Protected from harm,harmed by protection: ethical consequences of the exclusion of pregnant participants from clinical trials

Abstract

Pregnancy is a frequently applied exclusion criteria for many forms of research. Common justifications for this exclusion include the potential for teratogenicity, as well as the potential for physiologic changes in pregnancy to impact the research itself. The systematic exclusion of pregnant persons from clinical studies has created a significant gap in knowledge regarding medication safety and efficacy in pregnancy, which continues to cause significant harm to pregnant persons in need of medical therapy. To produce meaningful data and facilitate effective knowledge translation to the clinical setting, special consideration to the pharmacology of pregnancy, as well as to outcomes of concern for this population is essential. The exclusion of pregnant participants from research is not ethically justifiable, as it violates the principles of autonomy, justice and nonmaleficence. While the inclusion of pregnant patients in research presents it’s own challenges, with appropriate methodological, ethical, and clinical considerations, we may be able to narrow the knowledge gap and improve drug availability and safety for pregnant patients and their children.

Medication use in pregnancy is common; over the course of pregnancy 90% of individuals require medication in some form, and 70% require at least one prescription medication (Wesley et al., 2021). Antibiotics, asthma medications, pain medications, and antiemetics are commonly used, and in most cases their use is essential to maternal wellbeing (van der Graaf et al., 2018). However, only 2.4% of these commonly used drugs have been subjected to testing in controlled human clinical trials during pregnancy, with the majority of data resulting from animal studies only (50%), or no studies at all (37.8%) (Wilson, 2007).

The primary reason for the paucity of data is that pregnancy is a commonly applied exclusion criterion in the design of clinical drug trials (ACOG, 2016). This exclusion is often justified by the potential for teratogenic effects of medications, as well as the potential confounding effect of pregnancy related changes in physiology impacting the results of pharmacologic trials (Food and Drug Administration (FDA), 2018; Shields and Lyerly, 2013). However, the systematic exclusion of pregnant participants is not ethically defensible, as it violates the principles of autonomy (in both research and clinical settings), justice, and non-maleficence, and amplifies existing inequalities.

While pregnant and lactating people are often considered to be a vulnerable population, blanket exclusion from research fails to recognise that the vulnerabilities of pregnant participants are not universal or insurmountable and does not acknowledge the ways in which people may be made more vulnerable by exclusion (Ballantyne and Rogers, 2016). The ethical inclusion of pregnant people in research is not as simple as lifting the exclusion criteria for all, but with appropriate methodological, ethical, and clinical considerations, the inclusion of pregnant individuals in research would promote equitable access to the benefits of research, support individual autonomy, and improve medication safety (Lyerly et al., 2008).

From a policy standpoint, guidelines and statements from governing bodies around the globe agree that there is a place for pregnant participants in research. For instance, the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines for Health-related Research Involving Humans is clear that ‘Pregnant women must not be considered vulnerable simply because they are pregnant’ (Council for International Organizations of Medical Sciences(CIOMS), 2016: 8). Likewise, the Council of Europe, the United States’ National Institutes of Health, the American College of Obstetricians and Gynaecologists, and the Canadian Tri-Council policy statement on Ethical Conduct of Research Involving Humans all echo this support for the appropriate inclusion of pregnant and breastfeeding individuals in clinical trials (American College of Obstetricians and Gynecologists (ACOG), 2016; Council of Europe, Steering Committee on Bioethics, 2012; National Institutes of Health (NIH), 2001; TCPS2: Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council, 2022).

Despite the overwhelming support by international research bodies, information surrounding medication efficacy and safety in pregnancy continues to be collected primarily in the post-marketing setting, not during clinical trials (FDA, 2018). Researchers designing and administering clinical trials for new medications are often concerned about the physiological complexity of pregnancy potentially adding heterogeneity to the results, as well as the potential for pregnancy specific complications and teratogenicity (FDA, 2018). Any unstudied medication carries the potential risk for adverse pregnancy outcomes; the risk of teratogenicity for the developing foetus and the potential for adverse outcomes such as pregnancy loss and foetal growth restrictions are often cited as an ethical barrier to inclusion (National Institutes of Health (NIH) and Office of Research on Women’s Health (ORWH), 2011; CIOMS, 2016).

On the other hand, the blanket exclusion of pregnant participants from clinical trials undermines the autonomy of the individual to assess the risks to themselves and their foetuses, and limits their ability to decide whether participation is in their best interests (Shields and Lyerly, 2013). Pregnancy status barring people from the benefits of research on the basis of foetal safety prioritises the wellbeing of the foetus over that of the mother, which undermines her autonomy as an individual, and instead acts on behalf of a being that does not yet have personhood (NIH and ORWH, 2011).

