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Research ethics
Vulnerability of pregnant women in clinical research
  1. Indira S E van der Zande1,
  2. Rieke van der Graaf1,
  3. Martijn A Oudijk2,
  4. Johannes J M van Delden1
  1. 1 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
  2. 2 Department of Obstetrics and Gynaecology, Amsterdam Medical Centre, Amsterdam, North Holland, Netherlands
  1. Correspondence to Indira Samantha Elisabeth van der Zande, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, P. O. box 85500, Utrecht, Utrecht 3508 GA, Netherlands; i.s.e.vanderzande{at}umcutrecht.nl

Abstract

Background Notwithstanding 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 no universally accepted criteria for considering pregnant women as vulnerable. Our aim was to explore whether and if so to what extent pregnant women are vulnerable as research subjects.

Method We performed a conceptual and empirical analysis of vulnerability applied to pregnant women.

Analysis A conceptual analysis supports Hurst's definition of vulnerability. Consequently, we argue that pregnant women are vulnerable if they encounter an identifiably increased likelihood of incurring additional or greater wrong. According to the literature, this increased likelihood could exist of four alleged features for pregnant women's vulnerability: (i) informed consent, (ii) susceptibility to coercion, (iii) higher exposure to risk due to lack of knowledge, (iv) vulnerability of the fetus.

Discussion Testing the features against Hurst's definition demonstrates that they all concern the same issue: pregnant women are only vulnerable because a higher exposure to risk due to lack of scientific knowledge comprises an increased wrong. Research Ethics Committees have a responsibility to protect the vulnerable, but a higher exposure to risk due to lack of scientific knowledge is a much broader issue and also needs to be addressed by other stakeholders.

Conclusions The only reason why pregnant women are potentially vulnerable is to the extent that they are increasingly exposed to higher risks due to a lack of scientific knowledge. Accordingly, the discussion can advance to the development of practical strategies to promote fair inclusion of pregnant women in clinical research.

  • Research Ethics
  • Research on Special Populations
  • Obstetrics and Gynaecology
  • Women

https://doi.org/10.1136/medethics-2016-103955

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    Introduction

    Fair inclusion of pregnant women in clinical research has been widely promoted over the last decades, due to the pressing need to produce evidence-based knowledge concerning medications that are prescribed to women during pregnancy for both obstetric and non-obstetric illnesses.1–6 A 2011 study on all medications approved by the United States Food and Drug Administration (FDA) from 1980 to 2010 found that 91% of the medications approved for use by adults did not have sufficient data on safety, efficacy and foetal risk of medication taken during pregnancy.7 At the same time, a 2004 study on drug use during pregnancy concluded that 64% of pregnant women took a prescription drug before delivery,8 ,9 and the total percentage of pregnant women who take medications including off-label medications may be as high as 84%–99%.10–13 Moreover, the number of pregnant women taking at least one prescription medication has increased over the past three decades, common ones including antibiotics, asthma medications and antinausea medications.14 Inclusion of pregnant women in clinical research could provide information on prevention and treatment options and potentially promote maternal and foetal well-being.

    Nevertheless, pregnant women remain under-represented in clinical research. Sometimes they are excluded because of their supposed vulnerability, even though there is no universally accepted definition of vulnerability. Uncertainty about what constitutes vulnerability has resulted in a variety of different interpretations and heated debate about the practical applicability of the concept in relation to for instance pregnant women. The Code of Federal Regulations classifies pregnant women as a vulnerable population15 while the new guidelines of the Council for International Organisations of Medical Sciences mention that pregnant women should not be considered vulnerable but that there are situations which can make them vulnerable.16 At the same time, bioethicists have questioned the idea that pregnant women are a particularly vulnerable group all together.17–21 Existing ambiguity poses a challenge for Research Ethics Committees (RECs), amplified by the lack of advice available through for example the letters of determination of the Office of Human Protection Research which address the requirement to protect vulnerable populations but do not provide substantive guidance on the matter.22 Out of precaution, RECs sometimes choose to interpret guidelines in a conservative way thereby routinely excluding pregnant women.20 ,23 The aim of our paper is to explore whether and if so to what extent pregnant women are vulnerable as research subjects, by way of an analysis of vulnerability applied to pregnant women.

