N. Scott Adzick: Fetal myelomeningocele repair: trials and tribulations. I'm going to cover the tribulations before, during and after the Management of Myelomeningocele study trial.
I will discuss fetal surgery for myelomeningocele, or what we call MMC for short, the most severe form of spina bifida. Myelomeningocele affects about 1,500 babies born each year in the United States. That translates to 30 per week, or almost five per day.
For the fetus with myelomeningocele, part of the spinal cord and spinal nerves which are usually which are usually encased in a sac protrude through an opening in the back and are exposed to the amniotic fluid.
The second feature of the fetus with a myelomeningocele is the Arnold Chiari II malformation. The brain stem, which is known as the hindbrain, descends or herniates into the spinal canal in the neck and blocks the circulation of the cerebrospinal fluid. This can cause a damaging buildup of fluid in the brain called hydrocephalus.
The natural history of myelomeningocele includes a constellation of findings depending on the proximal or superior extent of the spina bifida. This includes hydrocephalus, hindbrain herniation, need for ventriculoperitoneal shunt, motor and cognitive impairments, bladder and bowel incontinence, social and emotional challenges, and lifelong quality-of-life issues.
The treatment of myelomeningocele after birth is fairly standard. It includes early surgical coverage of the defect, usually placement of a shunt for hydrocephalus, posterior fossa decompression for asymptomatic hindbrain herniation feature of the Arnold Chiari malformation, release of tethered cords, release of joint contractures, and ongoing treatment of orthopedic urologic bowel and shunt complications. A daunting prospect.
The outcomes for myelomeningocele treated after birth are: about 14 percent die before age 5, and 35 percent of those with symptomatic brain stem compression die. 85 percent of these children require shunts, with about half of the shunts developing complications such as infection and occlusion within the first year. 33 percent of these children have an IQ of less than 80. And only about half can live independently as adults.
Here's the rationale for fetal myelomeningocele surgery. We believe the spinal cord damage is progressive during gestation, and fetal myelomeningocele surgery may prevent further damage and reverse the hindbrain herniation feature of the Arnold Chiari II malformation that causes hydrocephalus.
When I was in medical school 30 years ago, we thought that the spina bifida was result of the neural tube from not forming from the neural tube not forming properly by 4 to 6 weeks gestation. And then the outcomes were fixed in stone.
About 20 years ago a pathologist at Johns Hopkins named Grover Hutchins did autopsies on fetuses with spina bifida and showed that the later in gestation the autopsy was performed, the more damage there was to the exposed spinal cord, which led to the two hit hypothesis. That first there was a failure of the neural tube to close, and possibly normal neural development thereafter, except for the second hit, which was secondary damage acquired in utero by the in uterine environment such as amniotic fluid exposure. And the issue then was whether fetal surgery could ameliorate or prevent ongoing damage. The second hit to the two hit hypothesis.
Around this time, I had two talented research fellows from Zurich, Switzerland. Dr. Martin Meuli is now the surgeon in chief at Zurich Children's Hospital, and Claudia Meuli, a talented plastic surgeon, came to work with me. And they wanted to test the hypothesis that had been proposed by Grover Hutchins, so we went to the laboratory, did work in fetal sheep in midgestation where term is about five months. So we worked at about 75 days gestation. And I had them expose, by a lumbar laminectomy, the uninjured spinal cord by removing, as shown in this slide, the soft tissues and the hard tissues in the sides of the dura.
This shows myelomeningocele creation in a fetal lamb at 75 days gestation. This lamb is about half the size of my hand. You could see the cut edge of the uterus, the back of the fetal lamb, incision of the skin and subcutaneous tissue and then excision of paraspinal muscle because there is a deficiency in paraspinal muscle in children with spina bifida.
A complete lumbar laminectomy from lumbar levels 1 to 5 is being performed next. In the middle of photograph one can see the uninjured spinal cord as a little ribbon of tissue, and the fetus is then returned to the uterus. The uterus is closed, and the gestation continues.
This is what things look like at term on the left. The newborn lamb with a classic appearing myelomeningocele defect. This is a newborn lamb, of course, and you can see the lamb is wool bearing, and it looks strikingly like the defect we see in the human newborn with myelomeningocele on the right. So you can go back and forth and see that the two findings, grossly, are comparable.
When we look at these lambs at the time of the birth, you can see that they were paralyzed from the waist down. They were insensate, and they were completely lame. You could actually put a hemostat to pinch the leg or induce a pinprick of the lower limbs, and the lamb will not react. Histologically, the spinal cord within the myelomeningocele is completely destroyed.
So this showed that midgestational spinal cord exposure alone results in a human like myelomeningocele at the time of birth due to the ongoing damage by the in utero environment.
The next step was to do a second series of experiments in which the myelomeningocele defect was created, and then after a month or so, a reverse latissimus dorsi flap was raised to provide good multilayer tissue coverage of the myelomeningocele defect. And we learned from this that in utero coverage of myelomeningocele rescues neurologic function at birth. And this was described in a paper in Nature Medicine in 1995.
