Myelomeningocele Repair Drives Changes in Fetal Surgery

Publication of results from the landmark Management of Myelomeningocele Study last year established fetal surgery as a viable option, and possibly the best option for ameliorating the complications of spina bifida.

But the Management of Myelomeningocele Study (MOMS) also appears to have had farther-reaching effects. In the 18 months since the trial results appeared (N. Engl. J. Med. 2011;364:993-1004), myelomeningocele (MMC) repair in fetuses repositioned from investigational surgery performed at just three U.S. centers to arguably standard of care that could potentially be done at whichever centers gear up to offer it. Beyond that, the possibility of effective and reasonably safe fetal MMC repair that the MOMS results documented is also proving to be a catalyst in the transformation of the still-young field of fetal surgery from an investigational, niche specialty to a more mainstream intervention.

Courtesy Children's Hospital of Philadelphia

"For many of the other [fetal surgery] interventions, there are so few cases that having more than a few centers doing them did not make sense. To have a fetal center you need a dedicated, multidisciplinary team available 24/7/365 that does a certain number of cases per year to keep up its team’s skills. For fetal surgery to be successful, it will need to be regionalized so that there is access for all patients, but also focused at centers of excellence so there is enough volume to keep skills sharp," said Dr. Mark P. Johnson, obstetrical director of the Center for Fetal Diagnosis and Treatment at the Children’s Hospital of Philadelphia (CHOP).

The MOMS result "has already had a profound effect on the treatment of MMC, on reimbursement standards for fetal intervention, and has defined how fetal surgery centers should be organized and staffed across the United States," wrote Dr. Shinjiro Hirose, a fetal surgeon at the University of California, San Francisco (UCSF), and his associates in an article on maternal-fetal surgery that appeared in June (Clin. Perinatology 2012;39:269-78).

Growing fetal-intervention options also put unprecedented responsibility on the physicians who provide primary obstetrical care to identify pregnancies early that may have an anomaly that’s amenable to surgical intervention and make an appropriate referral so that the disorder can be confirmed and intervention offered if it is possible.

Growing Numbers of MMC Repairs and Other Fetal Surgeries

Although the exact number of fetal MMC repairs done in the United States during the 18 months since publication of the MOMS results is hard to pin down, experts estimate roughly 80 surgeries occurred during April 2011-March 2012. They project as many as 100 or more being done in 2012, with about eight U.S. centers now offering the surgery, including the three centers that participated in MOMS and another five or so that have begun performing the procedure since the results were announced.

The other "high volume" fetal surgery now done is fetoscopic laser ablation of communicating vessels on the placental chorionic plate in monochorionic twin pregnancies that develop Twin-Twin transfusion syndrome (TTTS), which first became established as standard of care in 2004 (N. Engl. J. Med. 2004;351:136-44). It is now widely accepted as the preferred option in these cases, done on upward of 500 U.S. pregnancies a year. When the annualized rate of 600+ MMC repairs and laser ablations for TTTS couples with various low-volume fetal surgeries done for selected, rare anomalies, U.S. fetal surgery is on track this year to treat some 700-1,000 cases, and this number will likely rise substantially in the near future. The current, annual U.S. incidence of spina bifida in fetuses is about 2,500 (with about 1,500 infants born with MMC each year), suggesting that as fetal MMC repair becomes more widely accepted and performed, the number of U.S. surgeries for this indication could eventually run into several hundred a year.

Planning for Fetal MMC Repairs After MOMS

Driven primarily by concerns about how the MOMS results would translate into routine practice, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the agency that sponsored MOMS, organized an expert panel with representatives from 11 U.S. professional and patient groups to come up with recommendations on which centers should perform fetal MMC repairs and the clinical issues that the teams at each center should address. Participants came from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the American Institute of Ultrasound in Medicine, the Society for Maternal-Fetal Medicine, the Spina Bifida Association, and six other groups.

Formal publication of these recommendations had not occurred yet but was expected before the end of 2012. The article by Dr. Hirose and his coauthors provided a preview of some of the panel’s key recommendations, including a minimum annual volume of at least five MMC repairs as well as at least 30 fetuses with MMC evaluated for surgery; strict adherence to the MOMS protocol until improvements are proven better; comprehensive counseling that includes a reflective period for families of at least 24 hours; and participation in a national registry.

