The following article is from Current THE MAGAZINE OF THE SPINA BIFIDA AND HYDROCEPHALUS ASSOCIATION OF ONTARIO Winter 2012 edition
Management of Mylomeningocele Spina Bifida (MOMS)
By Mary J. Dufton
In-utero Spina Bifida Repair
Dr. James Drake provided an overview of an exciting breakthrough of the past year, the Management of Mylomeningocele Spina Bifida (MOMS) trial, which was published in the New England Journal of Medicine in March 2011. The MOMS trial compared two approaches to the treatment of babies with spinabifida mylomeningocele: surgery on the baby in the womb at the gestational age of approximately 24 weeks with a second caesarean section at term (or as possible to it); and the usual standard surgery for mylomeningocele after the baby is born.
The study compared several important outcomes. The first outcome was whether or not the mother and baby survived and whether or not the baby needed a shunt. The secondary outcomes examined the baby’s spinal cord level of functioning compared to the anatomical bony level on the lower spine, their level of functioning developmentally and whether or not they were ambulatory.
Magnetic Resonance Imaging (MRI) has been a very useful tool in the trial because it provided important detail in examining the status of the foetus and the pregnancy. The degree of Chiari malformation, the size of the ventricles, the organ structures and the mylomeningocele can all be seen on the MRI.
The trial, which began in 2001, was very carefully conducted. It was meant to happen over two years, but it took ten because it was not easy to recruit patients. The mothers had to go to one of three trial centres and stay there if they received the in-utero repair.
While 1,037 families were screened, only 187 were entered into the trial. Having a body mass index that was over a certain level excluded 230 patients. Some decided not to proceed once they were told about the risks. And there may have also been some more abnormalities or conditions that weren’t recognized before the MRI.
The patient groups were very well balanced. The infants receiving the in-utero repair had slightly higher lesions, which were expected to have a slightly worse outcome. Because the in-utero surgery infants were born prematurely, their birth weights were lower. They also had a higher incidence of respiratory distress, which is common in premature babies; however that didn’t seem to have any dramatic adverse effects. Of the infants operated on before birth, there were two deaths but they were unrelated to this treatment.
There were significant differences in the shunt rate of the infants treated before birth compared to those carried to term. The shunt rate was 40 per cent in the patients that were treated with in-utero surgery and 82 per cent in patients who were carried to term. Imaging performed on the infants predicted whether or not they needed a shunt. A committee determined that 96 per cent of the patients carried to term should have a shunt whereas 64 per cent of the in-utero group should have a shunt.
The Chiari malformation in the patients receiving the in-utero surgery was reduced and there was also improved mobility in the lower extremities. At thirty months, 42 percent of the in-utero group were walking versus 20 per cent in the group that were carried to term.
Although the results are promising, it is important to be cautious. There are still some significant risks for the infant and the mother, and the use of less invasive approaches should be investigated.
What’s next? A meeting will be held to discuss the issues further, and particularly treatment options for patients in Canada and across North America. Patients can be referred to the United States where there three centres that participated in the trial. There is definitely a need for probably one Canadian centre to offer this treatment.
Experts are needed in both foetal surgery and in the management of high-risk pregnancies. The paediatric neurosurgery part is less important, because it’s a fairly standard operation. The issues of obstetrics and anaesthetists seem to be much more important. And it is critical to reduce complications for the mother.
A National Institute of Health meeting was held in October to discuss the issue, within the United States, about where the surgery should be done, by whom and the physicians who will be responsible for the patients. In his concluding remarks Dr. Drake said, “I think we all believe that there is good application for improved technology to make this operation better and less risk to the mother.”
Maternal and Infant outcomes
By Mary J. Dufton
Dr. Greg Ryan is a Perinatologist at Mount Sinai Hospital, Toronto where he is in charge of the Fetal Medicine Program. He is a professor in the department of Obstetrics & Gynaecology, Division of Maternal-Fetal Medicine, University of Toronto.
Dr. Gregory Ryan, a Maternal-Fetal specialist at Mount Sinai Hospital in Toronto talked about the significant health impacts and risks for both the mother and infant from having surgery for the management of mylomeningocele. Although the surgery holds promise, further investigation is needed to examine ways to make the procedure easier and less invasive for both.
According to current figures, 1,500 babies are born each year with spina bifida. However, since Health Canada does not contribute to the data, the data, it records the official number as 240 babies per year.
