Pregnant and lactating women remain one of the most systematically excluded populations in clinical research, a practice that has persisted despite decades of medical progress and ethical debate. Rooted in outdated regulatory norms and historical tragedies, this exclusion has left a critical evidence gap that undermines safe prescribing and widens health disparities. Clinicians are forced to make decisions without adequate pharmacokinetic or safety data, while patients are denied the right to informed, evidence-based care. This article examines the origins and ongoing consequences of this exclusion — from ethical tensions to regulatory inefficiencies — and highlights emerging frameworks that can support responsible inclusion. Drawing on recent guidance from global health bodies, regulatory agencies, and bioethicists, it outlines practical solutions ranging from trial design innovations to incentive structures and infrastructure investments. Ultimately, it argues that true protection for pregnant and lactating individuals requires not their omission, but their thoughtful and empowered inclusion in clinical science.
A Hidden Population in Plain Sight
Despite decades of medical advancement and bioethical discourse, one population remains systematically sidelined from clinical research: pregnant and lactating women. In the United States, fewer than 1% of clinical trials explicitly include pregnant individuals, even when the investigational drug is likely to be prescribed to them once on the market.1 This exclusion is not an oversight but a reflection of entrenched regulatory caution, liability fears, and outdated assumptions about risk and vulnerability.
The consequences of this exclusion are far-reaching. Clinicians are often forced to prescribe medications off-label during pregnancy and lactation without adequate data on pharmacokinetics, safety, or efficacy in these populations.2 This knowledge gap exposes both patients and fetuses to uncertain risks while depriving healthcare providers of the evidence they need to offer sound medical guidance. The downstream effects include inconsistent treatment approaches, avoidable adverse events, and the exacerbation of existing maternal health disparities — particularly in low- and middle-income countries.3
A History of Caution: How We Got Here
The near-universal exclusion of pregnant and lactating women from clinical trials is rooted in a legacy of scientific failure and ethical catastrophe. The most emblematic of these is the thalidomide disaster of the late 1950s and early 1960s, when thousands of children were born with severe congenital deformities after their mothers took the drug to alleviate morning sickness. Around the same time, exposure to diethylstilbestrol (DES), a synthetic estrogen prescribed to prevent miscarriage, was later found to cause rare cancers and reproductive anomalies in the daughters of women who took it during pregnancy. These tragedies left an indelible mark on regulators and researchers alike, generating a culture of extreme caution that continues to shape clinical research policy.4,5
In response, the U.S. Food and Drug Administration (FDA) took steps to limit fetal exposure to investigational agents. A 1977 guideline recommended the exclusion of women of childbearing potential from early-phase trials, and although this policy was rescinded in 1993, its influence has persisted in practice. More recent FDA guidance, including its 2004 and 2018 documents on research in pregnant women, has attempted to encourage appropriate inclusion, but these have lacked the clarity, incentives, or enforcement mechanisms to meaningfully reverse the trend.5,6
Institutional review boards (IRBs) have also played a role in perpetuating exclusion. Pregnant women are still widely classified as a "vulnerable population" in federal research regulations, a designation originally intended to promote special protections but one that has, in effect, rationalized their omission from trials. Layered on top of this are legal liability concerns for sponsors and investigators, especially in the absence of established risk thresholds for fetal exposure. These factors create a regulatory and ethical bottleneck where avoidance often seems the path of least resistance.7,8
What began as a well-intentioned effort to protect women and fetuses from harm has calcified into a structural barrier to evidence-based care. To move forward, it is first necessary to understand how this protective stance evolved and why it is no longer tenable in the current clinical and ethical landscape.
