Fair access challenges in maternal-fetal surgery trials

Abstract

Maternal fetal surgery (MFS) trials have the potential to substantially increase the survival and quality of life of fetuses with life-threatening conditions, but they also entail relevant and yet overlooked fair access challenges. In this topic piece, we will present the fair access concerns in MFS trials/practice and their ethical ramifications as well as some possible ways to address them.

The most obvious challenge is cost. Although the cost of the surgery itself is generally covered, costs are high for participants, including commute or housing near the hospital. This might hinder participations of parents from lower economic status. Strict eligibility criteria aimed at protecting participants further limit accessibility. These issues further affect the scientific validity of the trial. For example, the above-mentioned issues contribute to difficulties in recruitment which already lead to MFS trials delays and cancellations. They also contributed to homogeneous samples that are difficult to generalize. Hence, it is important that researcher first acknowledge the existence of fair access issues beyond those related to the cost of the surgery itself and that these issues affect participants’ right to fair access to the trial benefits as well as the scientific validity of the trial. Second, it is important that researchers actively try to foresee and reduce these issues.

Background

Maternal fetal surgery (MFS) trials have the potential to increase the survival and quality of life of fetuses with life-threatening conditions, such as congenital diaphragmatic hernia (Chen et al., 2023). These trials might also lead to better treatment and outcomes for fetuses with treatable but complex conditions, such as spina bifida (Adzick et al., 2011). However, these trials are also ethically and clinically challenging (Chervenak et al., 2004). Many challenges of MFS trials and their subsequent clinical implementation are related to the overlooked issue of “fair access” (Wilpers et al., 2022). Interestingly, many of these fair access challenges result from choices aimed at reducing participants’ risks and ensuring scientific validity (Stolar et al., 2021; Ville, 2020). Choices that paradoxically lead to the occurrence of some of the same risks they were meant to avoid, showing once again that ensuring both participants’ benefits and scientific rigor can be a difficult balancing act (Cavolo and Pizzolato, 2024). We will present the fair access ¹ challenges in MFS trials/practice and their research ethics ramifications, and some possible ways to address them.

Fair access challenges

A first obvious challenge is cost. Although the cost of MFS itself is generally covered, the costs for parents are still high. Parents might need to commute or find accommodation near the hospital, pay for childcare if they have another young child, or account for loss of income if they cannot work (Crombag et al., 2021). These costs might hinder participation from parents from low socio-economic status (Crombag et al., 2021). Moreover, a systematic review of MFS trials found that 13% of trial protocols excluded parents from low socio-economic status (Wilpers et al., 2022). This exclusion criterion was established to prevent undue influence, but it might also further reduce access to trial benefits to lower-income parents. Hence, in designing a trial it is important to consider not only the direct costs of the trial but also the additional indirect costs that participants must sustain to be able to participate. We do understand that these trials are already extremely expensive and that making public services responsible also for the additional parental costs might render the trial financially unfeasible, delaying research and better care for these vulnerable families. However, we still believe that these costs should be considered to ensure that all options for covering indirect costs at least for participants from low socio-economic status have been exhausted and to better understand the consequences of not covering indirect costs. If covering all participants’ expenses will make the trial financially unfeasible, at the very least attention should be paid to foresee and reduce the risks resulting from it because, as we will see later, participants’ difficulties in accessing the trial might generate other ethical issues. Further, fair access issues due to costs will be even more accentuated in the subsequent MFS implementation in clinical practice. While during a clinical trial at least the costs of the surgery itself is covered, this might not be the case in the post-trial era, when pregnant persons’ access to MFS will likely depend on their insurance status or on the national healthcare system willingness to subsidize an expensive surgery. We argue that while designing the trial researchers and clinicians should already look beyond the trial itself and question who will benefit from the implementation of MFS and how we can ensure fair access not only to the trial itself but also to the future implementation of the surgery. In other terms, we question the use of public resources to fund expensive trials that will only benefit a small percentage of the population, not because the condition is rare, but because patients cannot afford it.

Another leading factor contributing to unfair access is the fact that MFS trials are mostly carried out in few highly specialized hospitals (Lally and Skarsgard, 2017). This ensures that only centers that have the right expertise will offer the experimental surgery and optimizes care for these rare and complex conditions. However, aggregating the relevant MFS expertise in few centers generates logistical issues. For example, the diagnosis might take longer in less specialized centers that do not see as many of these conditions as the more specialized ones. This is relevant because MFS cannot be conducted on an older fetus, meaning that MFS is only offered below a certain threshold, typically set between 26 and 28 weeks of pregnancy depending on the specific conditions, surgery, and guidelines (Sacco et al., 2018). Consequently, delays in the diagnosis might result in parents being refused the surgery as it is too late for MFS (Chescheir and D’Alton, 2005). Further, referring physicians might not be aware of the trials being carried out in other centers resulting in potential participants not being informed of the trial (Chescheir and D’Alton, 2005). Therefore, to ensure fair access and a sizable sample it is essential to foresee these logistical issues and, as much as possible, address them. To do so, it is necessary that articles reporting on trials outcomes also report on the practical difficulties they met, how they address them, and what was successful (or not) and why.