Additionally, the lack of high-quality evidence that has resulted from exclusion from research creates barriers to informed choice and further undermines the autonomy of individuals who are pregnant, may become pregnant, or whose reproductive decisions are influenced by the safety of medications on which their own health depends. It is not possible to properly weigh the risks and benefits and determine the option most in line with one’s values when information regarding these risks does not exist (NIH and ORWH, 2011).

Ironically, the exclusion of pregnant people from clinical trials due to concern for maternal and foetal harm in the research setting has led to significant harms for women, their children, and the general population in the following ways:

1. Limiting what is known about toxicity and dosing specific to pregnancy, thereby putting patients who require medication at risk.

2. Discouraging patients from accessing beneficial medication due to fear of unknown adverse effects.

3. Exposing pregnant people and their foetuses to potentially harmful medications through off label use without benefitting from safeguards and monitoring that is normally embedded in clinical trials (NIH and ORWH, 2011).

Historically, the use of medication in pregnancy without knowledge of its safety has led to tragic consequences, most notably in the cases of thalidomide and diethylstilbestrol (DES) (CIOMS, 2016). While the devastating teratogenic effects of these medications are often cited as a barrier to pharmaceutical research during pregnancy, this argument is inherently flawed (van der Graaf et al., 2018). Neither thalidomide nor DES use in pregnancy were studied in controlled trials before being approved for general use. By relying on post marketing safety data, the exposure to these medications and subsequent harmful effects was far more widespread (CIOMS, 2016). Instead of impacting a small group of individuals consenting to the risks of research, the devastating consequences of thalidomide and DES in pregnancy have affected thousands of families who likely were not afforded a detailed consent process as would have been provided for anyone enrolling in a clinical trial (CIOMS, 2016; Gomes et al., 2017).

While the cases of thalidomide and DES highlight that there is a significant potential for harm secondary to medication use in pregnancy, these examples also highlight how women and their unborn children are not protected from these harms by their exclusion in research (CIOMS, 2016). Close monitoring, rigorous analysis, and explicit informed consent are essential for ethical research, and both participants and the pregnant population as a whole benefit from these safeguards. Teratogenicity and adverse effects are much easier to detect and analyse in a clinical trial than in a post-market setting. Once adverse effects are detected, a trial can be stopped and appropriate counselling or compensation provided (Caritis and Venkataramanan, 2021). In the absence of such studies, the general population is harmed directly through exposure to potentially dangerous medications over a longer period, as well as indirectly through hesitancy to use necessary medications (Beauchamp and Childress, 2019; NIH, and ORWH 2011).

The absence of high-quality safety data does not diminish the need for medical therapy, but health care providers and patients are understandably anxious when faced with the prospect of medication use with an unknown safety profile (van der Graaf et al., 2018). However, allowing medical conditions to go untreated often causes greater harm to both the mother and the foetus (FDA, 2018). Pregnant people suffer from the full range of chronic and acute diseases and are at increased risk of a multitude of pregnancy specific medical conditions (NIH and ORWH, 2011). Many of these conditions are treatable, but in the absence of safety data we are left with a dilemma: do we take on the unknown risks associated with inadequately studied medication, or assume the known harms of forgoing treatment? (NIH and ORWH, 2011).

Pregnancy is a unique physiological state and as such the effect, required dosing, and excretion rates of medications are often different to those of the general population. This can be a challenge for clinical trials that require a certain degree of homogeneity within the study population to show statistical significance of benefit, establish dosing, or identify toxicity levels for the general population (FDA, 2018). There can be concern that the inclusion of pregnant participants acts as a significant confounding factor, especially in small trials or when a drug has a narrow therapeutic index (NIH and ORWH, 2011).

However, the normal physiological changes of pregnancy that are highlighted as confounders within a clinical trial, also significantly alter the pharmacokinetics of medications when used clinically (NIH and ORWH, 2011). Alterations in absorption, metabolism, and excretion of a medication have a direct impact on optimal dosing and potential for toxicity (NIH and ORWH, 2011). In the absence of controlled trials there is no way to accurately determine efficacy, toxicity, or proper dosing for a pregnant person, and physicians are left to extrapolate dosing based on their knowledge of physiology and clinical experience with similar medications (CIOMS, 2016; FDA, 2018). This is problematic for several reasons. First, meaningful post-marketing analysis becomes extremely difficult when providers are using ad hoc dosing, as it introduces profound heterogeneity into the observed outcomes. Second, novel medications are often completely avoided or used with careful titration, since there is no previous experience on which to rely. This period of uncertainty is essentially an uncontrolled experiment, placing people in a position where they are assuming all the risks that researchers try to avoid, but without the surveillance, protection, or long-term societal benefits of a clinical trial.