Next I want to show a video moderated by Martin Meuli and you'll see Claudia Meuli as well, and you'll see lambs that underwent creation of the myelomeningocele defect in midgestation, subsequent closure with the second fetal surgery operation, 4 to 6 weeks thereafter, continuing gestations, cesarean section, and then you'll see these cute little lambs.
Histologically, if you do a transverse section of the spinal cord in a normal lamb you could see the spinal cord in the middle and you could see the posterior boney arches for a normal lamb at term.
The lambs that had the myelomeningocele created in this defect, the boney arches were, of course gone, because they were excised. And the spinal cord that remains is a little ribbon of tissue on top of the vertebral body.
And those lambs that had creation of the defect and then subsequent repair, on the top you can see the latissimus dorsi flap and the skin closure, and you can see a deformed spinal cord, but actually overall, it looks quite good.
One of the criticisms of surgical models of myelomeningocele is that the lesion is artificially created in midgestation, just in our just like in our lamb model, and is therefore unable to really replicate the primary defect in neurulation.
Work in our own laboratory included the development of a retinoic acid induced myelomeningocele model in rats. If given midgestation pregnant rats oral gavage or retinoic acid in a certain dose, a high proportion of her fetuses will develop a myelomeningocele.
So here on the left hand side you can see a human embryo with a myelomeningocele, and you can see the rat model with a myelomeningocele right next to it on the right.
The next slide shows underneath is the way a myelomeningocele appears after birth in the human circumstance on the left, and the rat on the right. They look very similar.
Late in gestation, several days before birth in the rats, there is some preservation of the spinal cord morphology, and the same is true in the human fetuses with myelomeningocele, though there is evidence of damage.
And then by the time of birth, on the left hand side, the human spinal cord is destroyed by the in utero milieu, and the same is true with the rat spinal cord at term.
The retinoic acid induced myelomeningocele model also has the Chiari II associated hindbrain herniation. You can see the control normal rat on the left with a normal configuration for the hindbrain. And on the right there is a hindbrain herniation through the foramen magnum.
So lessons from the rat model of myelomeningocele are that they appear to be structurally and functionally similar to the human defect. This provides additional direct evidence for the two hit hypothesis.
We have also done neurologic function in these rats and shown that neurologic function is lost with advancing gestational age. We have come up with an assay from amniotic fluid to correlate with neural tissue destruction based on the levels in the amniotic fluid, a glial fibrillary acidic protein.
This model might be also useful for to test tissue engineering techniques to eventually be applied clinically.
The rationale for early gestational repair of myelomeningocele in human fetuses is shown here. It was a big step in the late 1990s to go from treating a life threatening birth defect in utero, like a congenital cystic adenomatoid malformation associated with hydrops, to treating a devastating, but not life or death, birth defect.
We know that spinal cord damage is progressive during gestation, based on the work that you saw in lambs and in rats. And in serial sonographic studies of human fetuses have shown evolution of club feet and progressive ventriculomegaly or hydrocephalus.
The rationale for early gestational repair in terms of reversal of hindbrain herniation feature of the Arnold Chiari malformation. There are some theoretical issues with regard to myelination and regeneration, that if you do an operation early in gestation, and if the baby is born very prematurely, then the baby can die. And actually in the first fifty human cases we did at The Children's Hospital of Philadelphia, there were three deaths from very premature birth.
This has always been our approach, to treat this lesion prior to 26 weeks gestation.
We reported successful fetal surgery for spina bifida in an early gestation human fetus in The Lancet in 1998.
One serendipitous finding was that when we began to do human fetal surgery for myelomeningocele we learned that the hindbrain herniation component of the Arnold Chiari malformation was reversed after fetal repair. This assessment was greatly helped by the development of ultrafast fetal MRI at CHOP.
On the left side of this slide panel is a 22 week gestation fetus, and a sagittal view with the face on the right. And one can see the hindbrain herniation in which the hindbrain has gone down into the upper portion of the cervical spinal canal, which is an important factor in the development of hydrocephalus. And also after birth hindbrain herniation can cause problems with the cranial nerves.
After fetal repair, one can see on the right hand side the same patient and this is after birth the hindbrain is floated up into an anatomically normal position. The hindbrain herniation has resolved.
This shows the drawing of a fetus schematically with myelomeningocele. And we think that the cerebrospinal fluid simply runs out the back before birth, and the hindbrain herniates down. In utero repair stops the cerebrospinal fluid leak. The pressure column is reestablished in the spinal canal, and the hindbrain floats back up. So this schematic cartoon shows the hindbrain herniation on the left. And then with closure and reinstitution of that pressure gradient, the hindbrain herniation resolves.
Now this has been shown in the laboratory as well, initially by Rusty Jennings at the University of California San Francisco, and Sarah Bouchard at CHOP in the late 1990s, working in the fetal sheep model that I just showed you.