    Analysis of vulnerability

    In the past decades, questions about what constitutes vulnerability have led to animated debate among bioethicists which has resulted in a complicated field with different interpretations of the concept. On one side of the spectrum, there are authors who argue for a broad approach to vulnerability. They state that every protocol needs to be assessed on different features or layers which change depending on a specific situation.24 ,25 In the middle of the debate, there are authors who propose a more explicit approach to vulnerability, arguing that there are a number of set features that could possibly indicate a risk of increased or additional harm and which are therefore worth scrutiny at the minimum in each protocol.26–30 Authors within this category have composed different lists of aspects that indicate when persons are vulnerable. On the other end of the spectrum, there are authors who state that the concept of vulnerability might not be useful at all and might as well be eliminated. They argue that vulnerability should rather be seen as a linguistic tool that functions as a warning signal but which does not require a further conceptual foundation,31 or that special scrutiny for all research participants instead of only the vulnerable should be employed.17

    But although a universally agreed definition of vulnerability is lacking in the bioethical literature on vulnerability of subjects in clinical research, a number of similarities can be noticed. First, there is a general consensus that all human beings are vulnerable due to their universal embodiment and fragility which might be at risk in clinical research. Because of this universal condition, all human subjects who are participating in clinical research are protected by some form of regulation, code or guideline. Second, there appears to be a sentiment that next to the universal vulnerability of all humans, there are particular persons who are at an increased or additional risk of being harmed or wronged in clinical research.27 ,32 ,33 For example, because they are less able to protect their own interests or because of specific circumstances which put them at a disadvantage.i ,34

    Moreover, it is agreed that various stakeholders, such as RECs, researchers and drug authorities, have special obligations to these vulnerable persons because the baseline protection as provided in the general guidelines or regulations does not suffice to protect them.25–29 ,32 ,35–38 Previously, specific group characteristics were said to make a group vulnerable, for instance being a child, a prisoner or a woman. However, the so-called labelling approach has been criticised as being too narrow, too broad and stereotyping entire groups.17 As a result, there is a last point of consensus in the literature, namely that mere characteristics of people alone are not sufficient to deem them vulnerable. Instead, the context of the person in the protocol as well as the research environment needs to be taken into account. As Florencia Luna explicates, it is not about ‘thinking that someone is vulnerable, but by considering a particular situation that makes or renders someone vulnerable’.24 Vulnerability has become a matter of degree, depending on a specific situation.

    To summarise, even though differences with respect to a conceptual analysis of vulnerability persevere, it is agreed that (1) vulnerability is a universal human condition, (2) some persons are vulnerable in the meaning of risking an increased harm or wrong in clinical research, (3) vulnerable persons need special protection atop of the standard guidelines and (4) establishing who qualifies as vulnerable requires a context-specific examination instead of a labelling approach. A definition of what constitutes vulnerability preferably incorporates these aspects.

    Application to pregnant women

    Working definition

    Adding yet another definition to the already large body of literature on vulnerability is not our objective. Instead, we aim to move the discussion forward by electing a working definition from the existing literature that best encompasses the common aspects that are agreed upon. As such, we find that Samia Hurst has undertaken one of the most extended analyses of vulnerability. Her formulation of vulnerability expresses the common ground mentioned above. The formulation also resembles formulations in a number of guidelines.35 ,36 According to Hurst's definition, vulnerability as a claim to special protection should be understood as ‘an identifiably increased likelihood of incurring additional or greater wrong’.27 We use her formulation as our working definition. However, her definition does not clarify what constitutes vulnerability in pregnant research participants. To determine when research participants are vulnerable, Hurst starts by assessing the set of research ethics principles as described by Emanuel and colleagues (among others social value, scientific validity and informed consent) and argues that if any of these principles is fragile or threatened, research participants may be vulnerable.38 ,39 However, if all acts that render a certain study unethical would also render a research participant as vulnerable, it would be too demanding and little specific in what constitutes an identifiably increased likelihood compared to ordinary research participants. Therefore, we will have to further reflect on what constitutes this increased likelihood.