Folic acid supplements are critical for reducing the incidence of neural tube defects. All pregnant women and women considering becoming pregnant should take small doses of folic acid. A woman in a higher risk group should be taking a higher dose of folic acid, ideally before she becomes pregnant or as soon as she realizes she is.
In Canada, folic acid has been added to white flour, pasta and corn meal products—since 1998. This has had a dramatic impact with a 50 per cent reduction in the incidence of neural tube defects since this initiative. Many other countries have had the same results.
Neurological conditions occur for two reasons. The first is the failure of the neural tube to form. The second is the negative effect of the amniotic fluid.
An examination of the significant health impacts of spina bifida were in the rationale for examining strategies to reduce some of the damage caused by this condition.
Obstetricians have two patients, the mother and the baby. What is done for one has many safety implications for the other. Implications for future pregnancies after the surgery have to be considered.
Dr. Ryan says that up until now, foetal surgeries were always done if the mother’s life was in danger. He thinks great strides have been made in fixing these conditions.
Although spina bifida is not a lethal condition, experts believed there was a role for the MOMS trial in improving the health effects of babies born with spina bifida. However, much scepticism remained about the role of this particular intervention.
“By fixing the lesion, can the pressure be removed to allow the brain to return to its normal state?” Dr. Ryan asked. “It’s a unique trial. There are approximately twenty-five major foetal therapy centres. There are three in Canada—Vancouver, Montreal and Toronto—and there are several in the United States. These centres are all pushing to develop new techniques.”
“The collaboration was unique because everyone else stepped back from the procedure until there was proof that it worked. Three centres were identified—California (USCF), CHOP (Children’s Hospital of Philadelphia) and Vanderbilt. The statistics would be reviewed at George Washington and overseen by the ICSD the goal was to compare the safety and effectiveness of operating on the pregnant woman compared to the standard surgery which is performed on the baby after it is born.”
Two hundred pregnant women were studied. One hundred and eighty-seven were recruited. The primary outcome was fetal or neo-natal death and then the requirement for a shunt at the age of 12. The secondary outcomes were that some of the infant’s developmental skills were affected. The results of the trial were viewed with some scepticism.
The criteria were strict. The study participant could not live outside of the United States. Women and their families were required to travel to one of the centres identified, it would be determined whether or not the surgery would take place and the baby would be followed for the first year and a half.
A very detailed evaluation took place in order to assess the parents’ suitability for the procedure. All of the imaging would be repeated; there would be various psychological testing, lots of meetings with many members of the teams in order for the parents to be well aware of what they were doing—the pros, cons and particularly the potential risks.
Up until they were discharged, the mothers who were having he surgery penatally would be admitted to the centre where the surgery would be done and those families would stay close by those centres for the whole pregnancy. The babies would be delivered at thirty-seven weeks by caesarean section, if they hadn’t gone into labour before then.
The group that were not given the intervention would return to their own centres and they would return to have their babies and the required post-natal surgery. Essentially, the country was divided into three parts. The west went to the University of San Francisco, California Medical Center, the northeast went to the Children’s Hospital of Philadelphia and the southeast went to Vanderbilt University Medical Center in Tennessee.
When the babies reached their first year, their urological and developmental functioning was studied through looking at images of their brains and spines. Further similar tests were conducted when they reached thirty months.
According to Dr. Ryan, “Over five hundred women were excluded from the trial for various reasons, which delayed the progress of the trial. It was proposed that the trial should be completed in approximately two to two and a half years time. This was a real lesson to us, as it took the best part of ten years before the trial could be finished.”
The health risks from the prenatal surgery include separation of the membrane during in-uter procedures, a reduction in amniotic fluid and resulting complications. Rupture of the membrane was almost totally restricted to the prenatal surgery and so was spontaneous premature labour.
Heart rate complications may arise during the repair, but tend to be minor because the group that has surgery would deliver at much earlier gestations than the group that did not have surgery. For every early delivery, conditions such as respiratory distress syndrome, infection, necrotizing enterocolitis, bleeding in the brain occur at a much higher rate in early deliveries. They decrease in deliveries that are closer to term.
Dr. Ryan notes that although survival is improving significantly beyond twenty-four weeks, any procedure that might cause premature delivery may be causing a problem that didn’t exist previously.
