How Should the Precautionary Principle Apply to Pregnant Women in Clinical Research?

BackgroundThere is ambiguity with regard to what counts as an acceptable level of risk in clinical research in pregnant women and there is no input from stakeholders relative to such research risks. The aim of our paper was to explore what stakeholders who are actively involved in the conduct of clinical research in pregnant women deem an acceptable level of risk for pregnant women in clinical research. Accordingly, we used the APOSTEL VI study, a low-risk obstetrical randomised controlled trial, as a case-study.MethodsWe conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed healthcare professionals, Research Ethics Committee members (RECs) and regulators who are actively involved in the conduct of clinical research in pregnant women, in addition to pregnant women recruited for the APOSTEL VI case-study in the Netherlands.ResultsThree themes characterise the way stakeholders view risks in clinical research in pregnant women in general. Additionally, one theme characterises the way healthcare professionals and pregnant women view risks with respect to the case-study specifically. First, ideas on what constitutes an acceptable level of risk in general ranged from a preference for zero risk for the foetus up to minimal risk. Second, the desirability of clinical research in pregnant women in general was questioned altogether. Third, stakeholders proposed to establish an upper limit of risk in potentially beneficial clinical research in pregnant women in order to protect the foetus and the pregnant woman from harm. Fourth and finally, the case-study illustrates that healthcare professionals’ individual perception of risk may influence recruitment.ConclusionsHealthcare professionals, RECs, regulators and pregnant women are all risk adverse in practice, possibly explaining the continuing underrepresentation of pregnant women in clinical research. Determining the acceptable levels of risk on a universal level alone is insufficient, because the individual perception of risk also influences behaviour towards pregnant women in clinical research. Therefore, bioethicists and researchers might be interested in changing the perception of risk, which could be achieved by education and awareness about the actual benefits and harms of inclusion and exclusion of pregnant women.

BackgroundBioethicists argue that inclusion of pregnant women in clinical research should be more routine to increase the evidence-base for pregnant women and foetuses. Yet, it is unknown whether pregnant women and others directly involved are willing to be routinely included. Therefore, we first need to establish what these stakeholders think about research participation in regular pregnancy-related research. However, studies on their views are scarce. In our study, we piggy-backed on a relatively conventional RCT, the APOSTEL VI study, to identify the views of stakeholders on inclusion of pregnant women in this study.MethodsWe conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed pregnant women (n = 14) recruited for the APOSTEL VI study, in addition to healthcare professionals (n = 14), Research Ethics Committee members (RECs) (n = 5) and regulators (n = 7) involved in clinical research in pregnant women.ResultsThree themes characterise stakeholders’ views on inclusion of pregnant women in the APOSTEL VI study. Additionally, one theme characterises stakeholders’ interest in inclusion of pregnant women in clinical research in general. First, pregnant women participate in the APOSTEL VI study for potential individual benefit and secondarily for altruistic motives, contrary to hypothetical studies. Second, a gatekeeping tendency hampers recruitment of pregnant women who might be eligible and willing, and questions about pregnant women’s decisional capacities surface. Third, healthcare professionals sometimes use the counselling conversation to steer pregnant women in a direction. Fourth, all stakeholders are hesitant about inclusion of pregnant women in clinical research in general due to a protective sentiment.ConclusionsPregnant women are willing to participate in the APOSTEL VI study for potential individual benefit and altruistic motives. However, an underlying protective sentiment, resulting in gatekeeping and directive counselling, sometimes hampers recruitment in the APOSTEL VI study as well as in clinical research in general. While bioethicists claim that inclusion of pregnant women should be customary, our study indicates that healthcare professionals, regulators, RECs and pregnant women themselves are not necessarily interested in inclusion. Advancing the situation and increasing the evidence-base for pregnant women and foetuses may require additional measures such as investing in the recruitment and feasibility of RCTs and stimulating pregnant women’s decisional capacities.