    We have chosen to employ a bottom–up approach in the form of a literature review in addition to our conceptual analysis, to determine the increased or additional wrongs. Using empirical methods to obtain insight into issues of ethical interest is nowadays a respected method. The literature may provide us with morally relevant facts and considered judgements about vulnerability applied to pregnant women participating in clinical research.40 We will identify these issues and accordingly test them to our working definition of vulnerability, which means that we assess whether they comprise an increased risk for pregnant women in comparison with ordinary, non-vulnerable research populations in clinical research.

    Literature search

    Our study design for the literature search was based on the review of reasons as developed by Sofaer and Strech and the thematic synthesis method for the categorisation of the reasons, since it is well suited to identify arguments to address conceptual questions enhance ethically relevant discussion.41 ,42 For the literature search on indications of vulnerability of pregnant women in clinical research, we used a broad search strategy in PubMed/MEDLINE (February 2016). Online supplementary appendix 1 contains the database and search string. We included articles in which reasons for the presumed vulnerability of pregnant women in clinical research were specifically mentioned. We screened 65 unique references on title and abstract; 49 were assessed in full text; 28 met the inclusion criteria. After further assessment for eligibility, 13 articles were finally included (see online supplementary appendix 2: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart). We were able to gather all the features indicating vulnerability of pregnant women in clinical research from the articles in table 1.17 ,21 ,43–53 Since there was considerable consistency among the reported reasons, we were able to categorise them around four themes (table 2): informed consent (n=9), susceptibility to coercion (n=7), higher exposure to risk due to lack of knowledge (n=7) and vulnerability of the fetus (n=6). The results are discussed below.

    View this table:
    Table 1

    Summary of selected articles

    View this table:
    Table 2

    Categorisation of features of vulnerability

    Discussion of the results

    The results of the literature search seem to indicate that the alleged vulnerability of pregnant women in clinical research is particularly related to autonomy issues, such as informed consent and coercion. Since there is no immediately obvious reason to assume that pregnant women are incapacitated during pregnancy, the results are unexpected. We need to adequately assess the features and discuss the meaning to establish if the results mentioned in the literature are indeed increased features of vulnerability. In accordance with Hurst, pregnant women would be vulnerable and in need of protection if their research participation would mean risking an identifiably increased likelihood of incurring additional or greater wrong. We briefly describe and then assess the four features that were found in the literature, before determining in which case protection because of vulnerability is rightly warranted.

    Informed consent

    Informed consent was most frequently cited as a reason for vulnerability (n=9). Six authors argue that there are two specific circumstances, namely during labour and when a serious fetal condition is diagnosed, when informed consent of pregnant women would be hindered due to the severe pain and highly stressed emotional state women are in.51 ,52 Another reason that the authors mention as problematic for informed consent is the complex risk–benefit consideration that pregnant women have to make (n=3). The decision about research participation would be more complex due to the lack of scientific knowledge on research in pregnant women. As such, the decision often has to be made without much knowledge on possible risks of participation.48

