Winter 2003 Vol. 10, Issue 1
By Frank A. Chervenak, MD
Department of Obstetrics and Gynecology
New York Presbyterian Hospital
Weill Medical College of Cornell University, New York
and
Laurence B. McCullough, PhD
Center for Medical Ethics and Health Policy
Baylor College of Medicine, Houston, Texas
Fetal surgery involves the repair of a fetal anomaly either through a hysterotomy or endoscopy. Such procedures carry risks of harm and potential benefit to both the pregnant woman and the fetal patient. For the pregnant woman, these risks include morbidity and, rarely, mortality associated with major surgery and anesthesia, the psychosocial risks of losing a pregnancy or living with the burden of iatrogenic injury to a future child, and risks to future pregnancies from uterine rupture. Risks to the fetal patient include iatrogenic prematurity, injury and, rarely, death. The potential benefits of fetal surgery are reduction of mortality and improvement in functional status for the fetal patient with consequent psychosocial benefit to the pregnant woman and her family. Although fetal surgery has been attempted to correct a variety of fetal anomalies, including meningomyelocele, diaphragmatic hernia, cystic adenomatoid malformation of the lung, and sacrococcygeal teratoma, at this time fetal surgery is not considered standard treatment. Increasingly, investigation in that area is being conducted under research protocols. 1,2
A randomized, controlled clinical trial of surgical repair of spina bifida is being sponsored by the National Institutes of Health. These and other trials that are sure to follow underscore the need for an ethical framework for experimental fetal surgery.
The purpose of this article is to outline such a framework, which the authors have presented in greater detail elsewhere. 3 We will address ethical criteria for the initiation and assessment of clinical trials, the informed consent process, selection criteria based on abortion preference, and cooperation of physicians in the clinical investigation.
Ethical criteria for initiation and assessment of clinical trials
Innovation in fetal surgery usually begins with a single case and then case series, preceded by work on appropriate animal models. These steps are necessary to determine the feasibility, safety and efficacy of innovations.
We have defended three criteria that must be satisfied in order to conduct such preliminary investigations in an ethically responsible fashion that takes into account beneficence-based obligations to both the fetal patient and the pregnant woman. 3 The previable fetus is a patient in these cases because the woman has made a decision to continue her pregnancy 4 to have the opportunity to gain the potential benefits of the innovation. She remains free to withdraw that status before viability. 4 The viable fetus is a patient in these cases in virtue of viability. 4
Our criteria include: 1) the proposed fetal intervention is reliably expected (on the basis of previous animal studies) either to be life-saving or to prevent serious and irreversible disease, injury, or handicap for the fetus; 2) among possible alternative designs, the intervention is designed in such a way as to involve the least risk of mortality and morbidity to the fetal patient; and 3) on the basis of animal studies and analysis of theoretical risks, both for the current and future pregnancies, the mortality risk to the pregnant woman is reliably expected to be low and the risk of disease, injury or handicap to the pregnant woman is reliably expected to be low or manageable.
The third criterion is important because fetal surgery is also maternal surgery. Investigators have an independent beneficence-based obligation to protect human subjects from unreasonably risky research and should use beneficence-based, risk-benefit analyses. The phrase "maternal-fetal surgery" is useful when it reminds investigators of the need for such comprehensive analysis. If it is used to subordinate fetal interests to the pregnant woman's interest and rights, it undermines the concept of the fetus as a patient in favor of the concept that the fetus is merely a part of the pregnant woman.
Preliminary innovation should cease and randomized clinical trials begin when there is clinical equipoise. Clinical equipoise means that there is "a remaining disagreement in the expert clinical community, despite the available evidence, about the merits of the intervention to be tested." 5 Brody notes that one challenge here is identifying how much disagreement can remain for there still to be equipoise. 5 Lilford has suggested that when two-thirds of the expert community, measured reliably, no longer disagrees, equipoise is not satisfied. 6 When the experimental intervention is more harmful than non-intervention, equipoise cannot be achieved. We propose that the satisfaction of the previous three criteria with slight modifications should count as equipoise in the expert community. 3
The above three criteria can be used in a straightforward manner to define stopping rules for such clinical trials. When the data support a rigorous clinical judgment that the first or third criterion is not satisfied, the trial should be stopped. When the clinical trial is completed, its outcome can be assessed to determine whether the innovative fetal surgery should be regarded as standard of care. The trial results should meet the three criteria in order to establish the innovation as standard of care. 3
Brody has underscored the value of data safety and monitoring boards to prevent investigator bias and to protect subjects. 5 Such boards should be used in fetal research, especially to ensure adherence of the above-mentioned ethical criteria as a basis for monitoring such research.
The informed consent process
The informed consent process should always be led by a physician competent to explain any intervention, its alternatives and their benefits and risks. This requirement means that the physicianinvestigator should lead the consent process.
Like all consent processes for human subject research, counseling the pregnant woman about initial innovation or clinical trials should be rigorously non-directive. Investigators should emphasize the distinction between research and treatment to prevent the therapeutic misconception. This is the belief of patients that research, like treatment, will be beneficial and not involve disadvantages that do not occur in the therapeutic setting. 7 Words such as "mother," "father," and "baby" should not be used, because these suggest moral relationships and moral status that do not apply. 8 Words such as "pregnant woman," "husband," "fetus," and "fetal patient" should be used instead. The pregnant woman should be clearly informed that she is under no obligation to the fetal patient to enroll it in a clinical research project.
To protect a woman from potential coercion, her husband or partner and other family members should be reminded that while they may have strong views for or against her participation, their role should be to support and respect the woman's decisionmaking process and its outcome.
Selection criteria based on abortion preference
There should be no exclusion criteria in research on fetal surgery based on willingness to countenance elective abortion. Study designs would therefore have to include elective abortion and birth of adversely affected infants as endpoints. 3
Cooperation of practicing physicians with clinical investigation
It is widely accepted that practicing physicians are justified in informing their patients about relevant clinical investigations, and, with the patient's consent, referring them to the investigators. In our view, there is also an obligation to do so. The justification for this obligation cannot appeal to the benefit to the pregnant woman or fetal patient, because by definition, the existence of clinical investigation does not establish clinical benefit. However, there is an obligation to future patients, pregnant and fetal alike, to establish whether fetal intervention improves the current standard of care or not. All physicians should take seriously their obligation to future patients to assure that innovation has the opportunity to be validated scientifically and ethically, rather than introduced in an unmanaged fashion or simply ignored. 3
Footnotes
1 Bruner JP, Tulipan N, Paschall RL, et al. Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999;282:1819-25.
2 Sutton LN, Adzick NS, Bilanivic LT, et al. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999;282:1826-31.
3 Chervenak FA, McCullough LB. A comprehensive ethical framework for fetal research and its application to fetal surgery for spina bifida. Am J Obstet Gynecol 2002;187:10-4.
4 McCullough LB, Chervenak FA. Ethics in Obstetrics and Gynecology. New York: Oxford University Press, 1994.
5 Brody BA. The Ethics of Biomedical Research: An International Perspective. New York: Oxford University Press, 1998.
6 Lilford RJ. The substantive ethics of clinical trials. Clin Obstet Gynecol 1992;35:837-45.
7 Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep 1987;17(2):20-4.
8 DeCrespigny L, Chervenak F, McCullough L. Mothers and babies, pregnant women and fetuses. Br J Obstet Gynaecol 1999;106:1235-7.
in collaboration with
Dartmouth-Hitchcock Medical Center
The opinions expressed in the journal, Lahey Clinic Medical Ethics,
belong to the individual contributors and do not represent the institutional position
of Lahey Clinic on any subject matters discussed.