That article was removed from Clinics in Perinatology in early October at the request of the publication’s consulting editor.

According to a note on the publica­tion’s website, "It was learned after pub­lication that the guidelines for fetal repair of myelomeningocele that were pre­sented as being published by the NIH were neither supplied by the NIH nor published by them. To prevent this in­formation from being erroneously cit­ed, the article has been removed."

At press time, the article was still ac­cessible via the National Library of Med­icine’s PubMed.gov.*

Having a U.S. agency sponsor a major trial and then organize an expert panel to deliberate on how to best implement its results is unusual, but fetal MMC repair is unusual surgery, said Dr. Julie S. Moldenhauer, a maternal-fetal medicine physician and a representative to the NICHD panel appointed by the North American Fetal Therapy Network. "It is very high-risk surgery that is elective, it is an open procedure, not fetoscopic, and it depends on a very multidisciplinary team," she said in an interview. These are a combination of features that makes it unique, said Dr. Moldenhauer, who is an attending physician at the Center for Fetal Diagnosis and Treatment and the medical director of the special delivery unit, both at CHOP.

One other element of MOMS also adds to its special character: The trial lasted nearly 8 years and randomized just 183 patients, and during that time fetal MMC repair for U.S. patients was limited to three centers – CHOP, UCSF, and Vanderbilt University in Nashville, Tenn. Then, when the researchers reported their positive results last year, NICHD officials and others in this field faced the dilemma of how to make the surgery available elsewhere while ensuring that the results would be as good as in MOMS. "What the NICHD fears is that if MMC repair is offered uncontrolled, the outcomes won’t be what they were in MOMS," said Dr. Johnson.

Making Fetal MMC Repair Better

MMC repair is not easy and still has limitations, most notably the risk for extreme prematurity. "The risk of prematurity is the big obstacle to making it more mainstream," said Dr. Noel B. Tulipan, professor and director of pediatric neurosurgery at Vanderbilt University Medical Center.

Most fetuses treated in MOMS were delivered at 34 weeks’ gestation or later, and "these days, we almost don’t consider 34 weeks premature, because most of these babies do extremely well," Dr. Tulipan said in an interview. "But in MOMS, there was a 13% rate of extreme prematurity" with the infants delivered at less than 30 weeks.

This limitation is improving. The challenge, he said, is the incision and closure of the uterus. Dr. Tulipan and his colleagues have recently given increased attention to suturing the amniotic membranes to prevent them from separating from the uterine wall "With this change, our results have gotten substantially better. We’re getting to a rate that could make it mainstream. If the [extreme] prematurity rate was less than 5%, it would be hard to argue against this surgery."

Fetal MMC repair "will continue to grow, but not by an order of magnitude until there is a new technique that could be offered earlier in gestation and in a minimally-invasive way," said Dr. N. Scott Adzick, surgeon in chief and director of the Center for Fetal Diagnosis and Treatment at CHOP. Currently, MMC repairs are done at 20 weeks’-25 weeks’ 6 days gestation. His group at CHOP, as well as others, is also trying to perfect less-invasive approaches. "We are working on a tissue-engineering approach to seal the MMC defect before birth, and thus prevent exposure of the spinal cord to damaging amniotic fluid, and also prevent leakage of the cerebrospinal fluid from the spina bifida. CSF leakage is the underlying cause of hindbrain herniation and hydrocephalus seen with spina bifida. The goal is for this tissue-engineered component to be introduced through a single fetoscopic port or through an amniocentesis needle under sonographic guidance," Dr. Adzick said.

The risk of prematurity, as well as potential complications for the mother, means that centers offering fetal MMC repair provide extensive counseling for potential parents. "We are proud of the fact that over half of our families decide not to have prenatal surgery after the counseling," said Dr. Hanmin Lee, professor and chief of pediatric surgery at UCSF, and one of the leaders of that center’s MMC fetal repair program.

At CHOP, during the first year after the MOMS publication 238 pregnancies underwent evaluation, with 137 making it to a more extensive stage of assessment. Of these, 40 mothers (29%) underwent fetal MMC repair, Dr. Adzick said.

