Performing delicate surgery in the womb, months before birth, can substantially improve outcomes for children with a common, disabling birth defect of the spine. Experts at The Children's Hospital of Philadelphia (CHOP) co-led a new landmark study showing that fetal surgery for spina bifida greatly reduces the need to divert fluid from the brain, improves mobility and improves the chances that a child will be able to walk independently.
Spina bifida is the most common birth defect of the central nervous system, affecting about 1,500 babies born each year in the United States.
"This is the first time in history that we can offer real hope to parents who receive a prenatal diagnosis of spina bifida," said N. Scott Adzick, M.D., Surgeon-in-Chief at The Children's Hospital of Philadelphia, director of Children's Hospital's Center for Fetal Diagnosis and Treatment, and lead author of a federally sponsored study reporting results of a clinical trial of fetal surgery for myelomeningocele, the most severe form of spina bifida. Adzick, who led a team at CHOP that pioneered fetal surgeries for this condition and set the stage for this clinical trial, added, "This is not a cure, but this trial demonstrates scientifically that we can now offer fetal surgery as a standard of care for spina bifida."
Myelomeningocele is devastating, occurring when part of the spinal column does not close around the spinal cord, failing to protect it during stages of fetal development. Long-term survivors of the condition frequently suffer lifelong disabilities, including paralysis, bladder and bowel problems, hydrocephalus (excessive fluid pressure in the brain), and cognitive impairments.
Fetal surgery researchers have now reported long-awaited results from an unprecedented clinical trial that compared outcomes of prenatal, or fetal, surgery versus postnatal surgery, the conventional surgery for this disabling neurological condition. The study appears today in an Online First article in the New England Journal of Medicine.
Two and a half years after fetal surgery, children with spina bifida were better able to walk, when compared to children who received surgery shortly after birth. Patients who received fetal surgery also scored better on tests of motor function. Within a year after fetal surgery, they were less likely to need a shunt, a surgically implanted tube that drains fluid from the brain.
How the Fetal Surgery Trial was Conducted
Three fetal surgery centers participated in the Management of Myelomeningocele Study (MOMS) trial—at The Children's Hospital of Philadelphia, Vanderbilt University, and the University of California San Francisco. The biostatistics center at George Washington University (GWU) served as the coordinating center and oversaw data collection and analysis, while the Eunice Kennedy Shriver National Institute of Child Health and Human Development sponsored the trial.
The MOMS study was a prospective, randomized clinical trial. One sign of its prominence is that all U.S. fetal surgery centers not participating in the trial agreed to perform no fetal surgery for spina bifida during the 7-year duration of the trial. The trial goal was to enroll 200 patients, but the NIH ended the trial in December 2010, after 183 surgeries had occurred, based on clear evidence of efficacy for the prenatal procedure.
Throughout the trial, women whose fetuses had been diagnosed with spina bifida contacted the trial's coordinating center at GWU if they chose to volunteer for the study. That center randomly assigned half of the eligible women to receive prenatal surgery, the other half to receive postnatal surgery.
Postnatal surgery entailed delivery by planned cesarean section at 37 weeks gestation, after which the surgical team repaired the opening in the newborn's spine, usually within 24 hours after birth. In prenatal surgery, done between 19 and 26 weeks' gestation, the surgical team made incisions in the mother and her uterus, then repaired the spina bifida lesion while the fetus was in the womb. Mothers in this group stayed near the center for ongoing monitoring, then underwent delivery by planned cesarean section at 37 weeks, or earlier, because many of the babies in the prenatal surgery group arrived prematurely.
The complex requirements of this fetal surgery require a highly sophisticated multidisciplinary team. The CHOP program includes specialists in fetal surgery, neurosurgery, obstetrics, maternal-fetal medicine, cardiology, anesthesiology and critical care, neonatology, and nursing.
In both study groups, surgeons used the same technique to cover the myelomeningocele with multiple layers of the fetus's own tissue. "This lesion leaves the spinal cord exposed, so it's essential to protect this tissue from neurological injury," said study co-author Leslie N. Sutton, M.D., Chief of Neurosurgery at The Children's Hospital of Philadelphia. Previous research had established that in myelomeningocele, amniotic fluid and other features of the intrauterine environment damage the exposed spinal cord.