A myelotomy was added to the model to allow the cerebrospinal fluid from the central canal to run out through the back and through the defect, and we showed that this induced hindbrain herniation and that repair reversed this herniation.
So on the right is the unrepaired lamb, showing hindbrain herniation through the foramen magnum, and on the left hand side is the repaired myelomeningocele lamb, posterior view showing resolution of the hindbrain herniation.
Well, how is the fetal surgery performed for myelomeningocele? Well, this shows schematically the patient position. And a transverse maternal laparotomy is performed, and one can see where the myelomeningocele lesion is by sterile intraoperative ultrasound and also determine the position of the placenta.
This shows an intraoperative photograph. The maternal laparotomy has been performed, sterile intraoperative ultrasound is used to map the placental edge, and the hysterotomy needs to be made at least six centimeters away from that edge. If an anterior placenta is present, a fundal or posterior hysterotomy is performed, and the opposite is true if there is a posterior placenta present. Sometimes a maternal fetal medicine specialist needs to do aversion of the fetus to bring the myelomeningocele directly underneath where we plan to do the hysterotomy.
And for that, we use a uterine stapling device that we invented at University of California San Francisco more than 25 years ago, which quickly and bloodlessly opens the uterus and keeps the amniotic membranes tacked up against the myometrium.
And this shows the uterine stapling device being fired.
This shows the hysterotomy. You can see the uterine staples. Those are the white objects on the uterine edge. The fetus stays inside the uterus, of course. The myelomeningocele lesion is exposed here. You can see the membranes. You can see the myelomeningocele sac.
On the far left, the fetus is about to get an intramuscular shot of a muscle relaxant and a narcotic to make certain that the fetus is anesthetized in addition to deep maternal general anesthesia which also anesthetizes the fetus.
We've learned that it's important that fetal echocardiography be performed during the operation. That's the best means of monitoring the fetus in terms of myocardial function. If there is a change in the function, we need to understand why. So Jack Rychik and his team from the Fetal Heart Program play a crucial role here.
A wound is made at the junction of the myelomeningocele sac and the skin.
Here, the junction of the arachnoid to the skin is incised by Dr. Lee Sutton, the neurosurgeon performing this operation.
Here the dural closure is beginning, myofascial flaps have been raised and then closed at the midline.
And then the skin is closed, followed by closure of the uterus in the laparotomy. If skin flaps are inadequate to close that final layer, we use an AlloDerm patch to bridge the gap.
This shows the laparotomy wound close. And only a Tegaderm is placed because a bulky dressing would interfere with postoperative ultrasonography and echocardiography, each of which is performed once for at least the first two days postoperatively.
This shows intraoperative video of a myelomeningocele closure. You could see the sterile intraoperative ultrasound probe. The uterus is exposed. The edge of the placenta is being marked with a Bovie cautery under sonograph guidance. Full thickness stay sutures times two are placed under sonographic guidance, then tied to make certain that the membranes are tacked up against the myometrium.
The Bovie cautery is used to incise the myometrium, and then the uterine stapling device is placed while watched sonographically and then is fired to give a nice bloodless hysterotomy approximately three inches long. An irrigating tube on the right, called the level one, instills warm body temperature Ringer's lactate to keep the fetus warm and buoyant.
The incision is then made near the skin and arachnoid junction. The dura is then closed and now myofascial flaps are being raised and those flaps, once they are created, are closed, shown here on the midline. Skin flaps are then raised, then stretched. The skin is closed. This is neural gestation fetus at 21 weeks gestation, and the skin is somewhat gelatinous. The uterus is then closed in two layers. Stay sutures are placed first with double ended needles, passing from inside to outside, and running full thickness. Inner layer is performed as shown. And then the amniotic fluid is replenished with Ringer's lactate. Antibiotics are placed intraamniotically, and then an omental flap is brought down on the hysterotomy closure.
This shows various views of slides that Dr. Mark Johnson gave to me, photographs of different myelomeningocele defects. You could see in the upper left hand corner a large sac, and then the lower left hand corner, a myeloschisis without a sac. In the middle is the way the postnatal closure site looks at the time of birth which hopefully will be many weeks later. And one can see that the fetus heals beautifully.
There are results from the first 50 cases of early gestation, fetal myelomeningocele repair performed at CHOP between 1998 and 2003, with the upper anatomic level being as high as thoracic level 8 and as low as sacral level 1. The gestational age at time of surgery was just shy of 23 weeks gestation. The average gestational age at delivery was premature at 34.5 weeks gestation. So the average gestation postoperatively was about 12 weeks in these cases.
There were 3 deaths out of 50 cases due to extremely premature birth. Partial or complete reversal of hindbrain herniation occurred in all the remaining 47, as judged by serial MRI examinations before birth. Preemptive ventricular size was 11.2 millimeters with a range of 6 to 17. Cortical index, which is a measure of brain growth, was improved in this cases. 40 percent require placement of the ventricular perineal shunt within the first year of life. All the babies were born and cared for in the intensive care nursery at CHOP. And then assessment of neonatal leg function versus the anatomic level showed that about 2/3 had better than expected motor function.