At Cincinnati Children’s Hospital, which began offering fetal MMC repairs following publication of the MOMS results, the winnowing was about as sharp as at CHOP. Since the program began, the Cincinnati team evaluated 53 pregnancies and performed 10 repairs, said Dr. Foong-Yen Lim, surgical director of the Fetal Care Center there. A handful of these patients who were first seen at Cincinnati decided to travel to Vanderbilt or CHOP instead for the surgery and thereby take advantage of the greater experience those centers offered.

That sentiment underscores a challenge faced by the programs that are trying to establish themselves as new options for fetal MMC repair, as the procedure rolls out post-MOMS.

"There is nothing wrong with patients going to a higher-volume center; they know that their outcome will be close to what is available today, compared with new centers that have not done as many of these procedures," Dr. Lim said in an interview. "Patients should hear the options and pick what’s best for them, not just whether to choose the procedure, but also to decide where to go. The reason why MOMS had such difficulty recruiting patients was that they had to uproot themselves to go to a MMC repair center, and a lot of patients decided not to go.

"Regionalization is the future. Spina bifida is one of the most common birth defects, so there is a large number of cases that could benefit" from fetal repair. But what does it mean to be a fetal surgery center, and what does it require," said CHOP’s Dr. Johnson. "These are the ideas that the fetal surgery community is struggling with and trying to address. The big question is which will be the centers of excellence. The first step toward answering this will be to see whether the new centers can replicate the MOMS results, he added.

Spreading the Word About Fetal Surgery

Another key element in growing fetal MMC repair, and fetal surgeries of all types, is boosting awareness of repair options among primary care obstetrical providers and making referrals more timely.

"The market is controlled by the number of physicians who are aware of surgical interventions," said Dr. Mark I. Evans, a clinical professor of obstetrics, gynecology, and reproductive services at Mount Sinai Medical Center in New York. "The number of anomalies that are potentially amenable to treatment is a small percent of all pregnancies, but with more than 4 million U.S. births per year, it adds up to a fairly substantial number."

Fetal interventions "are accepted therapies; in the fetal community, I don’t think anyone thinks they are still investigational. But the number of cases is small, and a lot of the people who are diagnosing these may not be aware of how successful a lot of the procedures are," said Dr. Johnson.

"Obstetricians and maternal-fetal medicine physicians need to be more aware of what we can do. Our biggest challenge is to disseminate the information. The treatments are safe and effective, and families should at least have the option of going to centers to get more information and make informed decisions."

In addition, "screening ultrasound at between 18 to 20 weeks would be a great thing," he added.

"In the United States, ultrasound screening is becoming more the standard of care, but a lot of screening is not done until 22 or 23 weeks, often too late for patients to be referred to fetal treatment centers for evaluations before 24 weeks so that the option of termination is often no longer available to them. Also, with some anomalies irreversible damage has already occurred by 24 weeks so that fetal therapy would not help. In cases of lower urinary tract obstructions, well over half the cases we see are too late to offer therapy. It is recognized that screening at 19-20 weeks won’t pick up all anomalies, but it would pick up a lot of major anomalies," Dr. Johnson said.

A Fetal Surgery Checklist

Aside from myelomeningocele repair, placental laser ablation in cases of severe twin-twin transfusion syndrome is the fetal surgery with the best evidence base and, for now, it’s also the most frequently performed fetal surgery, although experts say it’s also underused.

"The success story of fetal surgery is laser ablation for TTTS," said Dr. Francois I. Luks, director of the Fetal Treatment Program at Hasbro Children’s Hospital in Providence, R.I. "Left untreated, severe TTTS leads to greater than 80% dual mortality. With laser surgery, survival of at least one twin is in excess of 80%."

First established as a good alternative to standard amnioreduction therapy in a 2004 randomized trial (N. Engl. J. Med. 2004;351:136-44), placental laser ablation has since become standard-of-care for TTTS.

"More and more groups are taking [laser ablation for TTTS] on because they believe they should provide it to patients," and it currently is available at about 30 U.S. centers, said Dr. Lim. "The maternal risk [from placental laser ablation] is acceptable and the outcomes are quite good. But some cases [of TTTS] are still being misdiagnosed," he said.

"Awareness is more widespread, but not at the rate it should be. We still have patients who are not referred until something bad happens," Dr. Lim said in an interview.

In Cincinnati alone, the program does more than 100 placental laser ablations each year, he added.

