Editor's Note: Open spina bifida, or myelomeningocele, is a congenital neural tube defect caused by primary failure of neural tube closure during the embryologic period. Myelomeningocele, the most common and devastating form of spina bifida,[1] is characterized by protrusion of the meninges and spinal cord through open vertebral arches. The consequences of myelomeningocele depend on the proximal anatomical extent of the defect and include hindbrain herniation, hydrocephalus, motor and cognitive impairments, orthopedic abnormalities, bladder and bowel incontinence, social and emotional challenges, and lifelong quality-of-life issues.[2]
When an infant is diagnosed prenatally with myelomeningocele, some women choose to terminate the pregnancy. Those who do not usually deliver by cesarean section to avoid birth trauma to the exposed spinal cord.[3] After birth, pediatric neurosurgeons perform surgical closure of the spinal defect. Most infants will require placement of a ventriculoperitoneal shunt to treat hydrocephalus and require subsequent shunt revisions for infection or occlusion. Some children do not survive beyond 5 years of age,[4] and survivors have sequelae that require a lifetime of costly care.
Scott Adzick, MD, and his team, first at the University of California, San Francisco (UCSF) and then at the Children's Hospital of Philadelphia (CHOP), have developed fetal surgical techniques that allow prenatal closure of myelomeningocele.[5] This work was recently highlighted in a PBS documentary titled Twice Born: Stories From the Special Delivery Unit. Recently, Dr Adzick spoke with Medscape about the long and complicated journey that started more than three decades ago, and continues to the present day as fetal surgery programs work to refine these life-changing procedures.
The Current State of Fetal Surgery
Medscape: For our readers who aren't familiar with this, could you summarize the work you have done to develop techniques of fetal surgery, and in particular fetal myelomeningocele repair?
Dr Adzick: The concept of fetal surgery started more than 30 years ago at UCSF, where I worked with my mentor and then pediatric surgery partner, Dr Michael Harrison. At that time, maternal/fetal ultrasonography was being refined, and for the first time, we were diagnosing birth defects in utero. As pediatric surgeons, Dr Harrison and I were frustrated, taking care of babies with life-threatening malformations that caused such progressive and severe organ damage before birth that the babies didn't survive. These fetuses had such problems as a huge congenital cystic adenomatoid malformation of the lung, lower urinary tract obstruction, congenital diaphragmatic hernia, very large sacrococcygeal teratoma, twin/twin transfusion syndrome, and so forth.
The concept of repairing these anatomical defects before birth was very controversial when we first introduced it more than three decades ago. To get to the point of being able to do this clinically (and this was long before we were thinking about intrauterine repair for myelomeningocele), we had to do our homework—experimental work, mostly in fetal sheep and fetal rhesus monkeys—to make sure that the biology was right, such that if we fixed a birth defect prenatally, it could be done safely and the condition of the fetus would be dramatically improved by the time of birth. Years of experimental work were done (that continue to this day) during which we problem-solved to make the eventual clinical enterprise safe.
Along the way, we did work at the California Primate Research Center in Davis, California, with rhesus monkeys. We operated on more than 400 maternal monkeys, and we showed that we could safely do fetal surgery with low risk, although not risk-free. We could effectively control preterm labor after the fetal surgery, although that is by no means a solved problem clinically. We followed the mother monkeys after they returned to the breeding colony to show that doing the fetal surgical intervention did not impair their future reproductive capacity.
After that work, we were ready to offer this to the first human patients clinically in the 1980s and early 1990s. Initially, we treated only the most severe cases. Early on, we had more failures than successes, but it was those failures that fueled the innovation that would subsequently help mothers and babies.
All of this experimental work and early clinical studies have a publication track record.[6] By 1993, we had a very large experimental laboratory at UCSF. We had about 12 research fellows who came to work with us from around the world, including a husband-and-wife couple from Zurich, Switzerland: Drs Martin and Claudia Meuli. Today, Martin Meuli is a pediatric general surgeon who serves as the surgeon-in-chief at the Zurich Children's Hospital, one of the most prominent children's hospitals in Europe. Claudia Meuli is a talented plastic surgeon, and they came to work with us on aspects of fetal diagnosis and therapy.
Medscape: What did you learn about timing of surgery?
Dr Adzick: Martin Meuli read an abstract written by a Johns Hopkins pathologist, Dr Grover Hutchins, who had done an autopsy series of aborted human fetuses with spina bifida.[7] He found that with increasing gestational age, fetuses with spina bifida had evidence of increasingly severe damage to the exposed spinal cord.
I was taught in medical school that the neural tube fails to close in spina bifida by 4-6 weeks' gestation (the "first hit"), and then all the downstream pathophysiologic effects were set in stone. We didn't know that there was a "second hit" before birth, owing to the ravaging neurotoxic effects of amniotic fluid on the developing spinal cord, nor did we fully understand embryologically the cause of hindbrain herniation or how hydrocephalus developed in these fetuses. Dr Hutchins' abstract stood the conventional thinking on its head. We set out to test the two-hit hypothesis experimentally.
We did this work in fetal sheep, much of which was published in the mid-1990s in Nature Medicine and other journals.[8] Term gestation for a fetal lamb is about 145 days, so we created the myelomeningocele model at 75 days gestation, about halfway through the pregnancy.
We did a simple experiment. We removed the hard and soft tissues around the lumbar aspect (L1-L5) of the spinal cord in fetal lambs so that the uninjured spinal cord would be exposed to the intrauterine environment, just as in human cases of myelomeningocele. We returned each lamb to the uterus, and when they were born 2.5 months later, they had all the clinical manifestations one would see in human babies with myelomeningocele. Their back lesions looked exactly like what we see with human neonates with myelomeningocele, including the presence of a sac.
When we evaluated these lambs and their neurologic function, they were paralyzed from the waist down—just what you would expect with an L1 level lesion superiorly. We looked at those spinal cords histologically and found that the exposed spinal cord and nerves were destroyed, not by the surgery but by the prolonged exposure to the neurotoxic effects of amniotic fluid.
The next step was to create the model in mid-gestation lambs, and then after 4-6 weeks go back and do a second fetal surgery to close the lesion and see whether we could mitigate some of these ill effects. And when those lambs were born after two fetal surgeries (one to create the lesion and one to close it later), they were remarkably different. These cute little lambs were not paralyzed. They could walk, run, climb stairs, and go down stairs. We did somatosensory evoked potential testing. and there was clearly nerve conduction across the in utero repaired spinal lesions. The remarkable innervation of their legs was an amazing finding.
© 2015 Children's Hospital of Philadelphia and Medscape
Cite this: Fetal Surgery: Pioneering Technology - Medscape - May 08, 2015.
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