The Seemingly ‘Wicked Problems’ Keeping Pregnant and Lactating Women From Participating in Clinical Trials Might be Fixable

By Deborah Borfitz 

June 20, 2024 | For anyone who has ever given birth, it will come as little surprise that few drugs have been approved for use during pregnancy and the breastfeeding period—even for something as basic as managing the symptoms of the cold or flu. The bigger shock may be that the absence of medicines extends to health conditions affecting pregnancy and birth such as postpartum hemorrhage and pre-eclampsia, two of the leading causes of maternal death, says Meghan Bohren, Ph.D., associate professor and unit head of the Gender and Women’s Health Unit at the University of Melbourne School of Population and Global Health (Australia). 

“Pregnancy-specific medications rarely progress through the research and development pipelines for multiple factors, including the absence of public stewardship, chronic underinvestment, and regulatory and market barriers, all underpinned by chronic gender biases,” she says. Clear examples of these participation barriers are covered in a comprehensive, “implementation-focused” review by Bohren and her colleagues that published recently in PLOS Medicine (DOI: 10.1371/journal.pmed.1004405).  

The paper systematically reviews all existing research (60 papers from 27 countries) on factors affecting the participation of pregnant and lactating women in clinical trials. Exclusion is happening on multiple levels, says Bohren, including “in funding prioritization, by ethics committees, within the health system and point-of-care, in their communities, and in decisions women make.” 

While many of the issues raised may seem like “wicked problems,” she continues, the authors also identify factors that facilitate participation. These include “women’s trust in the medical and research systems, therapeutic optimism, and clinicians’ belief in clinical equipoise.” 

Review findings were mapped to behavior change frameworks, thereby identifying strategies—falling in intervention categories such as education, training, enablement, persuasion, and environmental restructuring—which may help to address the barriers, says Bohren. The premise here is that potential obstacles and driving factors can be better addressed by understanding them within a given context.  

Researchers could use the review to “make credible arguments to funders and ethics committees about the importance of including pregnant and lactating women in clinical trials, and the negative health implications of their exclusion,” she says. “We also hope that researchers will adapt and adopt some of the potential [outlined] solutions to the existing challenges... and ultimately facilitate better access to medicines for women throughout pregnancy, birth, and postpartum periods.”  

Perspective of Women

The article offers suggestions on how to address barriers and promote the safe inclusion of pregnant and lactating women in clinical trials, “a critical step to improving health and gender equity,” Bohren says. In terms of the sentiments of the women themselves on willingness to participate, she elaborates on six of the findings. 

“Before participating, women weighed the risk of their medical condition and its impact, especially on the baby, against the risks of an intervention and its potential benefits,” she begins. “Women were less likely to participate if they felt healthy or perceived themselves at low risk of experiencing or being negatively affected by the condition, believed they had nothing to gain from participating, or felt concerned that the intervention risks were too high.”  

Therapeutic hope and optimism also played a critical role for health workers and research staff to administer trials, and for pregnant and lactating women to participate in trials, continues Bohren. “Prior knowledge about and experience with using the intervention, observation of potential beneficial effects, and trust in health workers” shaped the feelings of women. In some cases, “a lack of understanding of the differences between research and clinical care when combined with therapeutic hope led to therapeutic misconceptions and unmet expectations about the personal benefits arising from trial participation.” 

In terms of their experiences with health workers, pregnant and lactating women were “motivated to participate as a token of appreciation” for good quality care, she shares. Willingness to participate was also driven by the expectation that it “would result in higher quality clinical care or access to vaccines or therapeutic products that had previously been denied or were otherwise not accessible outside the context of a trial.” 

Evidence from Europe, the Americas, Africa, and the Western Pacific region supports this finding, she notes. “In particular, women highlighted the potential to access free medications and vaccines, greater frequency of diagnostic and monitoring tests, detailed information regarding care provided, and closer and continuous clinical observation.” 

Altruistic motivations were also at play in that pregnant women wished to contribute to the societal benefits of research, including “the potential to improve health and healthcare for pregnant women in the future,” says Bohren. Altruism either acted as “a stand-alone stimulus, secondary to or alongside beliefs around personal benefit, or conditional on no additional risk for participation.” Additionally, altruistic sentiments were “linked to perceptions that the research effort was worthy, well-intentioned, filled an important scientific gap, and addressed a pressing need.” 

In terms of intimate relationship dynamics, “pregnant women often discussed the benefits and risks of trial participation with their partners—especially in the context of fetal involvement—and their final decision may or may not have been influenced by their partners’ own attitudes,” Bohren says. “In some settings, pregnant women’s trial participation was contingent on partners’ buy-in, and the formality justified in the context of gender norms and roles [e.g., partner being head of household or a disease status casting doubt on women’s fidelity to their husbands].” 

Confidence and faith in medicine and research were also key determinants of the willingness of pregnant and lactating women to participate in trials, says Bohren. “Simultaneously, power imbalances between women and health workers, coupled with women’s therapeutic misconceptions, could lead to coercion in participation. 