Dr. Natalie Rintoul, one of our stellar neonatologists, did a study at looking at the need for a shunt in CHOP's Spina Bifida Clinic patients for a 17 year period, with all these children being treated after birth, of course. And this was between 1983 and 2000. She showed that the need for a shunt in these postnatally treated patients correlated with the anatomic level of the myelomeningocele. One hundred percent of thoracic level lesions required a shunt, 88 percent for lumbar level, and 68 percent for sacral level.
On average, these patients and these are nearly 300 that she reviewed 86 percent of postnatally treated kids required a shunt, whereas in this preliminary study at CHOP with early gestational fetal repair, only 40 percent required a shunt.
There were numerous obstetrical complications in these 50 patients treated before the onset of the MOMS trial in 2003. Chorioamniotic separation is usually a sonographic finding. That was present in 28 percent. And 4 percent required readmission for bed rest and monitoring due to global chorioamniotic separation.
Preterm labor requiring magnesium sulfate at 6 percent, 2 of 50 patients required a transfusion, so 4 percent. Postoperative oligohydramnios was present in 6 percent. The mean hospital stay for these mothers was just shy of 5 days after the operation. All were cared for on the ward. There was no need for an ICU bed.
Delivery before the planned elective cesarean section date of 36 weeks occurred in 44 percent of that group that delivered prior to 36 weeks gestation. The mean gestational age of delivery was 32 weeks gestation. And for the whole group, it was 34.5 weeks gestation.
There was no uterine dehiscence, noted at the time of the cesarean section delivery. And it's important to emphasize that all open fetal surgery mothers need a cesarean section for the fetal surgery pregnancy as well as for any subsequent pregnancy because of the higher location of the uterine scar and the risk that this will tear during subsequent labor and pregnancy.
Mark Johnson and others led follow up studies on pre MOMS trial patients at CHOP and showed that fetal myelomeningocele repair decreases the need for ventriculoperitoneal shunting and reduced hydrocephalus and shunt related morbidity. They show that reversal of hindbrain herniation reduces the Chiari-II related cumulative mortality and morbidity, and fetal repair improved neural functional outcome by age 5. Most of those children by age 5 -- 83 percent -- had overall cognitive functioning in the average to high range, and he also analyzed the ambulatory status. These case studies were being completed as the MOMS trial was going on.
This shows by ultrasound before birth that one could give a very accurate delineation of the anatomic level of the myelomeningocele. In this case, it runs from L2 to S4.
As you all know, the motor impairment in children treated after birth is related directly to the level of spinal cord injury. And you can see which muscles are affected by which levels, beginning at L2 or 3 and going all the way down to S2, 3, and 4.
We looked at the two study populations, those treated for myelomeningocele before birth -- 54 patients, between 20 and 25 weeks gestation. And then a control group of postnatal myelomeningocele repair. These were prenatally diagnosed myelomeningoceles that underwent standard postnatal neurosurgical closure.
It shows a striking difference in terms of lower extremity neuromotor function. Almost 60 percent of those treated before birth had two or more anatomic levels better function compared to their predicted anatomic level of function.
And the ambulatory status of the children showed that half of those children treated before birth, compared to 5 percent treated after birth, had an independent ambulatory status.
Transcranial electric motor evoked potentials were measured in several children who were treated before birth with myelomeningocele repair, and who after birth developed an epidermoid cyst. And this showed, by this inside tube monitoring, that there was good function of those exposed nerves.
So the summary is that fetal myelomeningocele repair appears to improve lower extremity motor function and ambulatory status and preserve structural integrity and neurophysiologic function of the spinal cord and ventral nerve roots.
This shows in more detail the neurodevelopmental outcomes after fetal myelomeningocele repair. Again, those 50 or so patients treated before birth at CHOP before the start of the MOMS trial.
And this shows the pie chart with neurodevelopmental outcomes which are actually quite favorable by age 5.
Symptomatic hindbrain herniation, which is reversed by fetal myelomeningocele repair, has functional effects.
And this shows that our data showed that symptomatic hindbrain herniation for those children that had reversal of hindbrain herniation was no longer an issue.
So we have fetal myelomeningocele repair, the potential benefits for the patient, for the baby are clearly shown. But there are several potential risks to the mother and the baby both, including fetal or neonatal death, complications from preterm birth, a variety of OB complications, and potentially future fertility and pregnancy complications. The problem was, for this cohort of patients there were no match controls, there were a variety of caveats such as possible selection bias, and the follow up was still relatively short term.
The NICHD sponsored MOMS trial, Management of Myelomeningocele Study, was crafted in response to several factors. First, we needed to have scientific proof that fetal repair was better than postnatal repair. There was, at this time, unusual publicity in the lay press regarding possible cures for fetal surgery for spina bifida. There was reporting of results in realtime on websites with an accompanying chat room for potential candidates. There were efforts to brand this as institution specific. And there was widespread interest nationally and internationally at many other institutions. So it was the right time, and probably the only time, to test this fetal therapy with a prospective randomized trial before the surgery became much more widespread.