The concept of vulnerability highlights groups at an increased likelihood of suffering harm, either due to an increased level of risk being undertaken, or a decreased capacity to protect oneself (Gordon, 2020; Johnson, 2016). In the clinical research context, all people are vulnerable to the risks of an experiment and the potential harm from side effects. However, specific ‘vulnerable groups’ have been identified as being at increased risk of physical harms, psychological harms, oppression, or coercion, and are owed special protections in research (Gordon, 2020).

The identification of research participants who may have increased susceptibility to harm in research is useful to avoid preventable harms and promote equitable treatment (Gordon, 2020). However, the type of vulnerability associated with pregnancy differs from many other examples of vulnerable groups in a number of key ways and there is substantial disagreement as to whether they should be considered vulnerable at all (Ren et al., 2021). Many populations considered vulnerable are at risk due to limited capacity for consent, such as young children, people with dementia, people with intellectual disabilities. Others might be considered at risk because of their susceptibility to coercion, such as incarcerated individuals (Johnson, 2016). The reasons why these groups are to be considered vulnerable are generally well defined, and possible solutions exist for mitigating specific risks while involving them in research (Ballantyne and Rogers, 2016).

By contrast, the ways in which pregnancy renders a person vulnerable are not well defined, and this has led to a tendency towards blanket exclusion rather than risk mitigation (Ballantyne and Rogers, 2016). Pregnancy adds complexity, with dramatic changes to a person’s physiology, pharmacokinetics, and social dynamics, and introduces uncertainty regarding potential foetal and obstetric effects (Caritis and Venkataramanan, 2021; CIOMS, 2016). However, while being pregnant can certainly exacerbate or unmask other medical, social, cultural, or psychologic vulnerabilities, a pregnant person does not experience decreased capacity to weigh risks and benefits and to make a value-based decision simply by virtue of their pregnancy. It has been argued that pregnancy infers a psychological vulnerability, whereby a pregnant participant may be willing to undertake significant personal risks if there is an opportunity for the foetus to benefit (Ashcroft, 2016). However, this position should not be confused with lack of capacity. A capable person is able to choose to undertake risks to benefit another person, or in this case, future-person, as is well established in the case of living organ donation. This type of consideration can be addressed via a carefully constructed and sensitively applied informed consent process.

Much of the historical basis for protectionist research policies have stemmed from concern for foetal wellbeing, rather than that of the participant themselves (van der Zande et al., 2016). A foetus (and subsequently the child that results from the pregnancy) has inherent vulnerabilities due to their developmental stage, rapid growth and total dependence on their mother. Drug and environmental exposures, which may be completely benign for the mother, may have devastating consequences for a developing foetus, and may persist into childhood and beyond (Johnson, 2016). The degree of uncertainty inherent in any clinical trial, together with the complexity of foetal physiology, make such harms difficult to predict based on theory alone. This introduces an unavoidable degree of risk into this type of research that must be appropriately addressed during the informed consent process (Ballantyne and Rogers, 2016). However, theoretical risks must be balanced against the tangible benefits of research participation which exist for the pregnant person, the future child, and society as a whole.

All people deserve the opportunity to benefit from advances in medical therapy, regardless of pregnancy status, and the existence of systematic barriers to this opportunity violates the principle of justice in both its substantive and distributive forms (TCPS2, 2022). In addition to providing valuable information to guide future care, the opportunity to enrol in a clinical trial provides people with complex medical conditions access to medications or therapies that would not otherwise be available to them. By reflexively excluding pregnant participants from these trials, people who might benefit from access to experimental medications are prevented from doing so. Some pharmaceutical trials investigating therapies for HIV/AIDS, tuberculosis, and malaria have recognised this inequality and have included pregnant participants when the potential for maternal benefit far outweighs the potential risks to the foetus (FDA, 2018; Gomes et al., 2017). However, such inclusion is not consistent. During the 2013–2016 Ebola epidemic, pregnant people were excluded from all Ebola vaccine trials in affected countries despite a previously observed 89-93% maternal mortality rate, and a 100% foetal mortality rate with Ebola infection in pregnancy (Gomes et al., 2017). By limiting access to the trial, and, therefore, a potentially lifesaving intervention, pregnancy status unjustly placed otherwise eligible people at a disadvantage (Gomes et al., 2017). Similarly, COVID-19 vaccination trials excluded pregnant people even though it was well recognised that pregnancy increased one’s risk of severe COVID infection. This exclusion initially resulted in conflicting guidelines regarding whether COVID vaccination should be recommended during pregnancy; despite a strong safety profile in post-marketing surveillance, widespread vaccine hesitancy persists (Bhattacharya et al., 2022; Rubin, 2021).

