Written by Anna Maria Azzini, Stefania Vitali, Evelina Tacconelli, Catherine Fleming, Domenico Benvenuto and Federica Scanavini
The historical tragedies linked to the use of medications during pregnancy that caused harm to the fetus in utero have cast a long shadow over the willingness to include these populations in clinical research. The example of thalidomide remains paradigmatic (Waggoner MR et al., 2022). Although it led to the development and subsequent implementation (FDA, 1962) of new laws and regulations aimed at strengthening the approval process for all new drugs, based on clear efficacy criteria and safety requirements (Moayad L. et al., Lancet 2025), it ultimately discouraged the inclusion of pregnant and breastfeeding women in clinical research.
The main reason commonly cited is the fear of severe side effects for the woman and the fetus/newborn and for subsequent legal repercussions. Yet this explanation only partially captures the issue. Less openly acknowledged factors, such as reputational risk for sponsors, increased trial costs, and the methodological complexity of designing studies for these populations, have contributed substantially to their exclusion (Shankar M. et al., PlosMed 2024)
Although the National Academies of Sciences, Engineering, and Medicine have documented limited evidence of legal liability associated with clinical research involving pregnant individuals and virtually no evidence of liability associated with research involving breastfeeding women, since the implementation of the modern regulatory legislation, these populations remain underrepresented and, ultimately, disadvantaged.
It is well known that these populations have distinct physiological characteristics and risk profiles that differ substantially from those of a “standard” adult male historically used as the reference population in clinical research (Bencheva V et al., 2024). However, because they are frequently excluded from clinical trials, clinicians are frequently forced to prescribe without robust evidence regarding appropriate dosing, safety, or efficacy, with the consequent risk of ineffective or even harmful therapies.
When treatment is necessary, women and healthcare professionals often face two unsatisfactory options: withhold therapy and risk harm from an untreated condition, or prescribe a medication with uncertain maternal-fetal risk and uncertain benefit. Every day, pregnant individuals take medications for chronic and acute conditions, generally with limited evidence-based data on dosing or safety. In a knowledge gap similar to the one that allowed thalidomide to cause such widespread harm, therapeutic decisions often have to be made/accepted based solely on post-marketing evidence. This exposes patients to the risk of adverse effects resulting from the use, later shown to be inappropriate, of drugs already approved in other populations, and exposes clinicians to potential legal implications.
A precautionary approach grounded primarily in fear does not eliminate risk; it merely shifts it into clinical practice without adequate evidence. It is therefore crucial to recognise the harm produced by exclusion and to promote the ethical and responsible inclusion of pregnant and breastfeeding individuals in clinical research. Ethical frameworks should prioritise the right to benefit from scientific progress, viewing pregnancy as a dynamic physiological state rather than an automatic condition of vulnerability.
We are beginning to see initial progress at the regulatory level. The European Medicines Agency (EMA) recently finalised a chapter on Good Pharmacovigilance Practices (GVP) for medicines used by pregnant and breastfeeding individuals. Furthermore, a draft guideline addressing the inclusion of pregnant and breastfeeding women in clinical trials is under public consultation. Maternal and infant research groups can consult such documents to understand the current European regulatory landscape and align their research with emerging standards.
Robust scientific evidence must be generated not only through real-world post-marketing data, but, crucially, through methodologically rigorous clinical trials with clearly defined study design, careful risk stratification, appropriate monitoring, and transparent oversight. This approach will minimise the risks for participants, mitigate legal concerns for investigators and sponsors, and, last but not least, overcome the hesitancy of potentially eligible participants (Riley MF et al., JAMA 2024).
The narrative should be reframed from “protection from research” to “protection through research”. Both researchers and regulators should collaborate to dismantle inclusion barriers, moving beyond the perception that these populations are too complex or too vulnerable to study, and instead recognising that they are too important to be systematically excluded.