A randomized controlled trial for a medication, say, is difficult. A randomized control trial for surgery is much more difficult. And a randomized control trial for fetal surgery is extraordinarily difficult.
This shows three crucial events for crafting the trial between 1993 and 2003. The first was an NIH sponsored fetal surgery summit in July 2000. Representatives from the three major centers -- Vanderbilt, University of California San Francisco and CHOP -- presented their data on fetal myelomeningocele repair which showed promise, but there was no clear data regarding benefits and risks. So there was a recommendation for a randomized controlled trial.
The second crucial event was the International Fetal Medicine and Surgery Society meeting in September of 2000 on Nantucket. This was a somewhat contentious meeting. But at the end, there were commitments from all three centers to engage in a randomized prospective trial. And importantly, agreement from other such centers interested in performing fetal myelomeningocele repair, to wait until the randomized control trial was complete and not provide a backdoor for fetal therapy outside the trial.
The third crucial event was the support of the National Institute of Health and the NICHD in moving forward. And we went through multiple grant submissions, had a completely standardized protocol, and, finally, funding was obtained in the year 2002. And randomization and the trial began in 2003. In my view, getting consensus and carrying out the trial was the most difficult thing that I've ever been involved in in my professional career.
The goal of the trial was to compare the safety and efficacy of in utero repair of open neural tube defects with that of standard postnatal repair.
Prospective randomized trial, three clinical centers: Vanderbilt, UCSF and CHOP. George Washington, under the leadership of Liz Tom, was the data and study coordinating center. Principal investigators at the three sites were, at UCSF, Mike Harrison, then Diana Farmer. At Vanderbilt, Joe Bruner and Ed Yang, and then John Brock. And then at CHOP, Scott Adzick. Mary D’Alton, the chief of obstetrics and gynecology at Columbia University, was the chair of this steering committee. And Cathy Spong, as the director of pregnancy and perinatology branch of the NICHD, was the scientific officer representative to the steering committee.
The inclusion criteria were very broad in terms of fetal anatomy. Myelomeningocele starting as high as thoracic level one, or as low as sacral level one, with evidence of hindbrain herniation in ultrafast fetal MRI. A singleton pregnancy between 19 weeks and 25 weeks, 6 days gestation, and a normal karyotype. And because this was sponsored by the National Institutes of Health, the trial subjects had to be residents of the United States and be at least 18 years of age. There were no exclusions for club feet, for massive ventriculomegaly, or absence of leg movement on ultrasound.
There were a variety of exclusion criteria, very importantly. Additional fetal anomalies being one, a prior history of preterm labor, various maternal health factors such as insulin-dependent diabetes or significant hypertension, or obesity as reflected in a body mass index greater than 35 because of the risks that would bring to an elective operation.
The triage of patients was basically a western United States to UCSF, a portion of the Midwest and the south to Vanderbilt, and the northeast and a portion of the Midwest to CHOP. There was centralized screening of potential candidates at George Washington, and then computer-based randomization.
The evaluation at the MOMS center was a two-day comprehensive evaluation. And this was for parents who had expressed an interest and that had been screened in the data study coordinating center. Evaluation at one of the three of MOMS trial clinical centers was a two-day process, as shown here, extensive counseling and evaluation. And at this point, a mother carrying a fetus with myelomeningocele of less than 24 weeks gestation had three choices. She could end the pregnancy; she could have a near-term cesarean section with postnatal myelomeningocele repair; or she could consider entering the MOMS trial if she was a candidate and then being randomized.
If she accepted entry into the trial and if she was randomized for prenatal surgery, the surgery was performed one to three days after randomization, but before 26 weeks gestation. The standardization of the surgical technique and all the postoperative care protocols, including postoperative tocolysis and treatment after discharge, usually on postoperative day number four. The mother and the accompanying person would stay in the same city as the clinical center for the duration of the pregnancy and would have delivery via C-section at 37 weeks gestation if preterm labor didn’t occur.
If the mother was randomized to postnatal surgery she could return home, have monthly ultrasounds by her local physician group, return to the MOMS center at 37 weeks gestation for a fetal lung maturity testing by amniocentesis and cesarean delivery if fetal lung maturity had been obtained, and then neonatal repair in the first day of life or two by the same MOMS neurosurgical team that was performing the repairs before birth.
Tocolysis, or treatment of preterm labor, were standardized which included indomethacin, magnesium sulfate, and then switched to oral nifedipine for the duration of the pregnancy. In this standardization of tocolytic agents in much smaller doses then we have used previously was a real advance, and made preterm labor much less of an issue, as well as the side effects of tocolysis less of an issue.
The primary outcome measure, one -- and there were two primary outcome measures -- was at 12 months of age, was death or the need for a ventricular decompressive shunt as defined by objective criteria, and these cases were reviewed by an independent committee of neurosurgeons who could determine whether or not shunt criteria had been met.
