Who is the patient?

There are few topics so controversial as the debate over the personhood status of the fetus. In Canadian law, a fetus becomes a person with legal rights only after birth.^{Footnote 13} Certain religious faiths alternatively argue that a fetus/embryo is a person from conception, while others argue that the fetus becomes a person once it reaches the age of viability—when it can survive outside the mother with technological support.^{Footnote 14} The age of viability is an evolving cutoff that depends on the capabilities of neonatal support services available, but generally occurs at around 24 weeks gestation in most developed countries. Still others argue that the fetus becomes a person when a particular organ system begins to function, such as when the fetal heart starts to beat or when the fetal brain produces its first electrical signals.^{Footnote 15}

Regardless of the personhood status of the fetus, there is no doubt that the pregnant woman is a person. Fetal surgery may be better termed maternal-fetal surgery, as the pregnant woman must also receive an operation in order to access the fetus. Depending on which definition of fetal personhood is used, it could be that the mother is the patient receiving medical treatment, or the mother and the fetus are both patients, or that a unique entity termed ‘the pregnant woman’ is the patient.^{Footnote 16} Some have argued that the fetus alone is the patient, while the mother is a healthy altruistic volunteer, similar to a healthy parent volunteering to surgically donate a part of their liver or a kidney to their sick child.^{Footnote 17}

Some degree of self imposed and/or societally imposed parental obligation is likely present from a mother to her child from the moment a woman learns she is pregnant until the end of her or her child’s life, unless the pregnancy is terminated or the child is adopted. A certain degree of this obligation is based around principles of nonmaleficence—the ethical duty of the mother to do nothing that is likely to harm her child during pregnancy and afterwards. An example of nonmaleficent behavior is the abstention from illegal drugs or heavy alcohol consumption. Beneficence drives mothers as well, to do what they can to optimize their child’s health outcomes for the child’s best interests, and is very likely the motivation behind a mother seeking fetal MMC closure. The somewhat less-recognized fact remains, however, that it is generally also in the pregnant woman’s best interest, not just her future child’s, to optimize her fetus’ health outcomes. A child that is healthier requires fewer resources and less work, and places a smaller financial and social-emotional burden on the mother and family.^{Footnote 18}

Given the significant burden of care placed on caregivers of children with MMCs,^{Footnote 19} a pregnant woman may be motivated through a combination of self interest, as well as altruism toward her future child, in minimizing her parenting workload by doing what she can to optimize functional and health outcomes of her child, even if that means taking on an upfront high personal risk.

Ultimately, given that pregnant women and their fetuses are irrevocably intertwined until miscarriage, abortion or birth, and since both are receiving surgery and are affected by the possible complications and benefits of maternal-fetal surgery, both should be considered patients for the purposes of clinical care, research study design, equipoise and informed consent.

Informed Consent

Informed consent is an essential component of ethical health care delivery as well as ethically conducted research.^{Footnote 20} The pregnant woman is clearly able to provide informed consent for herself, but it is less clear whether she is the only person required to provide informed consent for her fetus. Although the father typically is also expected to have a moral interest in the health of the fetus, the pregnant woman’s wishes should supersede those of the father when consenting to participate in fetal research and/or surgery. US federal regulations in the past have been distinctive for requiring the father’s consent as well as the mother’s in order for a pregnant woman to undergo fetal research and/or maternal-fetal surgery.^{Footnote 21} Despite this, in order to preserve her right to bodily integrity and autonomy, the pregnant woman should have the ultimate right to decide what is done to her fetus through her own body, regardless of the wishes of the father. The American College of Obstetricians and Gynecologists Committee on Ethics and the American Academy of Pediatrics Committee on Bioethics have provided their support for this position in a joint committee opinion paper.^{Footnote 22} Although historically, there have been cases where the right to bodily integrity of a pregnant woman has been revoked in the name of nonmaleficence or beneficence toward the fetus,^{Footnote 23, Footnote 24} in the context of fetal surgery, consent of the pregnant mother must be obtained.