BackgroundNotwithstanding the need to produce evidence-based knowledge on medications for pregnant women, they remain underrepresented in clinical research. Sometimes they are excluded because of their supposed vulnerability, but there are...

The article deals with the need of compulsory participation of pregnant women in clinical research of drugs. By the beginning of the 90‑s of the last century, the majority of drugs prescribed to women was characterized by unsubstantial evidence of effectiveness and safety for women. Moreover, pregnant women almost did not participate in clinical research. Though pregnancy is a dynamic condition that can be compared with itself only. Then supervisory bodies created some documents regulating compulsory participation of the population in the research of drugs. However, until now, women are not sufficiently involved in the research of new original drugs, and pregnant women do the same very rarely. Possible scenarios of participation of pregnant women in clinical research have been reviewed. In particular, research of drugs used in therapy of abnormal conditions associated with pregnancy; drugs to treat chronic and acute pathological processes not related to pregnancy, and when a woman gets pregnant during the research have been distinguished. The importance of inclusion of pregnant women into the trials of effectiveness and safety of drugs in the presence of socially significant diseases, including the ones found during COVID‑19 pandemics, is postulated.

Enrolling Pregnant Women: Issues in Clinical Research

Pregnant women had a large demand for diagnosis and treatment, but the clinical research was not sufficient, and there were many barriers for pregnant women to participate in clinical research. This study aimed to systematically identify these barriers and facilitators, map them with Theoretical Domains Framework (TDF) and Behavior Change Techniques (BCTs) to inform the development of interventions promoting pregnant women's involvement in clinical research. This was a mixed-methods systematic review. PubMed, Embase, Cochrane Library, APA PsycInfo, CINAHL, China National Knowledge Infrastructure, WanFang, VIP Database for Chinese Technical Periodicals, Chinese Biomedical Literature Database, and related references were searched. Qualitative, quantitative, and mixed-methods studies exploring barriers and facilitators to pregnant women's participation in clinical trials were included. The barriers and facilitators were extracted, after transforming the quantitative data into qualitative data, all qualitative data were used to thematic synthesis. The identified barriers and facilitators were mapped into TDF and BCTs. A total of 103 studies (66 qualitative, 24 quantitative, and 13 mixed-methods) were included. Three main themes were formed: personal factors, environmental factors and research characteristics, with identified barriers and facilitators within each theme. "Knowledge," "Environmental Context and Resources," and "Beliefs about Consequences" were the main domains where barriers and facilitators identified by pregnant women and researchers were mapped in TDF. Additionally, the barriers and facilitators identified by pregnant women also mapped on "Social Influences" and "Goals." "Instruction on how to perform a behavior," "restructuring the physical environment," "salience of consequences," "social support (unspecified)," "goal setting (outcome)" were the main BCTs identified based on barriers and facilitators. The barriers and facilitators to clinical research participation identified in this study involved three main themes of personal, environmental, and research characteristics, which mainly mapped to five TDF domains. Based on these barriers and facilitators, 23 BCTs were identified. Future research should focus on developing behavior change interventions, assessing their efficacy and implementability.

Scanty evidence exists about the safety and effectiveness of drugs-and of their efficacious dosing-that women may need to treat acute and chronic health issues during their pregnancies. This lack of evidence puts pregnant women and their fetuses at risk of harm from the use or avoidance of drugs during pregnancy. In light of the protectionist approach in regulations governing research with pregnant women and fetuses, trial sponsors, researchers, clinicians, and institutional review boards (IRBs) have been reluctant to include pregnant women in clinical drug trials, applying ethical reasoning for exclusions that reflects a default exclusionary approach. Yet in recent years, many clinicians, researchers, bioethicists, and professional societies have called for a reexamination of the routine practice of excluding pregnant women from clinical research. This paper proposes a practical approach to an ethical framework for IRBs that supports fair inclusion, rather than routine exclusion, of pregnant women in clinical research. This guidance will aid IRBs in ethically including and appropriately protecting pregnant women in research.