The criteria for shunt are shown here, and are really quite strict and standardized.
The primary outcome measure two –- and it’s curious in a trial to have two primary outcome measures, but that’s what the NIH reviewers wanted -- was composite outcome at 2 and 1/2 years of age, of two measures including the Bayley Scales of Infant Development, and then the difference between the motor lesion and the anatomic lesion levels. So it was a motor function and mental development scale.
The secondary outcome variables are shown here, and there are maternal, and neonatal, and a variety of infant outcome variables.
The follow-up examinations of the children in both limbs of the trial were at both 20 months and at 30 months of age at the individual MOMS center. They were performed by an independent group of physicians, what I call SWAT teams, of pediatricians and psychologists, who are independent of the investigators who would come in and do the evaluations and have been trained by the data study coordinating center. And the teams were blinded as far as what treatment assignment the children had been.
The oversight of this trial was quite strict. There was a local oversight committee at each of the three clinical sites that reviewed randomized cases on a monthly basis. There was a local IRB. There was a steering committee that included Mary D’Alton, the four principal investigators, and Cathy Spong. And then, of course, a data safety and monitoring committee that reviewed the data every six months. And the maternal-fetal medicine unit network at the NIH. The investigators were blinded as far as the results during the seven years of the trial.
The initial timeline plan for the fetal myelomeningocele repair trial, as outlined as presented in 2002, was that we thought we could randomize 200 patients in a two year time period. But, of course, patient accrual was much slower despite our best efforts.
The MOMS trial was stopped December 7, 2010 -- Pearl Harbor Day -- because the data and safety monitoring board stopped enrollment due the efficacy of prenatal surgery in terms of both primary outcome variables. The MOMS trial steering committee met the following week, and the report of this work came out in the New England Journal of Medicine, online first in February 2011, and the print version thereafter in March. For the patients who were screened, there were 1,084 total. 530 met exclusion criteria, 258 decided not to participate, 299 were referred to one of the three MOMS centers, and 183 patients were randomized. The follow-up groups included a 12-month follow-up for 158 patients, and a 30-month follow-up for 136 patients. Of course there were many patients that still required follow-up, so that we’ll get eventually to the entire data set for 183 patients. There is a separately funded urologic follow-up grant that is still in process.
The New England Journal of Medicine publication.
With regard to the primary outcome variable, the first one at 12 months of age, was a composite of death or meeting the criteria for a ventriculoperitoneal shunt. There were roughly 80 children in each of the two groups at that point. There were two deaths in each of the groups. The prenatal surgery group had two deaths, one due to an in utero fetal demise, and one due to a very premature birth.
The two deaths in the postnatal surgery group were both children who had ventriculoperitoneal shunts who subsequently died from manifestations of the Chiari malformation, from hindbrain herniation. It’s straightforward to see that, in terms for meeting criteria for shunts, the prenatal surgery group had a marked advantage with a very highly significant P-value compared to the postnatal surgery group, virtually all of whom met the criteria for shunting.
The take-home lesson is that shunts were placed in 40 percent of the prenatal group compared to 82 percent of the postnatal surgery group.
This shows the outcome of children at 30 months of age with that composite primary outcome variable. This was 2 and 1/2 years of age. There was a highly significant advantage for the prenatal surgery group, but note that as far as the primary outcome components go, the cognitive indices show no difference between the groups. The main difference was that motor function, on average, was much, much better in the prenatal group compared to the postnatal group in all testing parameters.
This includes the difference between the motor function and anatomic levels, the Bayley Psychomotor Development Index, the Peabody Developmental Motor Scales, the WeeFIM mobility scores, and then most importantly the ability to walk. 42 percent in the prenatal group could walk independently compared to the 21 percent in the postnatal surgery group.
This is despite the fact that on average there were higher and more severe myelomeningocele lesions in the prenatal surgery group just by serendipity. For those with a lesion of L3 or lower on ultrasonography, 68 percent of the prenatal surgery group were in that less severe class, whereas those lower levels were 84 percent at the postnatal surgery group. So better motor function than the prenatal surgery group on average, despite the fact that again on average they had higher more severe lesions.
Radiologic outcomes were much better in the prenatal surgery group in terms of hindbrain herniation, brainstem kinking, abnormal location of the fourth ventricle and syringomyelia.
Here are the maternal outcomes. Really the same results as the CHOP study I showed you before the MOMS trial. Important to note that 9 percent of mothers in the fetal surgery group required transfusion at the time of Caesarean section in the prenatal surgery group, compared to only 1 percent in the postnatal group. Hysterotomy status at delivery showed about 2/3 were intact and well healed. 25 percent were thin. And 9 percent had an area of dehiscence and one had a complete dehiscence so without an evisceration. Cesarean section for the fetal surgery pregnancy and for all future pregnancies of course.