Ensuring equality of access to a system of health protection, including access to medications, is a fundamental human right under the Universal Declaration of Human Rights (UNDHR, article 25). Additionally, the concept of fair inclusion is a fundamental principle of research ethics, and explicitly explored in the CIOMS guideline where it is stated, ‘Since information about the management of diseases is considered a benefit to society, it is unjust to intentionally deprive specific groups of that benefit. The need to redress these injustices by encouraging the participation of previously excluded groups in basic and applied biomedical research is widely recognized’ (CIOMS, 2016: 8).

However, fair inclusion of pregnant people in research is not as straightforward as simply eliminating the exclusion criteria (van der Graaf et al., 2018). The specific physiology and potential adverse outcomes of pregnancy can impact not only the participants, but also the research itself. Clinical trials may be stopped prematurely if significant harm or adverse effects to study participants is suspected and adverse outcomes specific to pregnancy, such as pregnancy loss, may introduce another dimension of risk for a given trial. Equally, the specific physiological changes of pregnancy may bias medication dosing and toxicity levels for the general population if the efficacy data of these groups were to be pooled and analysed together and the study was not powered appropriately to account for diverse physiology (van der Graaf et al., 2018). Given the potential for public good when a new medication is found to be a beneficial, as well as the immense investment required to bring a drug to market, researchers must carefully consider any factors that would put the trial itself at risk.

When considering the impact of inclusion in research, it is also important to note that population-specific risks and changes in physiology are not unique to pregnancy. Medical history, genetics, and inherent differences in metabolism can all impact individual response to medication, but usually do not prompt blanket exclusion from participation. The inclusion of small numbers of pregnant people across randomised study groups would not be expected to impact the findings of a given trial any more than inclusion of participants with, for example, obesity or liver disease. In fact, including participants with diverse physiology in a trial increases the generalisability of the results, and provides more meaningful clinical data to inform health care decision-making.

There are certainly valid reasons for excluding pregnant people from specific research studies, such as when there is strong evidence that participation could cause maternal or foetal harm, or when the probability of benefit from inclusion is minimal (NIH and ORWH, 2011). However, in the majority of cases, purposeful inclusion and the use of advanced analyses can provide meaningful information to guide the care of pregnant participants and promote equitable access to research benefits. Many issues can be addressed effectively through subgroup analysis, the use of pharmacometrics tools, or secondary clinical trials specifically for pregnant participants (Ren et al., 2021; van der Graaf et al., 2018). In addition to robust post-marketing surveillance, subgroup analysis and secondary trials allow for specific focus on pregnancy-related outcomes such as teratogenic effects, as well as determination of efficacy, dosing, and toxicity specific to pregnancy (van der Graaf et al., 2018).

These additional analyses could act to protect the trial as a whole and minimise the risk that pregnancy-specific contraindications to a drug impact information about the medication’s safety profile for the general population. If the possibility exists that a medication would be deemed safe and effective for the general population, but may have different effects in pregnancy, subgroup analysis may be beneficial to determine the risks faced by pregnant people and their foetuses to guide care and highlight differences in pharmacokinetics between the two groups (van der Graaf et al., 2018).

Changes in research design can be costly and there can be hesitancy to engage in such studies within the pharmaceutical industry (Wesley et al., 2021). In order to promote the interests of pregnant participants, external motivation for pharmaceutical companies to pursue pregnancy specific research may be required, whether through research ethics boards requiring justification of exclusion criteria, regulatory agencies limiting approval, or financial incentives (Wesley et al., 2021).

Medication use in pregnancy deserves special attention, both in terms of safety and pharmacology. While a degree of hesitancy to study medications in pregnancy is understandable given the potential for added risk and complexity, the systematic exclusion of pregnant people from clinical research has led to a paucity of data to guide their care, thereby worsening risks of harm and inequities. While the intention may be to protect study participants, the inequality created by this practice results in a net harm for those who are pregnant. Protection by exclusion has led to an unacceptable and avoidable knowledge gap that can be remedied to support autonomy, equality, and safety.