About 80 per year are performed at CHOP, and roughly 300-400 per year total at the 24 U.S. and Canadian centers that form the North American Fetal Therapy Network (NAFTNet), said Dr. Luks. (CHOP and Cincinnati Children’s are members of NAFTNet.) At least two other U.S. centers not in NAFTNet do more than 100 laser ablations each annually, and several other hospitals outside of NAFTNet do smaller numbers yearly, which means that while the current annual U.S. volume of these cases is uncertain it easily exceeds 500, Dr. Luks said.

All the other fetal surgeries each occur in fewer than about 50 U.S. cases a year, are available at fewer U.S. centers and, in some cases, have a checkered history of success and failure although today several are considered effective, relatively safe, and standard therapy.

The third most-common fetal surgery, based on NAFTNet records, are various types of selective umbilical cord occlusions in twin pregnancies, for reasons such as intrauterine growth retardation, placental insufficiency, and other situations in which problems with one twin puts a healthy twin at risk, said Dr. Johnson.

Dr. Johnson, Dr. Hirose, Dr. Adzick, Dr. Moldenhauer, Dr. Lee, Dr. Tulipan, Dr. Lim, and Dr. Evans all said that they had no relevant financial disclosures.

* This story was updated on 10/3/1012.

Publication of results from the landmark Management of Myelomeningocele Study last year established fetal surgery as a viable option, and possibly the best option for ameliorating the complications of spina bifida.

But the Management of Myelomeningocele Study (MOMS) also appears to have had farther-reaching effects. In the 18 months since the trial results appeared (N. Engl. J. Med. 2011;364:993-1004), myelomeningocele (MMC) repair in fetuses repositioned from investigational surgery performed at just three U.S. centers to arguably standard of care that could potentially be done at whichever centers gear up to offer it. Beyond that, the possibility of effective and reasonably safe fetal MMC repair that the MOMS results documented is also proving to be a catalyst in the transformation of the still-young field of fetal surgery from an investigational, niche specialty to a more mainstream intervention.

Courtesy Children's Hospital of Philadelphia

"For many of the other [fetal surgery] interventions, there are so few cases that having more than a few centers doing them did not make sense. To have a fetal center you need a dedicated, multidisciplinary team available 24/7/365 that does a certain number of cases per year to keep up its team’s skills. For fetal surgery to be successful, it will need to be regionalized so that there is access for all patients, but also focused at centers of excellence so there is enough volume to keep skills sharp," said Dr. Mark P. Johnson, obstetrical director of the Center for Fetal Diagnosis and Treatment at the Children’s Hospital of Philadelphia (CHOP).

The MOMS result "has already had a profound effect on the treatment of MMC, on reimbursement standards for fetal intervention, and has defined how fetal surgery centers should be organized and staffed across the United States," wrote Dr. Shinjiro Hirose, a fetal surgeon at the University of California, San Francisco (UCSF), and his associates in an article on maternal-fetal surgery that appeared in June (Clin. Perinatology 2012;39:269-78).

Growing fetal-intervention options also put unprecedented responsibility on the physicians who provide primary obstetrical care to identify pregnancies early that may have an anomaly that’s amenable to surgical intervention and make an appropriate referral so that the disorder can be confirmed and intervention offered if it is possible.

Growing Numbers of MMC Repairs and Other Fetal Surgeries

Although the exact number of fetal MMC repairs done in the United States during the 18 months since publication of the MOMS results is hard to pin down, experts estimate roughly 80 surgeries occurred during April 2011-March 2012. They project as many as 100 or more being done in 2012, with about eight U.S. centers now offering the surgery, including the three centers that participated in MOMS and another five or so that have begun performing the procedure since the results were announced.

The other "high volume" fetal surgery now done is fetoscopic laser ablation of communicating vessels on the placental chorionic plate in monochorionic twin pregnancies that develop Twin-Twin transfusion syndrome (TTTS), which first became established as standard of care in 2004 (N. Engl. J. Med. 2004;351:136-44). It is now widely accepted as the preferred option in these cases, done on upward of 500 U.S. pregnancies a year. When the annualized rate of 600+ MMC repairs and laser ablations for TTTS couples with various low-volume fetal surgeries done for selected, rare anomalies, U.S. fetal surgery is on track this year to treat some 700-1,000 cases, and this number will likely rise substantially in the near future. The current, annual U.S. incidence of spina bifida in fetuses is about 2,500 (with about 1,500 infants born with MMC each year), suggesting that as fetal MMC repair becomes more widely accepted and performed, the number of U.S. surgeries for this indication could eventually run into several hundred a year.