This shows the fetal and the neonatal outcomes. There were two deaths in each group which I reviewed before. Note that for the prenatal surgery group a premature birth was the norm just beyond 34 weeks gestation. 13 percent were delivered before 30 weeks gestation. And the full delivery cohort date subsequently showed this rate is 11 percent or one in ten births. The only significant difference in terms of the possible neonatal complications was that the prenatal surgery group had a higher incident of respiratory distress syndrome. 21 percent compared to 6 percent in the postnatal surgery group.
Here are the MOMS trial conclusions in brief. Prenatal repair of myelomeningocele is not a cure. But it did reduce the need for ventricular shunting to treat hydrocephalus and improve motor outcomes including the ability to walk at 30 months of age. Prenatal repair of myelomeningocele is associated with significant maternal and neonatal risks including premature birth and uterine scar issues.
I think it would be best though to hear from members of our team regarding fetal myelomeningocele repair in a video entitled, Birth of a Breakthrough.
Here are some of the other lessons from the MOMS trial. The format was crucial. No back door was important otherwise the MOMS trial would have been untenable. Standardization for a surgical trial was challenging but standardization advanced the field. The DSCC centralized intake performed site visits that worked well. And there were temporary suspension of two of the centers, UCSF and Vanderbilt, due to excessive number of protocol violations, so that's important. There was slow enrollment. The study took much longer than anticipated. But the NIH remained committed to additional funding until the study was complete. And there were some financial issues, for instance, it the three fetal surgery units underestimated the amount of money needed for support staff and so forth. But this does lay important groundwork for future fetal therapy trials.
So I'd like to give many thanks to participants in the MOMS trial, the various review committees as shown here. The Data Safety and Monitoring Committee. The MOMS trial is the lynchpin of this presentation and there are many, many people who made it work.
And at the sites, many thanks to all the different participants.
And thanks to the women, their children, and the families who have taken part and continue to take part in the MOMS trial. The International Fetal Medicine and Surgery Society, the Society for Maternal-Fetal Medicine, the fetal therapy community and the perinatal community.
Well, what now? What's next? Well, 40 percent of the children treated before birth still required a shunt. And not all had improved neuromotor function or a complete reversal of hindbrain herniation. So we need to complete the MOMS trial data set for all 183 patients. This has been done by Dr. Mark Johnson for the MOMS full delivery cohort and there were two important findings with regard to increased risk for preterm labor. The first was that longer surgical time correlated with premature rupture of the membranes and subsequent early preterm delivery, which speaks to the technical expertise of the team and the importance of that.
The second factor was the development of oligohydramnios postoperatively that placed patients at increased risk for preterm delivery. We need to thoroughly look at possible prenatal predictors of outcomes. Was the fetus with severe ventriculomegaly very likely to need a shunt and therefore may not have that benefit of fetal surgery? What about the anatomic level or the presence of the increased leg movements or the presence of club feet? How accurate is prenatal ultrasound at determining anatomic level? We will be looking specifically at maternal morbidity, future pregnancy considerations and maternal psychological aspects with a panel of tests that the mothers went through at the 1 year and 2 and 1/2 year follow up time period.
It will be important to critically examine cost. What is the cost of the prenatal surgery versus postnatal surgery? Cost projections including a report from Washington University using the MOMS trial data in a financial model predicted that prenatal repair would save more than $3 million per every hundred babies treated before birth. We're now immersed in the NIH-funded MOMS 2 study which is follow up of the same cohort of patients at school age, 6 to 9 years of age.
We have task force guidelines led by Julie Moldenhauer from CHOP that got multiple medical societies together to come up with guidelines for what a center needs to do fetal myelomeningocele repair. The North American Fetal Therapy Network has a redcap data registry to look at all cases done after the MOMS trial, and we need to examine critically what would be the effect of earlier and less invasive intervention because it appears that the damage to the spinal cord begins early in gestation and is progressive.
This shows the cohort of societies that provided guidance for the guidelines for fetal myelomeningocele repair and this is an American Journal of Ob-Gyn publication that will soon be published.
This shows the format for the MOMS 2 follow up study with the primary hypothesis being to determine whether prenatal myelomeningocele repair affects adaptive behavior at 6 to 9 years of age as compared to postnatal repair using the Vineland Adaptive Behavior Scales 2. And a variety of secondary outcomes and this is funded by the National Institution of Child Health and Human Development and the National Institute of Neurologic Disorders and Stroke.
This shows the payor landscape for fetal spina bifida repair. Over the first year after the New England Journal of Medicine publication there were a variety of developments as we began to work with payors to have insurance companies pay for the fetal surgery viewed as an alternative standard of care. There were some denials, and this lists some of them, during those first few months. And then there was case-by-case approval from various insurance providers and payors. Any finally there's been policy approval by all the major payors in the United States: Blue Cross Blue Shield, Aetna, United, Tricare, Cigna, Highmark, and so forth.