Given the potential pressures on pregnant women to sacrifice or put themselves at risk for their children, informed consent in maternal-fetal surgery interventions should always use noncoercive language. When participating in a research trial of a novel procedure, the interventions should not be called treatment or therapy, but rather experimental interventions, emphasizing the fact that the intervention may not have efficacy and indeed, may cause harm to both the mother and fetus. Even the terms mother, father and baby carry with them a strong emotional context and some have suggested that they not be used during the consent process for fetal surgery.^{Footnote 25}

Equipoise in maternal-fetal surgery research

Equipoise is achieved when two clinical management options are thought to be largely equivalent in terms of perceived benefits and risks to patients.^{Footnote 26} Equipoise is considered to be an ethical prerequisite to the design and implementation of randomized controlled trials. How is equipoise achieved when there are two patients involved, as in comparing a maternal-fetal prenatal surgical procedure with postnatal surgery as in the MOMS trial? Strictly speaking, the mother will receive no medical benefit from the fetal intervention and is exposed only to potential harm. There are physical risks to the mother in a prenatal intervention that are not present when the intervention is undertaken postnatally, so how can there be equipoise for her as a patient? In the MOMs trial, it would seem that clinical equipoise was achieved by weighing the potential risks and benefits to the fetus in order to justify offering the trial and its associated risks to pregnant women. A pregnant woman may then determine whether the possible benefits for her fetus are worth the risks to themselves, as well as to their fetus.

In fetal surgery trials, Lyerly has suggested that the pregnant woman is usually treated more like a volunteer/innocent bystander than a research subject,^{Footnote 27} and argues that considerations regarding the presence of clinical equipoise are preferentially centered on the fetus as the mother herself will not medically benefit. Thus, the mother is allowed to expose herself to risk provided there is equipoise for the fetus. Although this can be an autonomous decision on the part of the mother, during the consent process it must be ensured that there are no coercive or paternalistic undertones in the discussion. The risk that both potential patients/research subjects are exposed to during a fetal intervention adds a unique nuance to the concept of equipoise and informed consent.

As an example, until the safety of prenatal surgery can be improved for both pregnant women and fetuses, there is wide-spread consensus in the medical community that maternal-fetal surgery should not be undertaken for cosmetic reasons,^{Footnote 28} such as repair of fetal cleft lip to reduce postnatal scarring even if some women would desire taking on the risk.

Chervenak has proposed the following criteria as necessary for obtaining normative equipoise in maternal-fetal surgery research:

1. 1. The initial case series indicates that the proposed fetal intervention is reliably expected to be life saving or to prevent serious and irreversible disease, injury or disability.

2. 2. Among possible alternative designs, the intervention continues to involve the least risk for morbidity and mortality to the fetus.

3. 3. The case series indicates that the mortality risk to the pregnant woman is reliably expected to be low and the risk for disease, injury, or disability to the pregnant woman, including for future pregnancies, is reliably expected to be low or manageable.^{Footnote 29}

Though these criteria involve a degree of subjectivity in determining what is an acceptably low risk to the pregnant woman, they provide an acceptable balance between the risks and benefits to both the fetus and pregnant woman with appropriate deference to the woman’s right to autonomous decision-making.

Surgical Innovation vs. Surgical Research

The Society of University Surgeons defines innovation as “a new or modified surgical procedure that differs from currently accepted local practice, the outcomes of which have not been described, and which may entail risk to the patient.”^{Footnote 30} Innovation can involve modifying a device or procedure, or adding new equipment such as laparoscopy, or changing the system of care delivery.^{Footnote 31} Innovation in surgery is regulated differently than research, and typically entails significantly reduced oversight with many surgical innovations not requiring an ethics review board approval before being explored and implemented.^{Footnote 32}

The line between innovation and research can be blurry. As an example, in an effort to reduce the complication risk of open prenatal myelomeningocele closure, minimally invasive endoscopic and fetoscopic surgical techniques have been developed and performed on pregnant women following the MOMS trial. The results to date have been less than satisfactory, with increased risk of preterm labor, increased length of surgery, and increased CSF leak rates.^{Footnote 33,Footnote 34}