Planning for Fetal MMC Repairs After MOMS

Driven primarily by concerns about how the MOMS results would translate into routine practice, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the agency that sponsored MOMS, organized an expert panel with representatives from 11 U.S. professional and patient groups to come up with recommendations on which centers should perform fetal MMC repairs and the clinical issues that the teams at each center should address. Participants came from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the American Institute of Ultrasound in Medicine, the Society for Maternal-Fetal Medicine, the Spina Bifida Association, and six other groups.

Formal publication of these recommendations had not occurred yet but was expected before the end of 2012. The article by Dr. Hirose and his coauthors provided a preview of some of the panel’s key recommendations, including a minimum annual volume of at least five MMC repairs as well as at least 30 fetuses with MMC evaluated for surgery; strict adherence to the MOMS protocol until improvements are proven better; comprehensive counseling that includes a reflective period for families of at least 24 hours; and participation in a national registry.

That article was removed from Clinics in Perinatology in early October at the request of the publication’s consulting editor.

According to a note on the publica­tion’s website, "It was learned after pub­lication that the guidelines for fetal repair of myelomeningocele that were pre­sented as being published by the NIH were neither supplied by the NIH nor published by them. To prevent this in­formation from being erroneously cit­ed, the article has been removed."

At press time, the article was still ac­cessible via the National Library of Med­icine’s PubMed.gov.*

Having a U.S. agency sponsor a major trial and then organize an expert panel to deliberate on how to best implement its results is unusual, but fetal MMC repair is unusual surgery, said Dr. Julie S. Moldenhauer, a maternal-fetal medicine physician and a representative to the NICHD panel appointed by the North American Fetal Therapy Network. "It is very high-risk surgery that is elective, it is an open procedure, not fetoscopic, and it depends on a very multidisciplinary team," she said in an interview. These are a combination of features that makes it unique, said Dr. Moldenhauer, who is an attending physician at the Center for Fetal Diagnosis and Treatment and the medical director of the special delivery unit, both at CHOP.

One other element of MOMS also adds to its special character: The trial lasted nearly 8 years and randomized just 183 patients, and during that time fetal MMC repair for U.S. patients was limited to three centers – CHOP, UCSF, and Vanderbilt University in Nashville, Tenn. Then, when the researchers reported their positive results last year, NICHD officials and others in this field faced the dilemma of how to make the surgery available elsewhere while ensuring that the results would be as good as in MOMS. "What the NICHD fears is that if MMC repair is offered uncontrolled, the outcomes won’t be what they were in MOMS," said Dr. Johnson.

Making Fetal MMC Repair Better

MMC repair is not easy and still has limitations, most notably the risk for extreme prematurity. "The risk of prematurity is the big obstacle to making it more mainstream," said Dr. Noel B. Tulipan, professor and director of pediatric neurosurgery at Vanderbilt University Medical Center.

Most fetuses treated in MOMS were delivered at 34 weeks’ gestation or later, and "these days, we almost don’t consider 34 weeks premature, because most of these babies do extremely well," Dr. Tulipan said in an interview. "But in MOMS, there was a 13% rate of extreme prematurity" with the infants delivered at less than 30 weeks.

This limitation is improving. The challenge, he said, is the incision and closure of the uterus. Dr. Tulipan and his colleagues have recently given increased attention to suturing the amniotic membranes to prevent them from separating from the uterine wall "With this change, our results have gotten substantially better. We’re getting to a rate that could make it mainstream. If the [extreme] prematurity rate was less than 5%, it would be hard to argue against this surgery."

Fetal MMC repair "will continue to grow, but not by an order of magnitude until there is a new technique that could be offered earlier in gestation and in a minimally-invasive way," said Dr. N. Scott Adzick, surgeon in chief and director of the Center for Fetal Diagnosis and Treatment at CHOP. Currently, MMC repairs are done at 20 weeks’-25 weeks’ 6 days gestation. His group at CHOP, as well as others, is also trying to perfect less-invasive approaches. "We are working on a tissue-engineering approach to seal the MMC defect before birth, and thus prevent exposure of the spinal cord to damaging amniotic fluid, and also prevent leakage of the cerebrospinal fluid from the spina bifida. CSF leakage is the underlying cause of hindbrain herniation and hydrocephalus seen with spina bifida. The goal is for this tissue-engineered component to be introduced through a single fetoscopic port or through an amniocentesis needle under sonographic guidance," Dr. Adzick said.

