April 25, 2011

Fetal Surgery: A Promising Treatment for Spina Bifida
By Kim M. Norton
For The Record
Vol. 23 No. 8 P. 24

Prenatal surgery can reverse the damage of myelomeningocele and decrease the need for shunting by more than 50% compared with a postnatal surgery group, according to a recent study.

Hope for mothers carrying a fetus with myelomeningocele has arrived. In a recent study, prenatal surgery for the most common form of spina bifida was found to improve neurological and motor development by more than 20% compared with traditional postnatal repair of the spine.

Researchers found that at 30 months old, the children from the prenatal surgery group were twice as likely to be able to walk than those from the postnatal group. Also, the postnatal surgery children were twice as likely to require a shunt than the prenatal surgery group.

The results of the federally funded Management of Myelomeningocele Study (MOMS) were recently published in The New England Journal of Medicine.

“This is the first time in history that we can offer real hope to parents who receive a prenatal diagnosis of spina bifida,” says N. Scott Adzick, MD, surgeon-in-chief at The Children’s Hospital of Philadelphia (CHOP), director of the hospital’s Center for Fetal Diagnosis and Treatment, and the study’s lead author. “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.”

There’s no question that the MOMS trial proved in-utero surgery reduces the need for shunting for hydrocephalous, says Noel B. Tulipan, MD, director of pediatric neurosurgery at Vanderbilt University Medical Center and coauthor of the study. However, “I am hesitant to say that this surgery is the new standard of care for mothers carrying a patient with spina bifida. There is a lot of risk, specifically prematurity and premature labor. The risks should not be understated.”

Although the outcomes for the prenatal group were significantly better, there was a higher incidence of preterm labor, intraoperative complications, and uterine scar defects at delivery and a higher rate of maternal blood transfusion at delivery than the postnatal group, according to the study. Mothers who underwent prenatal surgery understood that all subsequent pregnancies would be delivered by C–section before the onset of labor as a result of the prenatal surgery.

In response to the MOMS trial and its impact on treatment options, the Spina Bifida Association’s Professional Advisory Council stated, “This study is a major milestone in the treatment of children with myelomeningocele, and used methods that maximize our trust in the findings [being both valid and reliable]. Time is necessary to see how well the positive differences hold up and to see if side effects might occur.”

Spina Bifida
Spina bifida is the most common neural tube defect, a group of serious birth defects of the brain and spinal cord, affecting seven of every 10,000 births or 1,200 children per year. There are four different types of spina bifida: occulta, occult spinal dysraphism, meningocele, and myelomeningocele, the most common and the most severe.

Myelomeningocele occurs during the first month of pregnancy as the nervous system develops from a ball of cells into the neural tube, which is the narrow tube that seals to form the embryo’s brain and spinal cord. As the embryo grows, the top of the tube develops into the brain and the lower portion becomes the spinal cord. The entire process is complete by the 28th day of pregnancy. But if the tube does not completely seal, a hole in the spine forms and a sac protrudes from the spinal cord, exposing its delicate nerves to the amniotic fluid and causing extensive damage to the fetus’ brain and limbs.

The maternal blood test called the quad screen is generally performed anywhere from the 12th to the 18th week of pregnancy. The test detects four specific substances: alpha-fetoprotein, human chorionic gonadotropin, estriol, and inhibin-A.

“Myelomeningocele can be diagnosed with an elevated alpha-fetoprotein and a routine ultrasound between weeks 16 and 20 of the pregnancy,” Adzick says. Once detected, it is imperative that the mother be counseled on her choices. “Prior to this study, moms had two choices: go forward with pregnancy or terminate. Now there is a third option with great promise for typical motor and neurological function,” he says.

The standard practice is to repair the open part of the spine within the first 24 to 48 hours after birth to prevent further nerve damage. If the baby is diagnosed with hydrocephalus, a shunt is placed to drain the cerebral spinal fluid into the abdominal cavity to relieve intracranial pressure buildup, which can cause further brain damage. Babies born with myelomeningocele may suffer from paralysis and rely on a wheelchair, crutches, or braces to ambulate and may also have decreased neurological function and difficulty with their bowels, according to the Spina Bifida Association.

Study Outcomes
To evaluate the efficacy of the surgeries, all children from both MOMS study groups were evaluated at 12 and 30 months of age for physical and neurological functioning. Independent pediatricians and psychologists, unaware of the child’s study group assignment, conducted the evaluations.

The trial found that 40% of the children in the prenatal surgery group received a shunt at 12 months of age compared with 83% in the postnatal group. All fetuses in both groups had evidence of hindbrain herniation at the time of prenatal diagnosis; however, 36% of the children from the prenatal group no longer had evidence of the herniation compared with only 4% in the postnatal group.

At 30 months of age, the independent evaluators found the children in the prenatal group had significantly better scores in motor function assessments. The number of children able to walk independently without crutches or braces was 42% in the prenatal group compared with 21% in the postnatal group.

 Another finding was that there was no increased risk of death for the baby or mother when the prenatal group was compared with the postnatal group. However, the study found there was a greater risk of preterm labor in the prenatal surgery group.