Given the risks involved to healthy pregnant women, ongoing innovations in prenatal surgery should be considered as research, with rigorous ethical oversight and adequate monitoring, in order to assess and evaluate outcomes on an ongoing basis. The IDEAL recommendations for evaluating surgical innovation, published in the Lancet in 2009,^{Footnote 35} provides an ethical framework on how innovations in maternal-fetal surgery might be evaluated and monitored. Among other recommendations, they call for public registration of protocols and cases (anonymously if necessary in cases with adverse outcomes), prospective databases to monitor early and late outcomes, and the use of randomized trials whenever possible.

Ethics of performing prenatal surgery for nonlethal, disabling conditions.

There is some debate over whether it is ethical to offer risky prenatal surgery to prevent a nonlethal but disabling condition.^{Footnote 36} We may be sending a message of intolerance to people with disabilities when we offer surgery that entails significant risk to both the pregnant women and the fetus in an effort to reduce the degree of disability the future child may live with. This is particularly relevant in MMC, where children with postnatally closed MMCs have been shown to have a similar psychosocial quality of life compared with unaffected children.^{Footnote 37} Though they have a reduced motor quality of life, it is the psychosocial quality of life that seems to matter most to life satisfaction.^{Footnote 38} Factors that are associated with a lower health related quality of life include shunted hydrocephalus and a symptomatic Chiari II malformation. Both of these are risks that are reduced, but not eliminated by prenatal surgery for MMC. Nonetheless, physicians must remember and counsel that prenatal surgery is not a cure for MMC related disability.

Ethical issues related to the MOMS trial and generalizability

The MOMs trial was plagued by low enrollment rates, taking nearly 8 years to enroll 183 pregnant women before the trial was stopped. Assuming that the cases were spread out evenly over time between the three involved centers, each center would have completed approximately seven cases per year based on referrals from across North America. Since publication of the positive trial results, there has been a proliferation of centers in the United States that now perform fetal closure for MMC. This raises two concerns: first, will the increased number of centers offering the procedure result in dilution in the number of cases performed at each individual center, resulting in diminished expertise and results that fail to replicate the improved neurologic outcome demonstrated in the MOMs cohort and second, will the strict inclusion and exclusion criteria within the trial be loosened, resulting in the procedure being done for a patient population in which the results are not necessarily generalizable?

One center offering fetal MMC closure has already loosened inclusion criteria to allow for the procedure to be done in women with a body mass index of up to 40.^{Footnote 39} These women would not have been eligible for the therapy during the MOMs trial because of concerns of increased risk in this patient population. Local IRB approval for this deviation from MOMs criteria has been received, but it remains to be seen whether this results in acceptable outcomes.

When new fetal MMC closure centers deviate from the strict inclusion and exclusion criteria used in the MOMs trial, it is unclear whether the results of the trial can be generalized to prospective patients during the informed consent process. The risks of preterm labor and uterine dehiscence may be unacceptably higher, or the likelihood of an improved outcome in the fetus may be unacceptably lower, with expanded indications and less centralized centers of excellence. This has been shown to be the case for prenatal surgery on fetuses with MMC who have enlarged ventricles prenatally, as they do not have the significant reduction in the need for CSF shunting seen in the MOMS trial.^{Footnote 40} Since the need for CSF shunting was one of the primary outcome measures in the MOMS trial, this means that the potential benefit of surgery is significantly reduced for this patient population. Clearly, given the risks to the healthy volunteer (the pregnant woman), providing the maternal-fetal surgery, outside of the MOMS trial’s inclusion and exclusion criteria, should be treated as research. It is essential to provide prospective patients with adequate disclosure of the experimental nature of the surgery in situations that are outside of the trial’s inclusion/exclusion criteria and protocol, in order to obtain true informed consent. This also underscores the need for rigorous monitoring and follow up of results, to ensure centers are able to, at least, duplicate the results seen in the MOMs trial.