The risk of prematurity, as well as potential complications for the mother, means that centers offering fetal MMC repair provide extensive counseling for potential parents. "We are proud of the fact that over half of our families decide not to have prenatal surgery after the counseling," said Dr. Hanmin Lee, professor and chief of pediatric surgery at UCSF, and one of the leaders of that center’s MMC fetal repair program.

At CHOP, during the first year after the MOMS publication 238 pregnancies underwent evaluation, with 137 making it to a more extensive stage of assessment. Of these, 40 mothers (29%) underwent fetal MMC repair, Dr. Adzick said.

At Cincinnati Children’s Hospital, which began offering fetal MMC repairs following publication of the MOMS results, the winnowing was about as sharp as at CHOP. Since the program began, the Cincinnati team evaluated 53 pregnancies and performed 10 repairs, said Dr. Foong-Yen Lim, surgical director of the Fetal Care Center there. A handful of these patients who were first seen at Cincinnati decided to travel to Vanderbilt or CHOP instead for the surgery and thereby take advantage of the greater experience those centers offered.

That sentiment underscores a challenge faced by the programs that are trying to establish themselves as new options for fetal MMC repair, as the procedure rolls out post-MOMS.

"There is nothing wrong with patients going to a higher-volume center; they know that their outcome will be close to what is available today, compared with new centers that have not done as many of these procedures," Dr. Lim said in an interview. "Patients should hear the options and pick what’s best for them, not just whether to choose the procedure, but also to decide where to go. The reason why MOMS had such difficulty recruiting patients was that they had to uproot themselves to go to a MMC repair center, and a lot of patients decided not to go.

"Regionalization is the future. Spina bifida is one of the most common birth defects, so there is a large number of cases that could benefit" from fetal repair. But what does it mean to be a fetal surgery center, and what does it require," said CHOP’s Dr. Johnson. "These are the ideas that the fetal surgery community is struggling with and trying to address. The big question is which will be the centers of excellence. The first step toward answering this will be to see whether the new centers can replicate the MOMS results, he added.

Spreading the Word About Fetal Surgery

Another key element in growing fetal MMC repair, and fetal surgeries of all types, is boosting awareness of repair options among primary care obstetrical providers and making referrals more timely.

"The market is controlled by the number of physicians who are aware of surgical interventions," said Dr. Mark I. Evans, a clinical professor of obstetrics, gynecology, and reproductive services at Mount Sinai Medical Center in New York. "The number of anomalies that are potentially amenable to treatment is a small percent of all pregnancies, but with more than 4 million U.S. births per year, it adds up to a fairly substantial number."

Fetal interventions "are accepted therapies; in the fetal community, I don’t think anyone thinks they are still investigational. But the number of cases is small, and a lot of the people who are diagnosing these may not be aware of how successful a lot of the procedures are," said Dr. Johnson.

"Obstetricians and maternal-fetal medicine physicians need to be more aware of what we can do. Our biggest challenge is to disseminate the information. The treatments are safe and effective, and families should at least have the option of going to centers to get more information and make informed decisions."

In addition, "screening ultrasound at between 18 to 20 weeks would be a great thing," he added.

"In the United States, ultrasound screening is becoming more the standard of care, but a lot of screening is not done until 22 or 23 weeks, often too late for patients to be referred to fetal treatment centers for evaluations before 24 weeks so that the option of termination is often no longer available to them. Also, with some anomalies irreversible damage has already occurred by 24 weeks so that fetal therapy would not help. In cases of lower urinary tract obstructions, well over half the cases we see are too late to offer therapy. It is recognized that screening at 19-20 weeks won’t pick up all anomalies, but it would pick up a lot of major anomalies," Dr. Johnson said.

A Fetal Surgery Checklist

Aside from myelomeningocele repair, placental laser ablation in cases of severe twin-twin transfusion syndrome is the fetal surgery with the best evidence base and, for now, it’s also the most frequently performed fetal surgery, although experts say it’s also underused.

