Therapeutic orphans no more: Revisiting the ethical justification for excluding pregnant women from pharmaceutical clinical trials

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-label, 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-legal counterpart of that shift: off-label prescribing in pregnancy is lawful but places risk and responsibility on the individual prescriber, so that the absence of pregnancy-specific evidence neither excuses nor incriminates off-label 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-stratified approach to trial design distinguishing early-phase from late-phase research and differentiating clinical scenarios from chronic maternal illness to acute obstetric conditions. Further, it analyzes Brazil's Law 14 874/2024 and its implementing Decree 12 651/2025 as a case study of regulatory modernization in a middle-income country, distinguishing what is transferable to other low- and middle-income 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-specific development plan analogous to the European Union's pediatrics investigation plan, and liability-mitigation 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.