This shows our results at CHOP with the cases referred to us between the close of the MOMS trial and more recently. So this is a three-year cohort of patients, 548 referrals, 321 onsite evaluations, close to 100 fetal surgery operations. About 2/3 of the patients are not fetal surgery candidates after screening. About 2/3 of them choose to have postnatal repair after continuing the pregnancy and about 1/3 interrupt the pregnancy. Just a handful of patients in each of those last two groups, postnatal repair or termination of pregnancies, were actually fetal surgery candidates. So most patients who come to see us are not fetal surgery candidates.
There are a few post MOMS trial lessons. Fetal myelomeningocele repair is difficult. It requires a seamless, experienced multidisciplinary team. Fetal resuscitation was required in four of 97 cases due to fetal bradycardia or decreased myocardial function, all were successful. An AlloDerm patch to enhance the skin closure was needed in 7 percent of myelomeningocele cases with a sack, in almost half of the myeloschisis cases which do not have a sack. The maternal cesarean section transfusion risk is 2 percent versus the MOMS trial at 9 percent. Gestational age of delivery at less than 30 weeks gestation, 7 percent versus MOMS trial at 11 percent. It's very important to do both ultrasound and an MRI for assessment of hindbrain herniation because only MRI can really clearly define when a hindbrain herniation is present or not, which is an important inclusion criteria. And we've learned from many visitors that many interested institutions cannot do fetal myelomeningocele repair safely because of lack of expertise or inadequate clinical volume.
This shows fetal surgery exclusion for absence of hindbrain herniation on MRI patients who did not have hindbrain herniation and did not need fetal surgery. But it also shows their ultrasound findings and it shows many cases where there was no hindbrain herniation on MRI but where hindbrain herniation was called on ultrasound or was equivocal on ultrasound. So the bottom line is that ultrafast fetal MRI must be done on mothers who might be fetal surgery candidates.
This is a photograph that I got from some proud patients recently. This is an 18-month-old infant with an L3 level myelomeningocele repaired in utero at 22 weeks gestation. He does not have a shunt and there are his footprints in the sand. I think this speaks for itself.
And here's that same child six months later playing with his favorite Christmas gift, the Stomp Rocket.
Here's another child who is not even a year of age and her mother is quite proud after fetal myelomeningocele repair that she's standing on her tippy toes, as the mom said. So these kids are great successes thus far but in general we can do better. And the way to do better is to use and explore the potential of a tissue engineering approach for a watertight prenatal myelomeningocele coverage through a single fetoscopic port or through an amniocentesis needle under ultrasound guidance, thereby to decrease the risk to the mother and the baby and improve outcomes by performing the operation earlier in gestation.
Now, standard fetoscopy using three or more ports is an appealing concept to mitigate maternal morbidity, but the Achilles' heel is that three ports lead to fixation of the membranes and tearing of the membranes with uterine growth and consequent premature birth three to six weeks after surgery and delivery before 30 weeks gestation. So compared to open fetal myelomeningocele repair, somewhat surprisingly, fetoscopic repair with multiple ports has higher rates of fetal death, premature rupture of membranes, chorioamnionitis, oligohydramnios, premature delivery, and persistent hindbrain herniation. So the problems of membrane rupture associated with multiport fetoscopy can be solved with this minimally invasive approach to repairing myelomeningocele before birth should be tested clinically.
We've used a tissue engineering approach experimentally for prenatal closure of myelomeningocele using the fetal rat myelomeningocele model. This is work done by Mijo Watanabe working in Dr. Alan Flake's lab, shows that on the left is a term fetal rat with a myelomeningocele due to retinoic acid given mid gestation. On the right is a term rat who was treated before birth with a minimally invasively injected gelatin hydrogel scaffold that can cover the defect, prevent exposure to amniotic fluid, and prevent exposure to uterine induced trauma to the myelomeningocele defect and prevent cerebral spinal fluid leakage from the back. This may be the way to go in the future.
We're working in the fetal myelomeningocele sheep model to test the ingredients for a tissue engineered solution. Including cool things like ultraviolet light-activated underwater adhesive derived from muscle shells. When you think about muscle shells they produce a liquid glue that solidifies and allows the shell to adhere to rocks in a salt water environment. Use nano-texture biodegradable elastomers using gecko technology. And also cell sheet technology.
So this shows closure of the fetal myelomeningocele with a gelatin hydrogel scaffold. So you can imagine the future state in which a mother carrying a fetus with a myelomeningocele diagnosed at 16 weeks gestation could have, through a tiny single fetoscopic port or with an ultrasound guided amniocentesis needle, injection of these tissue engineered components to basically seal the myelomeningocele before birth, prevent the ongoing damage by amniotic fluid exposure, stop the leak of cerebral spinal fluid that causes hindbrain herniation, and avoid the possible maternal and neonatal morbidity of open repair. Then formal anatomic myelomeningocele closure could be performed surgically after birth with a preserved spinal cord.
So this prenatal tissue engineering approach for coverage of myelomeningocele appears promising but needs optimization of many variables. And then eventual after proof of principle, conversion to a minimally invasive technique before this can be applied clinically. Thank you very much.