"The success story of fetal surgery is laser ablation for TTTS," said Dr. Francois I. Luks, director of the Fetal Treatment Program at Hasbro Children’s Hospital in Providence, R.I. "Left untreated, severe TTTS leads to greater than 80% dual mortality. With laser surgery, survival of at least one twin is in excess of 80%."

First established as a good alternative to standard amnioreduction therapy in a 2004 randomized trial (N. Engl. J. Med. 2004;351:136-44), placental laser ablation has since become standard-of-care for TTTS.

"More and more groups are taking [laser ablation for TTTS] on because they believe they should provide it to patients," and it currently is available at about 30 U.S. centers, said Dr. Lim. "The maternal risk [from placental laser ablation] is acceptable and the outcomes are quite good. But some cases [of TTTS] are still being misdiagnosed," he said.

"Awareness is more widespread, but not at the rate it should be. We still have patients who are not referred until something bad happens," Dr. Lim said in an interview.

In Cincinnati alone, the program does more than 100 placental laser ablations each year, he added.

About 80 per year are performed at CHOP, and roughly 300-400 per year total at the 24 U.S. and Canadian centers that form the North American Fetal Therapy Network (NAFTNet), said Dr. Luks. (CHOP and Cincinnati Children’s are members of NAFTNet.) At least two other U.S. centers not in NAFTNet do more than 100 laser ablations each annually, and several other hospitals outside of NAFTNet do smaller numbers yearly, which means that while the current annual U.S. volume of these cases is uncertain it easily exceeds 500, Dr. Luks said.

All the other fetal surgeries each occur in fewer than about 50 U.S. cases a year, are available at fewer U.S. centers and, in some cases, have a checkered history of success and failure although today several are considered effective, relatively safe, and standard therapy.

The third most-common fetal surgery, based on NAFTNet records, are various types of selective umbilical cord occlusions in twin pregnancies, for reasons such as intrauterine growth retardation, placental insufficiency, and other situations in which problems with one twin puts a healthy twin at risk, said Dr. Johnson.

Dr. Johnson, Dr. Hirose, Dr. Adzick, Dr. Moldenhauer, Dr. Lee, Dr. Tulipan, Dr. Lim, and Dr. Evans all said that they had no relevant financial disclosures.

* This story was updated on 10/3/1012.

Publication of results from the landmark Management of Myelomeningocele Study last year established fetal surgery as a viable option, and possibly the best option for ameliorating the complications of spina bifida.

But the Management of Myelomeningocele Study (MOMS) also appears to have had farther-reaching effects. In the 18 months since the trial results appeared (N. Engl. J. Med. 2011;364:993-1004), myelomeningocele (MMC) repair in fetuses repositioned from investigational surgery performed at just three U.S. centers to arguably standard of care that could potentially be done at whichever centers gear up to offer it. Beyond that, the possibility of effective and reasonably safe fetal MMC repair that the MOMS results documented is also proving to be a catalyst in the transformation of the still-young field of fetal surgery from an investigational, niche specialty to a more mainstream intervention.

Courtesy Children's Hospital of Philadelphia

"For many of the other [fetal surgery] interventions, there are so few cases that having more than a few centers doing them did not make sense. To have a fetal center you need a dedicated, multidisciplinary team available 24/7/365 that does a certain number of cases per year to keep up its team’s skills. For fetal surgery to be successful, it will need to be regionalized so that there is access for all patients, but also focused at centers of excellence so there is enough volume to keep skills sharp," said Dr. Mark P. Johnson, obstetrical director of the Center for Fetal Diagnosis and Treatment at the Children’s Hospital of Philadelphia (CHOP).

The MOMS result "has already had a profound effect on the treatment of MMC, on reimbursement standards for fetal intervention, and has defined how fetal surgery centers should be organized and staffed across the United States," wrote Dr. Shinjiro Hirose, a fetal surgeon at the University of California, San Francisco (UCSF), and his associates in an article on maternal-fetal surgery that appeared in June (Clin. Perinatology 2012;39:269-78).

Growing fetal-intervention options also put unprecedented responsibility on the physicians who provide primary obstetrical care to identify pregnancies early that may have an anomaly that’s amenable to surgical intervention and make an appropriate referral so that the disorder can be confirmed and intervention offered if it is possible.

