Expanding the ethical debate on human artificial placenta trials

Background

In 2017 Partridge et al. (2017) announced the first successful animal trial with an artificial placenta (AP). This technology mimics the human placenta to treat extremely preterm infants (EPIs) born at 23–25 weeks of gestation. Due to general immaturity, these infants still suffer from high mortality and morbidity rates. Artificial placentas ¹ are designed to prolong the development of the lungs by maintaining the lungs in a liquid environment with synthetic amniotic fluid, and by providing oxygenation through the umbilical cord (De Bie et al., 2021). Preventing the severe complications related to lung prematurity and mechanical ventilation would improve an infant’s chances of survival and quality of life (Partridge et al., 2017).

AP trials will likely be randomised controlled trials as this is considered the golden standard (Cavolo and Pizzolato, 2024). AP trials will likely involve two steps. First, the transfer in AP that requires a planned C-section on the pregnant person, and second the treatment in AP that only involves the preterm infant. This means that the trial will involve two participants: the pregnant person and the preterm infant, as it is not possible to use the AP on a less vulnerable population. However, this would be an invasive procedure and human trials would need to balance the ethical interests of the participant and the need to produce scientifically valid knowledge.

Although there is substantial literature on the ethics of APs, only a few papers have discussed the ethics of AP trials (e.g. Cavolo et al., 2023). One investigated some foundational ethical issues, such as the moral status of AP participants, how to appropriately select participants, and the trial design (Romanis, 2020a). In particular, Romanis (2020a) builds on the distinction between innovation and research to show how a clinical trial, in this case, is necessary. Other papers have provided more concrete advice and guidance, for example, that only parents who received complete and non-directive counselling can participate (Cavolo et al., 2023). However, this type of advice is valid for all clinical trials (Flake et al., 2023). This means that some of the unique challenges specifically posed by AP trials remain unanswered.

This Topic Piece aims to expand the ethical debate on AP trials by identifying some unanswered questions or questions that have proved to be more complex than they first appeared. We did not address questions that, although important, have been already discussed, such as protection of participants (Cavolo and Pizzolato, 2024; Romanis, 2020a; Verweij et al., 2021). We acknowledge that we can neither identify nor answer all questions, but we want to provide a blueprint of some further questions to consider ahead of AP human trials.

The double role of counselling

The primary focus of AP trials would be to develop safe life-saving treatment for EPIs (Partridge et al., 2017). This means that the human trials will likely aim at treating individual participants and creating generalisable knowledge valid for the whole EPI population. In this challenging setting, counselling has the double role to provide information for trials recruitment and counselling for (non)treatment decisions (Hay-Smith et al., 2016). Trial information such as how the technology works, and the risks and benefits, should be integrated into broader care counselling. Clinicians and parents might have to decide whether to choose treatment or palliative care, opt for experimental treatment or current treatment, and discuss how far to go with aggressive treatment. This counselling requires more than simple, neutral information. It calls for proper shared decision-making and support so that parents understand the best option for them and their child. Treatment decisions for EPIs are already difficult for clinicians and parents alike (Cavolo et al., 2021; Janvier et al., 2016). AP trials would add to those difficulties by providing another option and requiring trial information. Furthermore, many AP trials would require a planned Caesarean section for the benefit of the infant (Partridge et al., 2017). Women have reported feeling pressured to take part in maternal-fetal surgery trials for the benefit of their fetus (Crombag et al., 2021) and this risk should be considered in AP trials.

These challenges call for extra training and advice on the difficulties of double counselling. External science communicators, trained in conveying complex scientific information in lay and neutral terms, could help develop leaflets and information material that parents can consult between counselling sessions. Involving external counsellors could also help reduce the risk of undue influence from clinical researchers, who might be excessively optimistic, or the care team, who might be overly pessimistic (Verweij et al., 2021). This could also reduce the risk of therapeutic misconception, which is high in trials that have a double goal of treatment and research, such as AP trials (Romanis, 2020a; Verweij and Kingma, 2023). Digital tours of APs and neonatal intensive care units could also be helpful. These extra tools have already proven effective in helping treatment decisions for EPIs (Flynn et al., 2023). Importantly, these tools are meant to support clinicians’ counselling and the decision-making process, not to substitute their counselling or their therapeutic relationships with parents. These could also enable clinicians to focus more on the more ethical and personalised aspects of counselling, and to build a strong therapeutic relationship with parents. However, these tools would only be effective if clinicians, researchers, and parents, were involved in the design and development from the start.

Stakeholders’ involvement

To our knowledge, no stakeholders have been involved in empirical studies on AP trials, or their potential implementation, particularly for EPIs. Stakeholder involvement can not only improve the development of decision aids, but also identify potentially overlooked ethical issues and which issues are most important. For example, the most debated ethical issue about APs is the moral status of the recipient (Cavolo et al., 2023). However, this might not be the top issue for parents facing difficult decisions about whether they want their infant to undergo experimental treatment.