“This ethical dilemma was recognized by study investigators, ethics committee members, and women, especially in the context of the dual roles of clinician-researchers,” she continues. “However, power and credibility when combined with good rapport and clear communication generated trust to participate or comfort to decline.” Concerns about the vested interests of pharmaceutical companies were rare. 

Views of Health Workers and Research Staff

Research staff understood the importance of relationship-building with health workers who sometimes act as gatekeepers to clinical trial participation. But some health workers were reluctant to engage women in studies “due to a lack of knowledge about trial design and the research value, varying levels of acceptability of risk, perceived obligation to protect women, and a lack of trust in the research team,” says Bohren. 

“Health workers supported inclusion when trial protocols included close monitoring of risks and when there was clinical equipoise alongside therapeutic hope in the trial intervention,” she adds. “These factors were informed by their clinical knowledge, previous clinical experiences using the intervention, and observed outcomes in the current trial.” 

Among the multiple factors perceived by research staff to affect the recruitment of the women was their “emotional orientations” towards clinical trials, says Bohren, such as a shared sense of trial ownership and supportive teamwork. Frustration and lower enthusiasm were tied to “feeling pressured by the recruitment process, seeing it as a procedural activity and needing to implement complex study designs” impacting the ability to recruit women. 

The strategies recommended by research staff included paper and electronic promotional materials, regular physical presence of research staff at the recruitment site, and training of health workers covering recruitment pathways and trial protocols. “Some women preferred to have information about trials provided to them through their health workers,” Bohren reports. 

Recruitment barriers cited by research staff were inadequate physical infrastructure, time, finances, and insufficient quantity and quality of human resources. “For health workers specifically, heavy workloads made it challenging to incorporate trial recruitment into clinical workflows, and the added burden and sometimes insufficient compensation, contributed to poor morale,” she says.   

Research staff further indicate that women value an “individualized, humanized, and transparent approach to communication” with adequate discussion time during trial recruitment to help ensure informed decision-making, says Bohren. They also found that recruitment success increased by approaching potential participants at the “right time” and in an appropriate manner, providing adequate information and engaging in discussions. 

To personalize the recruitment approach, research staff “reviewed obstetric information from women’s charts and had discussions with health workers to tailor the recruitment information to women’s personal situations,” she says. Timing of the approach involved using their intuition based on how sick or unwell the women appeared at the time of recruitment. 

Ethical Complexities 

“While some regulators, ethics committee members, and study investigators strongly support inclusion of pregnant women in clinical trials, most stakeholders start from a presumption of minimal risk to the fetus,” Bohren says in explaining their exclusion. But the many identified challenges—“poor public stewardship, ambiguous guidelines, insufficient data on intervention safety, complexities and subjectivities in risk assessment, poor agreement on appropriate trial design, time-consuming ethical processes, and concerns about reputation”—are not insurmountable. 

The means for greater inclusion of pregnant women, according to investigators and ethics committee members, include a shared institutional commitment to that goal. They additionally cite the need to closely collaborate early on, understand their respective roles and responsibilities, and have practical guidance regarding regulatory interpretation and risk assessment, safety monitoring, and “safeguards for injury compensation,” says Bohren. 

As for the role of funders, she adds, their requests “might facilitate the inclusion of pregnant women or create ethical challenges in conducting trials.” Public and private funders and pharmaceutical companies have limited interest in investing in such trials due to the “ethical complexities, potential for adverse events, liability, and possibility of political fallout.”  

Tailoring Solutions 

Bohren reports that she and her colleagues are now working in collaboration with the Concept Foundation (Geneva, Switzerland), Jawaharlal Nehru Medical College (Karnataka, India), and Bayero University (Kano, Nigeria) to conduct a primary qualitative study in research-experienced and research-naïve sites in India and Nigeria to better understand gender bias and the participation of pregnant women in clinical trials. The study is capturing the perspectives of women, families, community health workers, facility-based health workers, and ethics committee members. 

Jawaharlal Nehru Medical College and Bayero University have run some of the largest global maternal health trials in recent history, including the E-MOTIVE trial (The New England Journal of Medicine, DOI: 10.1056/NEJMoa2303966), the WOMAN trial (The Lancet, DOI: 10.1016/S0140-6736(17)30638-4), the ASPRIN trial (The Lancet, DOI: 10.1016/S0140-6736(19)32973-3), and the A-PLUS trial (The New England Journal of Medicine, DOI: 10.1056/NEJMoa2212111). 

Results from the work in India and Nigeria will be used “to facilitate co-design processes in each country, to identify and tailor potential solutions to address the challenges raised, and then implement these solutions in future trials within our collaborations,” says Bohren. The University of Melbourne is formally partnered with the Concept Foundation in executing the vision and mission of the global Accelerating Innovation for Mother (AIM) initiative focused on pregnancy-specific conditions. 

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