Conducting the Study
Three fetal surgery centers participated in the MOMS trial: CHOP; Vanderbilt University Medical Center; and the University of California, San Francisco (UCSF) Benioff Children’s Hospital. The Biostatistics Center at George Washington University also participated and oversaw data collection and analysis.

“Enrolling participants in a surgical trial is extremely difficult; it is not like a trial for a pill. It is tough to recruit for and the stakes are higher,” explains Adzick. The trial intended to enroll 200 participants over a seven-year time frame, with 100 participants in each group. However, in 2010, the National Institutes of Health ended the trial with only 183 participants because of the clear efficacy of prenatal surgery for myelomeningocele, according to the journal article.

Inclusion criteria for the study were a maternal age of at least 18; the mother had to be carrying only one fetus; myelomeningocele had to be apparent; and the gestational age of the fetus had to be between 19 and 25 weeks. Major exclusion criteria included maternal health risks such as insulin-dependent diabetes, hypertension, a BMI of 35 or more; a history of preterm labor; and a short cervix and preeclampsia.

Mothers eligible for participation were randomized into one of the two groups. Those in the postnatal surgery group had a planned C-section at 37 weeks gestation, and the surgical team repaired the baby’s spine within 24 hours. In the prenatal surgery group, the surgery was performed between 19 and 26 weeks gestation, and the mothers stayed near the operating center for ongoing monitoring. These mothers were to have a planned C-section at 37 weeks gestation or earlier because of the increased risk of preterm labor as described in the study.

Surgery
In 1997, the first human prenatal surgery for myelomeningocele was performed at Vanderbilt University Medical Center. Prior to MOMS, there were more than 200 of these then-experimental surgeries performed at the involved centers.

“There was a hint in the pretrial patients that there might be some efficacy to the procedure as published by us [UCSF Benioff Children’s Hospital] in the Archives of Surgery and The Children’s Hospital of Philadelphia in Journal of OBGYN. However, it was not known if the benefits might be outweighed by the risks of fetal demise and prematurity. This is ultimately why a trial was performed. The trial fetal and infant mortality was less than that seen pretrial. We quoted a 5% to 10% risk of fetal/neonatal demise, and it was less than that,” says Diana Farmer, MD, surgeon-in-chief at UCSF Benioff Children’s Hospital.

“The results of the trial are promising, and there is a clear benefit, but we have a long way to go in perfecting this surgery,” says Tulipan, who hopes the surgery can eventually become less invasive. “Using an endoscope to reduce trauma to the uterus and to reduce preterm labor need to be explored.”

In Adzick’s view, it came down to a case of risk vs. reward. “Knowing that there were clear risks to the mom and the fetus, we had to quantify if the benefits outweighed the risks, and they did,” he says.

Although the surgeries were performed at different times across the two groups, both utilized the same technique of closing the hole in the spine with the fetus’ own tissue. In the prenatal surgery group, a laparotomy incision is made to expose the uterus, and an incision is made in the uterus with a specialized stapling device to repair the myelomeningocele prior to 26 weeks gestation.

“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,” says Leslie N. Sutton, MD, chief of neurosurgery at CHOP and coauthor of MOMS.

The surgery required a four-day hospital stay. Recovering patients were to remain close to the center, with restricted activity, for the duration of their pregnancy for close monitoring.

“Ultrasounds were taken every week and if there was evidence of membrane separation or any other complications, patients were admitted to the hospital and placed on bed rest for the duration of their pregnancy,” Farmer says. ”The extremely close follow-up is what contributed to the extraordinary good outcomes and safety profile for the pregnant women.”

In addition to close monitoring, the mothers were prescribed nifedipine, a calcium channel blocker, for the remainder of the pregnancy to relax the uterus and prevent preterm labor, according to Adzick. The goal for this group was to have a scheduled C-section at 37 weeks gestation.

 “Not all women or their fetuses will be eligible [for intervention]. Some may not want to take the risks of prematurity—12% of patients in the trial had extreme prematurity [less than 30 weeks] and some may not want to risk the maternal risks,” Farmer says. “At least two women have died from fetal procedures that we know about; it is not a simple C-section. Many people don’t realize this.”

Besides general surgical complications, “death, prematurity—and all of its complications—as well as the fetus failing to benefit from the procedure” are possibilities, according to Sutton.

Surgical Expertise
Sutton says the surgery requires “an experienced team of specialists, including a pediatric neurosurgeon with extensive experience with conventional postnatal myelomeningocele closure, a fetal surgeon, OB/GYN with fetal experience, a pediatric cardiologist with fetal experience to perform intraoperative echocardiography, and a team of anesthesiologists with experience caring for both mother and fetus.”

The Professional Advisory Council of the Spina Bifida Association agrees: “The surgery that was performed requires a tremendous amount of training on the part of the surgeons, as well as a large support team to provide care for the unborn baby and mother after surgery. This type of surgery cannot be performed in any community hospital.”

The good news is that the number of qualified facilities appears on the rise. Tulipan says he has been in contact with at least six centers across the country that plan to offer the surgery in the next three to six months.

“There is no reason why [these centers] can’t offer it. They need to realistically counsel the moms about the risks of the surgery and need an experienced maternal-fetal surgeon and a pediatric neurosurgeon,” he says.

— Kim M. Norton is a New Jersey-based freelance writer specializing in healthcare-related topics for various trade and consumer publications.