Building on Decades of Research
Starting two decades ago, pioneering animal studies by Adzick and collaborators such as Martin Meuli, M.D. (now Surgeon-in-Chief at Zurich Children's Hospital in Switzerland) showed that the timing of the myelomeningocele repair was important, a finding borne out by clinical experience in fetal surgery done before the MOMS trial. "The damage to the spinal cord and nerves is progressive during pregnancy, so there's a rationale for performing the repair by the 26th week of gestation, rather than after birth," said Sutton.
The abnormal spinal development underlying myelomeningocele triggers a cascade of disabling consequences, including weakness or paralysis below the level of the defect on the spinal column. In addition, leakage of cerebrospinal fluid through the open spina bifida defect results in herniation of the brainstem down into the spinal canal in the neck—a condition called hindbrain herniation. Hindbrain herniation obstructs the flow of cerebrospinal fluid within the brain, leading to hydrocephalus, a life-threatening buildup of fluid that can injure the developing brain. Surgeons must implant a shunt, a hollow tube that drains fluid from the brain into the child's abdominal cavity. However, shunts may become infected or blocked, often requiring a series of replacements over a patient's lifetime.
What the Study Found
The current study reports data on 158 patients who were followed at least one year after surgery. Clinicians who were independent of the surgical teams and blinded (not informed which of the two surgeries a given child received) evaluated the children from the study at one year of age and again at age 30 months.
--At one year of age, 40 percent of the children in the prenatal surgery group had received a shunt, compared to 83 percent of the children in the postnatal group. During pregnancy, all the fetuses in the trial had hindbrain herniation. However, at age 12 months, one-third (36 percent) of the infants in the prenatal surgery group no longer had any evidence of hindbrain herniation, compared to only 4 percent in the postnatal surgery group.
--At age 30 months, children in the prenatal group had significantly better scores in measurements of motor function. While the ability to walk depends on the level of the spina bifida lesion, the study found a twofold increase in the proportion of children able to walk without crutches or other assistive devices—42 percent in the prenatal group compared to 21 percent in the postnatal group.
--As with any surgery, fetal surgery carries risks. Fetal surgery in this study raised the risk of premature birth and scarring in the mother's uterus. "Additionally, the surgical site in the uterus used for fetal surgery requires that the mother will have to undergo a cesarean section for any subsequent births," said study co-author Mark P. Johnson, M.D., obstetrics director at the Center for Fetal Diagnosis and Treatment (CFDT).
"The mothers, children and families who participated in this MOMS trial, and who are continuing to be available for follow-up studies, have made an important contribution to our knowledge and treatment of spina bifida," said Lori J. Howell, R.N., M.S., Executive Director of the CFDT, and a study co-author. "Because of their involvement, we are better able to accurately counsel other families about what it will mean to have a child with spina bifida—and to offer a rigorously tested, innovative prenatal surgical treatment."
Next Steps in Fetal Surgery
Although the trial results mark a milestone in spina bifida treatment, not every woman carrying a fetus with spina bifida may be a suitable candidate for fetal surgery. For example, severely obese women were not included in the current study because they have a higher risk of surgical complications. Adzick noted that further research will continue to refine surgical techniques and improve methods to reduce the risks to mothers and fetuses.
In the meantime, concluded Adzick, "Both the experimental outcomes of animal studies and the results of the MOMS trial suggest that prenatal surgery for myelomeningocele stops the exposure of the developing spinal cord to amniotic fluid and thereby averts further neurological damage in utero. In addition, by stopping the leak of cerebrospinal fluid from the myelomeningocele defect, prenatal surgery reverses hindbrain herniation in utero. We believe this in turn mitigates the development of hydrocephalus and the need for shunting after birth."
Adzick added that this demonstrated success for fetal surgery may broaden its application to other birth defects, many of which are rarer but more uniformly lethal than spina bifida. Children's Hospital's comprehensive center already offers fetal surgery for selected life-threatening fetal conditions.
The Children's Hospital of Philadelphia began performing fetal surgery for spina bifida in 1998, three years after Adzick launched the Center for Fetal Diagnosis and Treatment. The Center's reports of neurological improvements in spina bifida, based on 58 fetal surgeries through 2003, helped lay the groundwork for the MOMS trial. For Adzick, who has been working to advance fetal surgery since performing preclinical studies in the early 1980s, "It's very gratifying to take this idea forward over 30 years, starting with a concept and now offering hope—to families, mothers and the children themselves."
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