    Assessing informed consent as a reason for vulnerability, it becomes evident that having to deal with acute circumstances such as being in labour or having to decide on research participation shortly after having received emotionally stressful news is not specific for pregnant women. Although pregnant women have to make a decision about themselves and their fetus at the same time, there is no reason to assume that in competent adult pregnant women their decision-making capacity is at fault. Instead, their decision-making capacity can be compared with for example the capability of acute patients in the emergency room or parents caring for a child with cancer, or other persons who are highly dependent on medical care.33 ,34 i Similarly, although they are confronted with stressful situations possibly affecting themselves as well as their family, and often in light of a lack of knowledge on risks, these persons are competent to make this decision. Moreover, in relation to the case of labour, the acute situation and following problems with informed consent could often be prevented. From the start of a pregnancy it is known that a woman will at some point be in that acute situation, and by informing and obtaining consent about existing studies for which they might be asked at an earlier stage in the pregnancy, recruitment during labour could be prevented.20 ,46 Such innovate strategies are already successfully implemented in practice.54 Most importantly, the narrow focus on labour undesirably diverts the discussion from the broader discussion about vulnerability of pregnant women in clinical research, which is what should be focused upon.

    In relation to the perceived informed consent issues due to greater risk–benefit difficulties, it could be argued that due to a lack of knowledge on risks, deciding on research participation might indeed be a challenge. Nevertheless, patients in similar situations in which there is no evidence base, such as patients with orphan diseases or elderly patients, are confronted with a similar choice. In short, although consent may be complicated due to a lack of scientific knowledge on possible risks and benefits, pregnant women do not risk an identifiably increased likelihood of incurring additional or greater wrong with regard to the feature of informed consent.

    Susceptibility to coercion

    Susceptibility to coercion was noted as another feature indicating pregnant women's vulnerability (n=7). Authors state that pregnant women might have an increased likelihood to be susceptible to coercion due to both their own desire and society's expectation to prioritise the needs of the fetus regardless of their own.21 ,52 ,53 This expected protectionism towards the fetus could mask their (un)willingness to participate in clinical research.

    We speak of coercion when an agent is confronted by another agent with a deliberative threatening proposal whereby not accepting the proposal will leave the agent worse off.55 Neither a woman's own desire nor society's expectation to prioritise the fetus' health encompasses a threatening proposal. Therefore, there is no immediately obvious indication that pregnant women are vulnerable because of coercion in comparison with ordinary research subjects. On further exploration of the topic, it becomes evident that while the term coercion, which was coined in the literature, can be disregarded, a type of moral pressure may be observable. To illustrate, the expectation of potential direct individual benefit for the mother, the fetus or both, could influence pregnant women's consent to participate in potentially beneficial clinical research. Pregnant women may be more prone to misconceptions or overestimation or underestimation of risks and benefits for the fetus.56 Another example is pressure from society or from the father to conform to standards of good motherhood which may influence pregnant women's decisions.18 ,29 As such, the ‘pregnant woman's wish to prioritise the needs of the fetus’ could be compared with the situation of parents of children (whether or not enrolled in clinical research). Here, the assumption is also that parents are best suited to make decisions about their children, in which they will often prioritise the need of their children above the need of themselves and have a desire to do what is best for them. One could argue that the decision for pregnant women is different in that it affects the fetus as well as herself. However, pregnant women generally want to stay well on behalf of themselves and their fetus, and we believe that they will therefore not (completely) disregard their own health.i Although in these scenarios we should be aware that moral pressure might indeed influence one's reasoning, thinking that pregnant women are being wronged because of coercion seems rather paternalistic and unfair. It is interesting that guidelines keep referring to coercion relative to pregnant women,15 ,35 since there is no indication that pregnant women are susceptible to coercion in clinical research.

    Higher exposure to risk due to lack of scientific knowledge

    A higher exposure to risk due to a lack of knowledge was cited as another reason for vulnerability (n=7). Authors explicate that both historically and juridically (referring to guidelines and regulations) pregnant women have been routinely excluded from clinical research which, as a result, has led to a lack of knowledge on medications and treatment options for their population. Consequently, information is based on incomplete sources which are often flawed and less dependable than randomised controlled trials. As such, authors argue that pregnant women are now a medically disadvantaged group risking an increased likelihood of incurring a higher exposure to risk when participating in clinical research.21 ,53

    Examining this feature, it appears that recent efforts to promote inclusion have started to be effective, for instance illustrated by guidelines which are currently changing their direction towards inclusion of pregnant women.35 ,37 In addition, pregnant women are not always disadvantaged as subjects in clinical research, since not all medications lack knowledge on safety and efficacy. Some medications are extensively studied in pregnant women, such as anti-epileptic drugs or labour inhibitors, and in those cases pregnant women in clinical research are not necessarily exposed to higher risks.