This chapter presents an ethics framework for decisions about whether to exclude pregnant women from a clinical research trial. It begins by articulating several background assumptions about the care of pregnant women in the clinical setting and the involvement of pregnant women in clinical research. The uncontroversial truth of these background assumptions supports the idea that pregnant women should be presumed to be included in clinical research, and that their exclusion requires justification. After making the case for the presumptive inclusion of pregnant women, I outline the ethics framework for the legitimate exclusion of pregnant women from clinical research. This framework consists of nine factors that researchers and research ethics committees should consider when deciding whether to exclude pregnant women. Details about research ethics committee review, the nature of risks in pregnancy, the balance between risk and potential benefit, and the context of clinical care are addressed by the framework.

U.S. researchers and scholars often point to two legal factors as significant obstacles to the inclusion of pregnant women in clinical research: the Department of Health and Human Services' regulatory limitations specific to pregnant women's research participation and the fear of liability for potential harm to children born following a pregnant woman's research participation. This article offers a more nuanced view of the potential legal complexities that can impede research with pregnant women than has previously been reflected in the literature. It reveals new insights into the role of legal professionals throughout the research pathway, from product conception to market, and it highlights a variety of legal factors influencing decision-making that may slow or halt research involving pregnant women. Our conclusion is that closing the evidence gap created by the underrepresentation and exclusion of pregnant women in research will require targeted attention to the role of legal professionals and the legal factors that influence their decisions.

Pregnant women deserve more from clinical research. Justice requires a research agenda that adequately addresses the health needs of pregnant women, and fair inclusion criteria that support the safe and responsible participation of pregnant women in relevant research. In recent years, there have been successful global efforts to expand paediatric clinical research and to achieve appropriate gender balance in clinical trials. Significant challenges remain, however, with respect to the fair inclusion of pregnant women in clinical research. Indeed, pregnant women continue to be routinely excluded from such research without justification beyond the generic beliefs that vulnerable foetuses must be protected from research-related harm and that one effective way to meet this obligation is to exclude pregnant women from clinical research.

The study of vaccines during pregnancy is one of the most rapidly evolving fields in medicine today. Pregnant women and young infants are particularly at risk of acquiring and developing complications from infectious diseases [1]. Vaccines administered during pregnancy have the potential to benefit both the mother and her newborn infant [2,101]. Along with the active and ongoing development of safe and effective vaccines, the importance of including pregnant women in clinical research is increasingly recognized. The unique susceptibility of pregnant women and newborns to infections has been recognized for decades, and preventive interventions have been implemented, when available, based on their potential for benefit and the relatively low risk for the mother and fetus. Routine administration of tetanus vaccine during pregnancy was recommended by the WHO in the 1960s after a small study conducted in a high-risk region demonstrated a significant reduction in mortality from neonatal tetanus in infants born to vaccinated mothers. Tetanus vaccination during pregnancy has successfully reduced maternal and neonatal tetanus mortality worldwide [102]. Similarly, influenza vaccine was recommended for pregnant women in the USA after increased morbidity and mortality were documented in women who were pregnant during the influenza pandemics of the early twentieth century and during interpandemic periods [3]. However, it was the 2009 A/H1N1 influenza pandemic that served as a stark reminder of the severity of influenza in pregnancy, its impact on prematurity and fetal–neonatal mortality, and the need to improve influenza vaccine coverage in pregnant women [4]. More recently, the global resurgence of pertussis has resulted in risk-based recommendations to vaccinate pregnant women with tetanus-diphtheriapertussis vaccine in the USA and other countries, in order to provide protection during the period of highest vulnerability to pertussis by increasing the concentrations of maternally transmitted antibodies to the newborn [5]. While the impact of routine maternal immunization with influenza and pertussis vaccines remains to be determined, immunization during pregnancy is now a recognized and accepted strategy to provide protection against specific pathogens that are relevant to the mother and the newborn. These include tetanus, influenza and pertussis, and other infections for which vaccines are currently available, such as meningococcus and pneumococcus, or for which vaccines are in development, including group B streptococcus and respiratory syncytial virus [6,7]. The possibility to protect mothers and infants with vaccines against other relevant pathogens is evident. Maternal immunization is a high priority for research worldwide given its potential to significantly impact maternal and infant health. As interest in maternal immunization as a desirable and feasible strategy to reduce maternal and child morbidity and mortality increases, the challenges associated with vaccinating pregnant women also continue to evolve. Probably the most “The unique susceptibility of pregnant women and newborns to infections has been recognized for decades, and preventive interventions have been implemented, when available, based on their potential for benefit and the relatively low risk for the mother and fetus.”

