Rethinking the inclusion of pregnant and breastfeeding individuals in clinical trials
Protecting pregnant and breastfeeding individuals may require inclusion in research rather than exclusion from it.
Historical protectionism and its unintended consequences
The exclusion of pregnant individuals from clinical trials is deeply rooted in historical precedent. Tragic episodes such as thalidomide-associated embryopathy shaped a regulatory culture prioritizing fetal protection. Over time, pregnancy came to be treated as a categorical vulnerability within research ethics frameworks, leading sponsors and ethics committees to default toward exclusion.
While this approach was intended to minimize harm, it contributed to a persistent evidence gap. Many women require pharmacological treatment during pregnancy for chronic conditions such as hypertension, diabetes, epilepsy, autoimmune disorders, or psychiatric illness. Yet for numerous medicines, safety and dosing recommendations rely largely on post-marketing data, observational evidence, or extrapolation from non-pregnant populations.
Physiological changes in pregnancy, including alterations in plasma volume, hepatic metabolism, renal clearance, and protein binding, can significantly modify pharmacokinetics and pharmacodynamics. In the absence of prospective data, clinicians often face therapeutic uncertainty. As highlighted in the academic literature, exclusion from research does not eliminate risk; it shifts risk from the controlled setting of clinical trials to routine clinical practice, where data collection may be less structured and variability greater.
Similar considerations apply to breastfeeding individuals. Limited data on drug transfer into breast milk frequently lead either to precautionary discontinuation of treatment or to cessation of breastfeeding, despite potential maternal and neonatal benefits. In this context, protective intent may inadvertently contribute to clinical uncertainty.
The regulatory shift: ICH E21 and international alignment
The draft ICH E21 guideline on the inclusion of pregnant and breastfeeding individuals in clinical trials represents an important regulatory development. Rather than mandating universal inclusion, the guideline establishes a framework for prospective consideration during drug development. Sponsors are encouraged to evaluate, at an early stage, whether inclusion is appropriate in light of available nonclinical and clinical evidence.
A central principle is that pregnancy should not automatically constitute grounds for exclusion. Instead, decisions should be based on a structured assessment that considers the nature and severity of the maternal condition, the consequences of untreated disease, available reproductive toxicity data, and existing human safety information.
In line with ICH E21, development programmes should aim to generate the nonclinical and clinical evidence needed to enable inclusion at an appropriate stage. The guideline promotes a systematic expansion of pregnancy-related data collection across relevant sources and populations under a data-driven approach. Dedicated pharmacokinetic investigations, modeling strategies, and post-authorisation evidence generation may all contribute to reducing uncertainty.
The EMA presents the guideline as a framework to support the safety and efficacy of treatments during pregnancy and breastfeeding through proactive planning, early consultation with regulators, and evidence generation both pre- and post-authorisation. Similarly, FDA’s E21 guidance emphasises appropriate inclusion and/or retention and the generation of robust clinical data to enable evidence-based decisions on safe and effective use for these women and their healthcare providers.
This convergence across regulatory jurisdictions signals a broader harmonisation effort and reflects a shift from default exclusion toward structured evaluation.
Protection through research: implications for clinical practice
The emerging paradigm reframes the ethical question underlying decades of exclusion. Rather than asking how to protect pregnant and breastfeeding individuals from research exposure, regulators increasingly focus on how to protect them through the generation of reliable evidence.
This shift does not diminish concerns about fetal or neonatal safety. On the contrary, it places greater emphasis on systematic risk assessment, transparent communication, and robust pharmacovigilance. By encouraging prospective planning and structured data collection, the framework aims to reduce the reliance on extrapolation and post hoc inference.
For clinicians, the implications are incremental but meaningful. Over time, improved data generation may support more precise dosing recommendations, clearer safety counseling, and more informed shared decision-making. Where treatment during pregnancy cannot reasonably be deferred, evidence produced under controlled conditions may ultimately offer greater protection than therapeutic decisions made in the absence of data.
Practical challenges remain, including methodological complexity, ethical review variability, and operational constraints. However, the conceptual direction is clear: exclusion is no longer regarded as the only protective strategy. Responsible inclusion, grounded in scientific evaluation and regulatory oversight, is increasingly viewed as a legitimate path toward reducing uncertainty in maternal and neonatal pharmacotherapy.
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH E21: Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials – Step 2 Draft Guideline. 14 May 2025.
- Sewell CA, Sheehan SM, Gill MS, Henry LM, Bucci-Rechtweg C, Gyamfi-Bannerman C, Lyerly AD, McKinney LC, Hatfield KP, Baer GR, Sahin L, Nguyen CP. Scientific, ethical, and legal considerations for the inclusion of pregnant people in clinical trials. Am J Obstet Gynecol. 2022 Dec;227(6):805-811. doi: 10.1016/j.ajog.2022.07.037. Epub 2022 Aug 4. PMID: 35934117; PMCID: PMC9351207.
- Moayad L, Mihan A, Peters SAE, Van Spall HGC. Inclusion of women who are pregnant, lactating, or of reproductive potential in clinical trials: health, ethical, and regulatory considerations. Lancet. 2025 Dec 13;406(10521):2858-2864. doi: 10.1016/S0140-6736(25)01497-7. Epub 2025 Oct 23. PMID: 41429679.