","unstructured":"Brasil.Lei n\u00b0 8.078 de 11 de setembro de 1990. Disp\u00f5e sobre a prote\u00e7\u00e3o do consumidor (C\u00f3digo de Defesa do Consumidor) art. 14 \u00a7 4\u00b0. Di\u00e1rio Oficial da Uni\u00e3o. 12 set1990."},{"key":"e_1_2_19_21_1","unstructured":"Brasil.Lei n\u00b0 10.406 de 10 de janeiro de 2002. Institui o C\u00f3digo Civil arts. 186 e 927. Di\u00e1rio Oficial da Uni\u00e3o. 11 jan2002."},{"key":"e_1_2_19_22_1","unstructured":"Brasil.Lei n\u00b0 14.874 de 28 de maio de 2024. Disp\u00f5e sobre a pesquisa cl\u00ednica que envolve seres humanos e institui o Sistema Nacional de \u00c9tica em Pesquisa com Seres Humanos. 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