The Cost of Exclusion
While the exclusion of pregnant and lactating women from clinical trials is often framed as a precautionary measure, the real-world consequences of this practice reveal it to be a form of systemic neglect. Across nearly all therapeutic areas, medications are routinely prescribed during pregnancy despite a lack of foundational data on pharmacokinetics (PK), safety, or efficacy in this population. In many cases, dosing regimens are extrapolated from non-pregnant adults, ignoring the profound physiological changes that accompany pregnancy and that can significantly alter drug metabolism, distribution, and clearance.9,10
This gap in evidence leaves clinicians navigating a dangerous gray zone — forced to balance incomplete data against immediate clinical need. The result is inconsistent practice, avoidable adverse outcomes, and persistent uncertainty that undermines both provider confidence and patient safety. The consequences are particularly acute in low- and middle-income countries, where access to alternatives may be limited, and maternal morbidity and mortality remain high. There, the absence of trial data is not just a research issue — it is a public health failure.3,11
The ethical implications are equally stark. While exclusion is often justified as a means of protecting vulnerable populations from harm, it paradoxically denies pregnant individuals the right to make informed decisions about their own care. Autonomy is replaced with paternalism, and the supposed protection becomes a barrier to access and informed consent. The persistent framing of these individuals as passive subjects rather than active participants in research perpetuates outdated notions of risk and erodes the ethical foundation of clinical science.4,7
From a regulatory and economic standpoint, this exclusion creates inefficiencies that ripple across the drug development life cycle. Without pre-market safety and efficacy data in pregnant populations, regulators often require post-approval studies to fill these gaps — studies that are frequently delayed, underenrolled, or never completed. This delays comprehensive labeling and fuels public mistrust, particularly when adverse outcomes arise in real-world use. It also creates hesitancy among manufacturers and sponsors, reinforcing the cycle of omission.12
In sum, the cost of exclusion is not hypothetical: it is clinical, ethical, and systemic. And it disproportionately burdens those already at greater risk of being underserved by the healthcare system.
Rethinking Risk: Emerging Frameworks for Ethical Inclusion
To break the cycle of exclusion, a fundamental rethinking of how risk is conceptualized in pregnancy is required. Increasingly, clinical researchers and bioethicists argue that pregnancy should not be treated as a blanket vulnerability, but rather as a dynamic physiological condition — one that deserves scientific understanding, not avoidance. Framing pregnant individuals as inherently “vulnerable” has obscured their capacity to consent and stripped them of autonomy, often ignoring the fact that many would prefer to participate in research if given the opportunity and adequate information.8,13
A growing set of tools and methodologies now offers a more ethical and practical path forward. Adaptive trial designs, which allow for protocol modifications based on interim findings, can help minimize risk while maintaining scientific rigor. Phased inclusion strategies — where pregnant participants are enrolled only after early safety has been established in the general population — can further mitigate uncertainty. Dynamic consent models, which facilitate ongoing communication and decision-making throughout the study, provide additional safeguards and respect individual agency.13,14
Alongside trial design innovations, advances in modeling and data analysis provide alternative avenues for generating evidence. Pharmacokinetic and pharmacodynamic (PK/PD) modeling can simulate drug behavior in pregnant physiology using existing data, helping to refine dose selection and reduce the need for large-scale exposure upfront. Real-world evidence from observational studies, pregnancy registries, and post-marketing surveillance can complement controlled trials and offer insight into outcomes in diverse, uncontrolled settings.9,10
These approaches represent not just technical progress, but a broader ethical shift: from a paradigm of protectionism to one of responsible inclusion. By leveraging modern methodologies and reaffirming the agency of pregnant and lactating individuals, the research community can begin to fill longstanding data gaps without compromising safety or trust.
Solutions and Calls to Action
Momentum is building to correct the systemic exclusion of pregnant and lactating women from clinical research, but meaningful change will require coordinated action across policy, industry, and academia. A growing body of recommendations from regulatory and scientific institutions is beginning to lay the foundation for reform. A recent report from the 16 called for urgent action by the National Institutes of Health (NIH), the Food and Drug Administration (FDA), and Congress to mandate and facilitate the ethical inclusion of these populations in clinical research. This echoes earlier guidance from the FDA, which outlined considerations for protocol development, risk minimization, and ethical oversight, yet stopped short of imposing requirements.6,15
To accelerate change, incentive structures must also evolve. Sponsors often avoid including pregnant individuals due to perceived liability, cost, and regulatory uncertainty. Financial and regulatory incentives — such as priority review vouchers, extended periods of market exclusivity, or eligibility for accelerated pathways —could help offset these disincentives and encourage earlier and more robust inclusion. Public-private partnerships may also play a key role in sharing both risk and infrastructure for pregnancy-focused research initiatives.7,12
In parallel, investment in specialized infrastructure is essential. Pregnancy-specific trial networks can streamline recruitment and protocol development, while centralized registries and biobanks can capture long-term data on maternal, fetal, and neonatal outcomes. These platforms create a more resilient and transparent evidence base, enabling not only better science but also more confident clinical decision-making.11,16
Perhaps most importantly, the process of inclusion must center the autonomy of the pregnant or lactating individual. Informed consent should not be an obstacle but a cornerstone, grounded in respect for personal agency, cultural context, and the right to participate in decisions affecting one's health and the health of one’s child. Shared decision-making frameworks and dynamic consent models can foster trust while ensuring that participants remain active partners in research, not passive recipients of policy.4,8
These reforms are not aspirational — they are necessary. Inclusion is not merely a regulatory box to check but a structural correction to decades of evidence gaps that have hindered care, clouded clinical judgment, and undermined public trust.
