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Spina bifida clinical trial brings unexpected ethical dilemmas
A study, The Management of Myelomeningocele Study (MOMS), that appeared in The New England Journal of Medicine found that if a baby suffering from spina bifida is operated on while still in the uterus, the most common and serious complication, myelomeningocele (MMC), can be greatly reduced.1 According to the study, prenatal repair of MMC might result in better neurologic function than repair delayed until after the baby is born.
"The primary ethical issue is related to the fact that MMC [myelomeningocele] is in general not a lethal disorder. Therefore, fetal surgery might not only put the mother at risk for a non-life threatening fetal condition, but might also replace disability caused by the disease, with death due to extreme prematurity of other causes," says Alan W. Flake, MD, director of the Children's Institute for Surgical Science and the Pediatric Surgery Residency Training Program, director of the Children's Hospital of Philadelphia (CHOP), and professor of surgery and obstetrics/gynecology, University of Pennsylvania School of Medicine, all in Philadelphia.
Mark J. Bliton, PhD, associate professor, Department of Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Center for Biomedical Ethics & Society in Nashville, TN notes that the woman is under general anesthesia, and major surgery, a C-section, in order to provide surgeons access to her fetus. "She does not benefit from this surgery, so a good analogy would be a genetically related live kidney donation for a family member," Bliton says.
Curiously, the ethics board at CHOP was not consulted when planning the surgeries. However, ethicists familiar with the ethical issues surrounding fetal therapy were involved in the early discussions of the trial and the meetings directed toward design of the trial at the National Institutes of Health (NIH) and other locations. "There was a tremendous amount of discussion about those legal issues at the meetings of professional societies for maternal-fetal medicine and fetal surgery, as well as at the NIH," says Bliton. There were also trained individuals at each of the three trial sites that interviewed the patients preoperatively and raised any social or ethical concerns on a case-by-case basis. The trial was conducted at three hospitals: Vanderbuilt University in Nashville, TN, Children's Hospital of Philadelphia (PA), and University of California, San Francisco. "The issue about only offering the surgery at selected medical centers is complex," notes Bliton. "The main point to convey is that the study was research on surgery. Surgical research of this kind requires a team of specialists that can work together, and have worked well together, in order to manage the inevitable complexities of such an ambitious study," says Bliton.
Interestingly, the researchers assumed that only a small number of women would consent to be involved in the trial if the surgery was available elsewhere, so they persuaded other hospitals that were not participating in the trial to stop performing the procedure. According to Bliton, given the time, effort and expense that the study would require, the leaders wanted to achieve a clear answer. "Limiting the number of medical centers who could enroll subjects and perform the interventions and collect the data was a reasonable way to reduce some obvious complexity," says Bliton.
Flake says, "The argument was based on true equipoise for a randomized trial existing in the medical community and the ethical obligation to prove efficacy of a surgical procedure prior to dissemination of the procedure as standard or accepted care." Flake continues to say, "there are many examples of harm to patients from early widespread application of unproven surgical procedures such as intestinal bypass for morbid obesity."
The randomization of the trial was a significant issue for accrual of patients for the trial, according to Flake. "Patients were not referred to a surgical center unless they expressed willingness for randomization during the initial evaluation and counseling at the Data and Study Coordinating Center [DSMC]," he says. Counseling was based on principles of equipoise, and attempts were made to objectively dispel biases within the patients regarding the efficacy of prenatal surgery, Flake says. "Nevertheless, accrual was much slower than anticipated, undoubtedly in part due to resistance," he says.
Surprisingly for some, there were few ethical objections from the various oversight bodies for the trial, according to Flake. "Those oversight bodies included the Maternal Fetal Medicine Network Advisory Board, the DSMC, the Steering Committee, the hospital IRBs, and our own Fetal Treatment Oversight Committee at CHOP. This suggested that there was agreement among these bodies that the disability related to MMC warranted the risks of prenatal treatment, that there was true equipoise with respect to efficacy justifying randomization, and that it was important to determine efficacy unequivocally before the procedure became widely disseminated," he says.
The trial was a success, says N. Scott Adzick, MD, pediatric surgeon, The Division of Pediatric General and Thoracic Surgery, The Children's Hospital of Philadelphia, and lead author of the study. "The current study reports data on 158 patients who were followed at least one year after surgery," Adzick explains. "At one year of age, 40% of the children in the prenatal surgery group had received a shunt, compared to 83% of the children in the postnatal group."
There were additional positive outcomes. "During pregnancy, all the fetuses in the trial had hindbrain herniation. However, at age one year, 36% of the infants in the prenatal surgery group no longer had any evidence of hindbrain herniation, compared to only 4% in the postnatal surgery group," says Adzick.
For more information about spina bifida and the clinical trial, visit: http://www.spinabifidaassociation.org, then on the right side of the page, click on "MOMs Study Results."
To view a video about fetal surgery for myelomeningocele, go to http://www.chop.edu/video/fetal-surgery/spina-bifida-video.html.