Fair access challenges do not only relate to trial access but also to access to the alternative, specifically abortion. In principle abortion is one of the options available to parents whose fetus is diagnosed with a condition eligible for MFS (Chervenak et al., 2004). Yet, abortion access substantially varies within and across countries (Fiala et al., 2022). Not only different countries have drastically different abortion laws spanning from complete ban to abortion being allowed up to delivery, but also within countries abortion access can substantially differ, either due to different regional/states laws (e.g. USA) or due to cultural and practical constraints that make abortion more accessible in some areas than others (e.g. Italy) (Fiala et al., 2022; Pizzolato et al., 2024). The fact that not all potential participants have access to the same options clearly undermines fair access. Further, abortion access itself might influence parents’ decision-making. In countries where abortion access is severely restricted more parents might opt for the MFS trial than in countries where abortion is easily accessible, which raises questions about undue influence. A crucial element to prevent undue influence is that potential participants can know and access all the options. Restricting access to abortion in the context of MFS trials is not only an interference with pregnant people’s (bodily) autonomy but it might also hinder their autonomy in deciding on whether to participate in the trial, which is the core tenant of research ethics (Pizzolato et al., 2024). Hence, we believe that in designing MFS trials it is important to guarantee that all potential participants have access to the same options, including abortion.

Research ethics issues resulting from (un)fair access

Fair access issues also generate research ethics issues that might affect clinical practice. For example, one of the main challenges of MFS trials is achieving a sizable sample, which lead to trials delays and cancellations and, consequently, to delays in achieving optimal MFS care (Ville, 2020). This is not only a waste of resources; more importantly, this means that the participants have been exposed to the risks of the trial pointlessly as the trial was inconclusive. As previously noted, costs and practical difficulties to participate are among the main reasons why potential participants opted against the trial (Crombag et al., 2021). Therefore, finding ways to subsidize the additional costs of MFS trials might help achieve a sizable sample in a timely fashion. ²

Another issue is that MFS trials have strict selection criteria to protect participants and ensure scientific validity, but they also hinder generalizability (Stolar et al., 2021; Ville, 2020). Common exclusion criteria in MFS trials were (1) being from a low socio-economic status, and (2) not having adequate psychosocial support, including a partner or designated support person (Laskay et al., 2017; Wilpers et al., 2022). The first was established to avoid undue influence, while the latter to minimize the invasiveness of the surgery and the intensiveness of the many follow-ups (Laskay et al., 2017). As a result, a US study found that people of color were consistently underrepresented and that non-trial participants were more likely to be younger, from a minority, and not cohabiting or married (Laskay et al., 2017). A sample that is too homogenous is clearly difficult to generalize from. Similarly, Marquart et al. noted that in the MOMS trial, which investigated the outcomes of MFS for myelomeningocele, maternal obesity, and fetal congenital anomalies were exclusion criteria because they are associated with complications in pregnancy and adult surgery. Therefore the trial was deemed excessively risky for these populations (Marquart et al., 2022). This might make sense within the trial setting, but it also makes it difficult to generalize the trial data to these populations in the implementation phase. Lack of data for specific populations could result either in offering an intervention that is not as safe for this specific population because safety was determined based on data from a different population, or in denying a potentially effective intervention because safety was not investigated for this specific population. This also generates clinical dilemmas. Healthcare providers will face the dilemma deciding whether to offer or accept a request for MFS for populations at risk and for whom we do not have conclusive data as it happened in the post-MOMS trial era (Marquart et al., 2022). Marquart et al. also questioned whether a criterion such as maternal obesity might be discriminatory given the increasing population with obesity (Marquart et al., 2022). To be clear, we are not proposing to overlook participants’ safety, which should absolutely be researchers’ primary concern in and post-trial. However, it is also important to avoid a scenario in which being too protective leads to impossible dilemmas for clinicians or to higher risk for already vulnerable populations in the post-trial phase. An ideal solution would be to conduct a follow-up trial on a broader population. However, this is not always practically or financially feasible. An alternative could be to split the trial in two phases, a first phase with strict inclusion criteria; if the intervention is proven safe and effective researchers could expand the trial to other populations in a second phase.

Conclusions

MFS trials entail important challenges to balancing participants’ benefit and scientific rigor with fair access that should be considered beforehand. If participation is too costly, too logistically challenging, and too restrictive, this will not only hinder fair access, but also scientific validity. Hence, it is important that researchers first acknowledge the existence of fair access issues beyond those related to the cost of the surgery itself and that these issues affect participants’ right to fair access to the trial benefits as well as the scientific validity of the trial. Second, it is important that researchers actively try to foresee and reduce these issues. To do so, publications should emphasize the practical challenges they met and how they address them. These are too often considered details non-worthy of publication but they can be immensely helpful for future researchers.