...It is our purpose (1) to describe how pregnant and nonpregnant\nHIV-infected women are included in clinical research; (2) to trace federal\npolicies concerning the inclusion of pregnant women in clinical research; (3)\nto document the inclusion of HIV-infected pregnant and nonpregnant women in\nclinical trials; (4) to discuss issues relevant to whether sponsors or\ninstitutions could be liable if harm were to result from pregnant women's\ninclusion in as well as the implications of restricting pregnant women's\naccess to AIDS research; and, finally, (5) to provide policy recommendations\nconcerning the circumstances in which HIV-infected pregnant women ought to be\nincluded in clinical research. It should be noted from the outset that we\nfocus on pregnant women because current regulations generally prohibit the\ninclusion of pregnant women in clinical research. Clearly, further research\nis necessary concerning the extent to which adverse reproductive outcomes are\nmale-mediated and whether liability and other concerns might arise in the\nfuture by virtue of including in research men of reproductive potential.

Canadian physician perspectives on the inclusion of pregnant women in trials of intervention for COVID-19

The lack of human data available to inform evidence-based treatment for illness during pregnancy has led to calls for greater inclusion of pregnant women in research, but the extent of their current representation is poorly characterized. Our objective was to measure the current exclusion of pregnant women from industry-sponsored clinical trials as a baseline for future comparison. We compiled data from studies enrolling women of childbearing potential posted on www.ClinicalTrials.gov between 1 October 2011 and 31 January 2012. The review was limited to open United States-based phase IV interventional studies sponsored by the pharmaceutical industry evaluating treatment of conditions that may be experienced by but are not limited to pregnant women and did not involve a medication classified as potentially teratogenic. If there was no mention of pregnancy in the inclusion or exclusion criteria, we contacted a study representative to confirm that pregnant women could be enrolled. Of 558 qualifying industry-sponsored studies, five (1%) were designed specifically for pregnant women. Of 367 phase IV clinical trials with verified inclusion and exclusion criteria, 348 (95%) excluded pregnant women and 19 (5%) did not. We found the exclusion of pregnant women from industry-sponsored clinical trials to be common practice. Moving beyond reflexive exclusion and developing thoughtful criteria for inclusion of pregnant women in clinical research would likely advance the evidence base to inform treatment decisions during pregnancy and lead to better health outcomes for women and children.

Various national and international research guidelines and regulations limit the inclusion of pregnant women in clinical research by classifying them as vulnerable. This exclusion has widely acknowledged negative consequences for the health of women, foetuses, and future children. Another negative consequence is the threat to a pregnant woman’s autonomy and agency when she is treated as a ‘vulnerable’ person without cause. Research guidelines and regulations around the world continue to be overly protectionist. The limitations on autonomy they imply (and create) infantilise pregnant women, treating them ‘as if’ they are vulnerable – as if they, in fact, lack autonomy and the capacity to make informed choices about their own research participation. The hypothetical ‘as if’ becomes actual as research guidelines and regulations effectively reduce the autonomy and agency of pregnant women, making them unable to protect their own interests, including their interests in protecting their future children.