On 19 September 2023, the US Food and Drug Administration (FDA) Paediatric Advisory Committee met to discuss artificial placenta technology and the ethical considerations for first-in-human-use.
Artificial placentas (also known as 'artificial wombs') are devices designed to facilitate partial gestation outside the body. Preterm birth is the biggest killer of neonates worldwide. Conventional neonatal intensive care has limitations: it can only help premature neonates born with solid lungs (to withstand mechanical ventilation) and treatment has a high incidence of complications (infection, lung damage etc.) I have argued in the Journal of Medical Ethics artificial placentas mark a paradigmatic shift in that they are conceptually distinct from existing conventional methods of care. They move us from interventions designed to help a preterm neonate perform the functions it needs to do to survive ex gestation (eg, breathing air) to attempting to continue the process of gestation so that the premature entity can continue to develop (eg, obtaining oxygen through liquid enables the lungs to continue to mature). Entities supported by the machine have fetal physiology.
There have been consistently promising results testing artificial placentas on animals, particularly lambs, and so talk is turning to clinical trials in humans. They anticipate testing the intervention on those born at 22 weeks gestation – just below what is currently recognised as viability. I have previously argued in Bioethics that this is more justifiable than enrolling premature human entities born at later gestation.
There has been growing interest in the potential for artificial placentas since promising animal studies were published in Nature in 2017. This meeting of the FDA shows that the ethical discussion is moving from the theoretical into the present. In this commentary, I reflect on some of my key takeaways from the meeting.
'Maternal considerations are outside the scope'
The meeting opened with the disclaimer that 'maternal considerations are outside the scope'. This was disappointing. The care pathway for artificial placentas clearly starts before the pregnancy has ended because the entity must be extracted from the pregnant person to be placed in an artificial placenta. In neglecting to centre extraction of the fetus from the pregnant person in debates about first-in-human-use, the pregnant person is rendered invisible. The importance of consent of parents was emphasised but in relation to the use of the device, but consent of the pregnant person was only briefly acknowledged in relation to extracting the fetus from them. This is perhaps unsurprising; the meeting was of the Paediatric Advisory Committee. But the focus could and should have been carefully shifted to reflect the fact that the pregnant person is the first subject in any research. They are subject to an experimental procedure and their consent will be needed for extraction and the use of an artificial placenta.
We need to think about which pregnant people are included in a clinical trial (the decision should be which pregnant people before which fetuses). There are large disparities in maternal morbidity and mortality in the USA. Prematurity disproportionately affects racialised groups and people from lower socio-economic backgrounds. This potentially means that this technology is more likely to be tested on people/premature entities with structural disadvantages and that may be less likely to access the technology if it became widely available. At times, disparities were acknowledged in the meeting, however, they must be more prominent in further discussions about clinical trials.
High-risk device
It was confirmed that artificial placentas are a 'Class III' (high-risk) device. This designation of the device was anticipated and is appropriate. The devices therefore need FDA pre-market approval for general use, but for clinical trials – an investigational device exemption can be afforded to enable an early feasibility study. Because the device is high risk, there must be the prospect of direct benefit for the subject of the technology, any risk must be justified by the anticipated benefit and there must be consent from parent(s). Known risks have to be compared to potential device-related risks. In the meeting it was emphasised that there are many known risks in neonatal intensive care and that there are ways in which the risks of artificial placentas can be anticipated and mitigated.
To determine if artificial placentas could be of benefit to humans, proof of concept animal data can be used. There was much debate about existing animal models. Artificial placenta researchers present were at pains to emphasise that there is no such thing as a perfect animal model, and that testing on primates was impossible (because they are too small).
For an early feasibility study, proof of concept data would need to show that artificial placentas are likely to increase survival or reduce critical morbidities for premature human entities. There was strong emphasis in the meeting that in evaluating risks and benefits of the device we must be attentive to morbidities in neonatal intensive care, which are incidences of complications and long-term health implications, rather than only looking at mortality (survival rates). Dr Alan Flake, speaking on behalf of the team developing an artificial placenta in Philadelphia, indicated that his team believed they had data supporting feasibility and safety for a clinical study in humans.
There was important acknowledgement of some of the unique challenges that will be faced when obtaining informed consent from parent(s). For example, the person who has to consent as a parent is also a research subject (the pregnant person) and is at risk of therapeutic misconception (when individuals mistakenly believe that research is treatment), undue influence, and the emotional impact of being in an exceptional circumstance. There was no discussion, however, about how the importance of obtaining the informed consent of a pregnant person should be a central feature in deciding who appropriate test subjects are.
A unique device
Artificial placentas are an alternative to neonatal intensive care, which is important to emphasise since it is not thought that this device has the capacity to 'grow babies from scratch'. However, we must also not lose sight of the fact that these devices are not just an extension of existing methods, but something fundamentally different. This is something that can easily get lost in ethical discussions and was the case at times in this meeting. Human entities gestating outside of the human body, as the device is designed to facilitate, are human entities we have never seen before: 'gestatelings' – and this has all sorts of implications for how we understand birth and raises new questions about how might treat this entity.
At times, the conceptual uniqueness of the device was emphasised, for example, when developers of the devices were explaining how they worked and how innovative they are. Equally, sometimes in reflecting on how to assess benefit and risk of this device there was acknowledgement of the unknowns. However, this acknowledgement was limited when it came to the ethical implications. Much of the discussion was shoehorning thinking about this technology in the way we think about neonatal intensive care. The implications, however, are much broader, in terms of the uniqueness of the 'gestateling' and especially pregnant people and decision-making about complicated pregnancies.
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