First, we should involve stakeholders who would be directly affected by such trials: parents, clinicians, and researchers. APs have only been tested on animals so far. However, parents who have already made treatment decisions about their preterm infants could provide valuable insights on what future parents may fear or need in the trials, what kind of information they need, etc. (Cavolo and Pizzolato, 2024). Many APs will require a planned Caesarean section for fetal benefit (Flake et al., 2023; Kukora et al., 2023). Parents who participated in maternal-fetal surgery trials could also provide insights into how parents make decisions on trials that require the pregnant person to undergo major surgery for fetal benefit, how they could be supported, and how to avoid pressure to participate (Cavolo and Pizzolato, 2024).

The role of the partner and/or the other parent (when present) is also important in the broader discussion regarding whether an AP is the right treatment for the infant, but has tended to be overlooked. The pregnant person rightly makes the decision about whether they want a Caesarean section, regardless of the partner’s opinion (Romanis, 2020b). However, both parents would acquire equal rights and duties after transfer in the AP, as the infant would no longer depend on the pregnant person’s body. What would happen if the parents disagreed on enrolling the infant in the trial? Should clinicians and researchers disenroll the child and pursue regular treatment as both parents have not consented? Or should they carry on with the experimental treatment because otherwise the surgery would have been pointless? One possible solution could be to only enroll parents who both agree. Another could be to continue the experimental treatment but discuss withdrawal if the child is not responding well. This should be done regardless of any trial, but in this specific case could also be a way to address both parents. Both options have pros and cons that should be investigated further. Moreover, one study showed that when fathers were confronted with EPI treatment decisions they struggled to balance the need to support their partner after her preterm delivery and their own concerns about having a preterm infant (Urbanosky et al., 2023). It is it also important to consider, how to provide the family with holistic support, as well as clinical support for the pregnant person and child. An integral part of these trials should be to collect insights from participants and their partners throughout the trial and follow-up. This will allow to further identify missed or misinterpreted issues and what improvements are required.

Second, we should involve stakeholders who are indirectly affected by AP trials. We need more societal involvement, as people may be affected if the trials and/or treatment are publicly funded (Adkins, 2023; Verweij et al., 2021; Verweij and Kingma, 2023). The fact that APs are not yet available gives us the unique opportunity to involve the public in a timely manner (Adkins, 2023) and to integrate the public’s views in the further development and trial of Aps (Adkins, 2023; Verweij et al., 2021; Verweij and Kingma, 2023). Importantly, involving the public requires education campaigns providing complete and neutral information on APs to allow the public to develop unbiased competent opinions, as well as an active effort to include marginalised groups to obtain a comprehensive and nuanced view of public’s opinion (Adkins, 2023).

To determine whether and how to fund AP trials, we should consider not only the immediate implications of the trials but also the long-term implications of AP implementation. Should we use public funds to support an expensive experimental treatment for patients who can already be offered a decent, effective alternative? If they don’t agree, we would also need to consider the ethical implications of not subsidizing APs. For example, EPIs from minority groups and financially challenged households already have worse outcomes than infants from white, financially stable households, mainly due to access difficulties (Horn, 2022). Not subsidizing APs could mean that only richer parents could afford the potentially better treatment, which would increase differences in outcomes. If AP trials and subsequent implementation will be publicly funded, it is also important to discuss how to ensure to redistribute this funding to ensure fair access within and after the trial (Horn and Romanis, 2020). For example, a budget could be allocated to provide travel expenses or housing close to the hospital. In this regard, it is important to involve also other indirect stakeholders, such as advocates and patient organisations, community representatives, policy makers, and regulatory bodies.

Cost-benefit analysis

The trial costs of APs could be justified by the health benefits gained and by future cost savings once APs were used in neonatal intensive care units. But how much would it cost? We can see two possibilities. First, neonatal intensive care costs could increase due to the use of expensive APs and the increased number of survivors with chronic and/or complex health needs. Second, the overall cost of neonatal intensive care could decrease due to shorter hospital stays and fewer iatrogenic conditions. We believe that health economists need to carry out proper cost-benefit analyses to understand the exact cost of this technology in the long run. We believe that, in principle, improving the survival and quality of life of any patient is always justified. However, when resources are limited, it is important to ask whether public funds should be used to fund trials and subsequent treatment.

Conclusion

This Topic Piece has discussed how comprehensive counselling, stakeholder involvement, and cost-benefit analyses need to be included in ethical debates on AP trials. However, further ethical questions and issues may also arise. Our reflections aim to increase awareness of the diverse ethical challenges that these trials could raise.