Furthermore, there is evidence to suggest that outcomes for any intervention may be better in the context of a research trial; the so called Trial Effect^{Footnote 41} where the benefits seen in a trial are not reproduced when an intervention is accepted into wide spread use. As another example of deviation from MOMS trial protocols, some new fetal surgery centers keep pregnant patients in close proximity to the center for two or three weeks after prenatal surgery for observation, but they are then allowed to return home to deliver by cesarean section away from the fetal surgery center, unlike in the MOMS trial where the women were obligated to remain at the trial center to deliver.^{Footnote 42} Hospitals outside of the trial centers may not provide high-risk obstetrical services and neonatal intensive care unit (NICU) services with the clinical experience present in the trial centers; both essential components of maintaining an acceptably low risk profile for the maternal-fetal surgery. Given the modest improvement in some outcomes seen in the MOMS trial, it is uncertain whether these results can be maintained outside of the research study protocol and centers, especially with expanding inclusion criteria, deviations from the trial protocol, and potential dilution of clinical expertise. Ongoing monitoring and evaluation is essential, and centers should take care to conform to the MOMS study protocol until outcomes can be proven to be equivalent to those in the trial.

The principle of justice is also relevant in the context of prenatal surgery for MMC. Generally, it is important for evidence-based medical care to be readily available to all people who need it. The opening of new fetal care centers may be an important means of providing improved access to maternal-fetal surgery for many pregnant women who otherwise could not afford to travel to one of the three MOMS trial centers, especially if the new centers can provide care to at least an equivalent standard. This is particularly relevant for women pregnant with fetuses with MMC, as these women are less likely to have access to adequate prenatal care, and are more likely to have a lower socioeconomic status than women pregnant with fetuses without a MMC diagnosis.^{Footnote 43,Footnote 44} They may also not be as easily able to afford the long-term costs associated with the increased risk that will accompany all future pregnancies which will require mandatory cesarean sections because of the hysterotomy associated with open fetal repair. As a result of this, issues of justice and uniform access to care need to be taken into consideration when determining standards for opening new centers. Care should also be taken in minimizing the risk to patients from the learning curve inherent in setting up a new program. We strongly recommended mandatory mentoring of new centers by those with more experience, as well as rigorous quality assurance initiatives to ensure results which are at least equal to those seen in the MOMS trial.

Economic implications of fetal MMC closure

There may be a politico-economic drive for medical centers to offer fetal surgery to elevate their reputation for being a cutting edge program and to attract prospective patients, especially in a for profit health care environment. Given the small numbers of available prospective patients, and the increasing number of centers, this may result in significant competition for patients, and with this, the potential for exaggerated claims of competency, and indeed, exaggerated claims of benefit from the procedure. There is an essential need to enforce recognized standards for centers to offer fetal surgery services in general and MMC prenatal surgery services in particular. At a minimum, the center must have a well-trained multidisciplinary team including high-risk obstetrics and a tertiary care neonatal intensive care unit, as well as a multidisciplinary MMC care team that manages children with this disorder after birth.

The fetal MMC Maternal-Fetal Medicine Management Task Force has developed optimal practice criteria for new fetal care centers, and for centers performing prenatal MMC closure surgery^{Footnote 45} which include (1) adequate volume of cases to maintain competency, (2) the initial 5 cases must be undertaken under the training of a competent surgeon from an established center, (3) precise adherence to the protocol followed in the MOMs trial, (4) any modifications to the protocol should be studied in the context of a cooperative trial, and (5) a national registry monitoring outcome should be established.

Although there is no mechanism for mandatory adherence, these criteria form a reasonable safety net, balancing the push for innovation and desire for increased access to this prenatal surgery, with the need to minimize the risks to pregnant women and their affected fetuses. Ongoing monitoring and research is currently being conducted in an unregulated fashion by some centers^{Footnote 46} and by NAFTNet;^{Footnote 47} this should be expanded to be a more comprehensive regulation and monitoring in line with the above recommendations.