    However, in the majority of cases, pregnant women in clinical research are indeed exposed to a higher risk in comparison to ordinary research populations due to the lack of knowledge on safety and efficacy of medications or interventions which are not always tested in their population. As a result, the majority of medications are currently characterised by the FDA as pregnancy category Bii or category Ciii.14 Pregnant women are rarely included in clinical trials and even in phase IV trials they are usually excluded.5 Hence, dosing and safety information is typically extrapolated from studies in non-pregnant patients. When (market approved) medications for humans are finally tested in pregnant women, phase I and sometimes phase II trials involving pregnant women are no longer undertaken due to various issues such as time and cost issues, liability fears or a fear of harming the fetus.20 ,57 Instead, phase III trials are initiated based on information obtained from safety data in non-pregnant humans; based on preclinical information with pregnant animals; based on voluntary case reports; or based on information from inadvertent pregnancy exposures in which women became pregnant during a clinical trial. Such information is often incomplete and difficult to interpret, for example, because coincidence and causation are hard to distinguish and because the information cannot be used to assess teratogenic risk.9 ,59 Moreover, in case of inadvertent pregnancy exposures during clinical trials of new products, available data are usually insufficient to permit an adequately powered statistical analysis that could then later be used for clinical research in pregnant women.59 We therefore assume that due to the lack of scientific knowledge on medications and interventions in the population of pregnant women, pregnant women may face an increased likelihood of incurring a higher exposure to risk in clinical research.

    Vulnerability of the fetus

    A last feature from the literature that seems to indicate vulnerability of pregnant women is the vulnerability of the fetus (n=6). Authors mention that the mere existence of the fetus which could potentially be harmed sometimes seems to deem pregnant women vulnerable. Moreover, it is argued that the lack of deliberative capacity of the fetus indicates that pregnant women are vulnerable.49

    Assessing this feature, it appears that the cognitive vulnerability of the fetus is not equivalent to the cognitive vulnerability of the pregnant woman. The fact that the fetus is incapacitated only means that there should be a surrogate decision maker, which can be found in the pregnant woman herself. Relative to the risk of harming the fetus, it can be noted that this risk, which is often disproportionally weighed and sometimes not at all present, is in fact related to the complexities of the risk–benefit analysis, which is more difficult in the case of pregnant women due to lack of scientific knowledge. Nevertheless, there is no reason to assume that the vulnerability of the fetus renders pregnant women increasingly vulnerable in comparison with ordinary research subjects. Neither the existence of the fetus nor the cognitive vulnerability of the fetus increases pregnant women's likelihood of incurring additional or greater wrong.

    The literature search indicated four different features of pregnant women's alleged vulnerability in clinical research. However, after assessment of these features, it seems that all aspects of vulnerability which are factually present can be attributed to the same feature: a higher exposure to risk due to lack of scientific knowledge.

    Discussion

    Neither informed consent, susceptibility to coercion or vulnerability of the fetus leads to an identifiably increased likelihood of incurring additional or greater wrong for pregnant women in comparison with ordinary research participants. Instead, all features concern the same issue: a higher exposure to risk due to a lack of scientific knowledge. This last feature does comprise an increased wrong and, depending on the context of a research protocol, may render pregnant women particularly vulnerable and in need of special protection. As such, we are confronted with a dilemma: pregnant women are potentially vulnerable in clinical research because of a lack of scientific knowledge (because they have not been included in clinical research), but to overcome this state of vulnerability, pregnant women should be more frequently included. Decreasing vulnerability is essential to overcome the dilemma.