“In looking at the trial, the group that delivered early had respiratory distress syndrome. For babies that reached a year of age, all of these outcomes were worse in the post-natal surgery groups; the need for a shunt was higher in the post natal surgery, any placement of a shunt, any hindbrain herniation or any hindbrain kinking was higher in this group, which was something of a surprise. When we looked at the outcome at thirty months, there was a higher chance of that child walking independently in the prenatal surgery group.”
Prenatal surgery before twenty-six weeks decreased the risk of death or the need for shunting by the age of twelve months. Scores on both intellectual and motor function improved along with the degree of hindbrain herniation, which is associated with the Chiari II malformation and the motor dysfunction.
There is a need to be very cautious where the surgery is concerned. The potential benefits must be higher than the risk of prematurity and the risk to the mother herself. Any prenatal intervention increases the risk of pre-term births. There are risks to future pregnancies, the scar opening up and risks to the mother needing a blood transfusion. The statistics may be small, but these are major complications when they occur. And the health risks to a baby born prematurely are very significant.
Uterine rupture is potentially catastrophic and fatal for the mother and baby in a future pregnancy because whenever the abdomen is weakened there is a risk of rupture.
And the risks are known to occur with previous caesarean sections.
“There is a risk of about 0.5 per cent in future pregnancies.” Dr. Ryan says “If we do a classical caesarean section, the risks are significantly higher, over 5 per cent and the risk of a hysterectomy in future pregnancies is much higher. If the mother at sometime has uterine surgery, then this also increases the risk of the scar opening up when she is again pregnant.”
Although the trial has shown important benefits, it remains controversial as it is still in its early stages.
Although the surgery showed promise, doctors in many countries favour a much less invasive approach to repair the neural tube and minimize the risks of premature labour of the baby and future complications for the mother.
What is next for the MOMS trial? There’s research examining prenatal stem cells in the role of spina bifida. This involves taking a cell that has essentially developed and inserting it into foetal tissue at a critical period so it develops as normal tissues. There is an animal trial with three groups; one group had standard post natal care, one group had prenatal intervention and the third group had standard surgical repair with the inclusion of neuro stem cells. The group that had the neuro stem cells appeared to show some potential benefits in that the neuro stem cells took over the function of the cells that had been damaged.
Questions from the audience:
Q The developmental outcome of the MOMS study to date, and I know this is all new, has been referenced to normal development, but we have finished a five-year NIH study where babies with spina bifida were tracked every six months. An interesting and useful thing to do would be to use that developmental data and have a look at the MOMS children against the developmental study.
A I think it’s a good idea. This trial was stopped early at 187 patients because when they looked at the data, it appears the children of in-utero repair are doing much better. But there is a wealth of information and we are still reviewing the patients. Not all of them are at the thirty month outcome.
Q I’m just curious about the PH of the amniotic fluid. Does the surgery affect this?
A Good Question. What happens is that when you replace the fluid with saline, the baby replaces it in twenty-four hours with urine, which is a low PH.
Q What about the drugs in the shunt trial?
A The pH of the drugs is probably a little bit different than but it’s in 1 cc of fluid and there is about 120 cc in the brain part of the neuro system. So it’s a very small amount and it does not alter the entire PH of the brain at all. And some goes down into the peritoneal cavity, which is not such a huge issue. We’re more concerned about the potential effects of the drugs themselves on the nervous system.
Q If metabolism is out of whack, does that mean that the folic acid does not work as effectively?
A No, the use of folic acid works extremely well. We know if the mom has a baby with a neural tube defect, she is at significant risks. She can reduce that risk by 70 per cent by taking folic acid. So, it has a huge impact.
Q Just wondering what percentage are males and females with this condition?
A Of the mylomeningocele it’s an even split.
Q Does father’s folic acid level have any effect on the baby?
A We don’t know. It’s a very good question. Probably significantly dwarfed by the influence of the mom. It’s not so much folic acid at the time of conception, it’s folic acid during development, particularly that crucial fist twelve weeks.
For those of you who know about this study and saw the piece that ABS/an ABC affiliate did on it recently, what do you think, was the story done well?
Was there anything that was left out or confusing based on how it was explained?
Were there any inaccuracies in the story and how it was presented?
What do you think re the implications of the study? Does it offer hope or is there more work to be done before this procedure can be offered more widely and be used to help improve quality of life for children worldwide?