Conclusion: From Protective to Inclusive Science
The persistent exclusion of pregnant and lactating women from clinical trials has long been rationalized as a protective measure. But in practice, it has become a form of institutional negligence — one that leaves patients and providers alike without the data needed to make safe, evidence-based decisions. It is no longer tenable to claim that absence from research equates to safety, when it instead creates uncertainty, inequity, and avoidable harm.
The moral, clinical, and scientific imperatives to change course are clear. Ethically, it is indefensible to deny pregnant and lactating individuals the opportunity to participate in research that directly affects their care. Clinically, the growing reliance on off-label prescribing without foundational safety and efficacy data puts maternal and fetal health at risk. Scientifically, the omission of these populations from trials results in blind spots that diminish the quality and applicability of our medical knowledge.
Moving forward, inclusion must become the default — not the exception. This requires a shift in mindset, infrastructure, and regulation, but also a renewed commitment to justice and autonomy in clinical science. The goal is not to take unnecessary risks, but to responsibly generate the evidence that pregnant and lactating people need and deserve. Protecting this population does not mean excluding them from research — it means designing research that respects, informs, and empowers.
Only by embracing an inclusive approach can we ensure that the future of medicine truly serves all those it intends to help.
References
1. Incorvaia, Darren. “Fewer than 1% of clinical trials in the US include pregnant patients, study finds.” Fierce Biotech. 29 Jan. 2025.
2. Schaeffer, Regina. “Report highlights dangers of excluding pregnant, lactating women from clinical trials.” Healio. 29 Apr. 2024.
3. Dey, Teesta, et al. “Advancing maternal and perinatal health through clinical trials: key insights from a WHO global consultation.” The Lancet Global Health. 13: e740–e748 (2025).
4. Baylis, Françoise and Scott A Halperin. “Research involving pregnant women: trials and tribulations.” Clin. Invest. 2: 139–146 (2012).
6. Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials: Guidance for Industry. U.S. Food and Drug Administration. Apr. 2018.
7. Becker, Jenna. “Excluding Pregnant People From Clinical Trials Reduces Patient Safety and Autonomy.” The Petrie-Flom Center. 16 Apr. 2021.
8. van der Graaf, Rieke, et al. “Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach.” Trials. 19: 78 (2018).
9. Sheffield, Jeanne S, et al. “Designing Drug Trials: Considerations for Pregnant Women.” Clin. Infect. Dis. 59(Suppl. 7): S437–S444 (2014).
10. Waitt, Catriona, et al. “Clinical trials and pregnancy.” Communications Medicine. 2: 132 (2022).
11. Jacobson, Melanie H, et al. “Understanding willingness and barriers to participate in clinical trials during pregnancy and lactation: findings from a US study.” BMC Pregnancy and Childbirth. 24: 504 (2024).
12. “Clinical trials and pregnancy: regulators weigh in.” Clarivate. 17 Mar. 2022.
13. “Clinical trials and observational studies.” World Health Organization. Accessed 23 May 2025.
14. Fultinavičiūtė, Urtė. “Inclusive drugs: designing clinical trials for the pregnant population.” Clinical Trials Arena. 19 Jan. 2023.
15. Urgent Action Needed from NIH, FDA, Congress, and HHS to Improve Inclusion of Pregnant and Lactating Women in Clinical Trials, Says New Report. National Academies of Science, Engineering, and Medicine. 10 Apr. 2024.
16. Shaikh, Hanif, et al. “Inclusion of Pregnant Women in Clinical Trials: Need, Ethical and Scientific Considerations and Current Status.” Journal of South Asian Federation of Obstetrics and Gynaecology. 23 Feb. 2022.