    By charging RECs with the task to approve or disapprove clinical research protocols, guidelines and regulations indirectly designate RECs as the institutions responsible for the protection of vulnerable persons in clinical research.36 However, since the vulnerability of pregnant women primarily comprises the lack of scientific knowledge, relying on RECs alone for protection is not sufficient for a number of reasons. First, RECs are concerned with assessment of research protocols (usually not including pregnant women) and when researchers do not put protocols up for assessment there is only so much RECs can do. Second, RECs are only involved at a later stage in the research process and by that time it might be too late to compel researchers to include pregnant women to reduce the knowledge gap. Third and most importantly, RECs are simply not the only bodies responsible for increasing the evidence base for pregnant women.

    Research Ethics Committees unquestionably have a role to fulfil in safeguarding pregnant women's interests in clinical research, for example, by interpreting guidelines more progressively and requesting justifications for the exclusion of pregnant women.4 ,18 ,60 But the issue, addressing the knowledge gap, comprises a much broader domain than that of RECs and the development of special protections alone. One could for example imagine a role for funding agencies and research sponsors. These organisations can prioritise clinical research in pregnant women by including at least one grant for research in this population per each application round. Or, as Greer Donley suggests, by creating financial incentives to generate data on pregnant women by granting a 3-month period of market exclusivity for drug companies that invest in research in this population (similar to the paediatric setting).45 In addition, the involvement of manufacturers will also be essential in addressing the lack of scientific knowledge, which is challenging due to their liability fears in relation to clinical research in pregnant women. However, as we have argued elsewhere, shifting liability or demonstrating the predicted low occurrence of liability claims could be viable solutions.57 Evidently, different stakeholders at different times in the research process have their own obligations with regard to reducing the lack of scientific knowledge. As several authors have previously indicated, reducing pregnant women's vulnerability requires a collaborative partnership among stakeholders such as funding agencies, drug authorities, researchers, methodologists, pharmacologists, guideline committees and RECs. Raising awareness on the efficiency and potential benefits of partnerships could motivate stakeholders to collaborate, particularly when supportive research structures are facilitated. At present, different strategies to increase the evidence base for pregnant women are explored, such as the development of new ways to systematically collect data or implement innovative research designs.2 ,4 Further collaboration might lead to new insights which could advance the process with the final goal to improve maternal and foetal well-being.

    Conclusion

    Our study once and for all demonstrates that there is no indication that pregnant women are vulnerable because of informed consent, susceptibility to coercion or vulnerability of the fetus. The only reason why pregnant women are potentially vulnerable in clinical research is to the extent that they are increasingly exposed to higher risks due to a lack of scientific knowledge which might render them vulnerable as research subjects. Depending on the context of a research protocol, pregnant women may therefore have a claim to special protection. RECs have a responsibility to protect vulnerable persons and as such they have certain obligations with regard to pregnant women. However, discussing the lack of scientific knowledge in committee review meetings is insufficient, for the issue comprises a much broader domain. Only a joint effort to promote fair inclusion by funding agencies, drug authorities, researchers, methodologists, pharmacologists, guideline committees and RECs can successfully reduce pregnant women's vulnerability. Now that we have established that there is really only one vulnerability that needs to be addressed, the discussion can advance to the development of practical strategies to promote fair inclusion of pregnant women in clinical research.

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    Footnotes

    • Contributors IZ and RG designed the study and IZ drafted the manuscript. MO and JD made critical revisions to the paper. IZ, RG, MO and JD contributed equally to the final version of the manuscript submitted for publication.

    • Funding Funding was provided by the Dutch grant supplier the Netherlands Organisation for Health Research and Development (ZonMw), grant number: 11310500.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • ↵i Unpublished data from the authors' qualitative study Stakeholders' Interests in Inclusion of Pregnant Women in Clinical Research.

    • ↵ii Category B: ‘Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women’.

    • ↵iii Category C: ‘Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks’.

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