Growing Numbers of MMC Repairs and Other Fetal Surgeries

Although the exact number of fetal MMC repairs done in the United States during the 18 months since publication of the MOMS results is hard to pin down, experts estimate roughly 80 surgeries occurred during April 2011-March 2012. They project as many as 100 or more being done in 2012, with about eight U.S. centers now offering the surgery, including the three centers that participated in MOMS and another five or so that have begun performing the procedure since the results were announced.

The other "high volume" fetal surgery now done is fetoscopic laser ablation of communicating vessels on the placental chorionic plate in monochorionic twin pregnancies that develop Twin-Twin transfusion syndrome (TTTS), which first became established as standard of care in 2004 (N. Engl. J. Med. 2004;351:136-44). It is now widely accepted as the preferred option in these cases, done on upward of 500 U.S. pregnancies a year. When the annualized rate of 600+ MMC repairs and laser ablations for TTTS couples with various low-volume fetal surgeries done for selected, rare anomalies, U.S. fetal surgery is on track this year to treat some 700-1,000 cases, and this number will likely rise substantially in the near future. The current, annual U.S. incidence of spina bifida in fetuses is about 2,500 (with about 1,500 infants born with MMC each year), suggesting that as fetal MMC repair becomes more widely accepted and performed, the number of U.S. surgeries for this indication could eventually run into several hundred a year.

Planning for Fetal MMC Repairs After MOMS

Driven primarily by concerns about how the MOMS results would translate into routine practice, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the agency that sponsored MOMS, organized an expert panel with representatives from 11 U.S. professional and patient groups to come up with recommendations on which centers should perform fetal MMC repairs and the clinical issues that the teams at each center should address. Participants came from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the American Institute of Ultrasound in Medicine, the Society for Maternal-Fetal Medicine, the Spina Bifida Association, and six other groups.

Formal publication of these recommendations had not occurred yet but was expected before the end of 2012. The article by Dr. Hirose and his coauthors provided a preview of some of the panel’s key recommendations, including a minimum annual volume of at least five MMC repairs as well as at least 30 fetuses with MMC evaluated for surgery; strict adherence to the MOMS protocol until improvements are proven better; comprehensive counseling that includes a reflective period for families of at least 24 hours; and participation in a national registry.

That article was removed from Clinics in Perinatology in early October at the request of the publication’s consulting editor.

According to a note on the publica­tion’s website, "It was learned after pub­lication that the guidelines for fetal repair of myelomeningocele that were pre­sented as being published by the NIH were neither supplied by the NIH nor published by them. To prevent this in­formation from being erroneously cit­ed, the article has been removed."

At press time, the article was still ac­cessible via the National Library of Med­icine’s PubMed.gov.*

Having a U.S. agency sponsor a major trial and then organize an expert panel to deliberate on how to best implement its results is unusual, but fetal MMC repair is unusual surgery, said Dr. Julie S. Moldenhauer, a maternal-fetal medicine physician and a representative to the NICHD panel appointed by the North American Fetal Therapy Network. "It is very high-risk surgery that is elective, it is an open procedure, not fetoscopic, and it depends on a very multidisciplinary team," she said in an interview. These are a combination of features that makes it unique, said Dr. Moldenhauer, who is an attending physician at the Center for Fetal Diagnosis and Treatment and the medical director of the special delivery unit, both at CHOP.

One other element of MOMS also adds to its special character: The trial lasted nearly 8 years and randomized just 183 patients, and during that time fetal MMC repair for U.S. patients was limited to three centers – CHOP, UCSF, and Vanderbilt University in Nashville, Tenn. Then, when the researchers reported their positive results last year, NICHD officials and others in this field faced the dilemma of how to make the surgery available elsewhere while ensuring that the results would be as good as in MOMS. "What the NICHD fears is that if MMC repair is offered uncontrolled, the outcomes won’t be what they were in MOMS," said Dr. Johnson.

Making Fetal MMC Repair Better

MMC repair is not easy and still has limitations, most notably the risk for extreme prematurity. "The risk of prematurity is the big obstacle to making it more mainstream," said Dr. Noel B. Tulipan, professor and director of pediatric neurosurgery at Vanderbilt University Medical Center.

Most fetuses treated in MOMS were delivered at 34 weeks’ gestation or later, and "these days, we almost don’t consider 34 weeks premature, because most of these babies do extremely well," Dr. Tulipan said in an interview. "But in MOMS, there was a 13% rate of extreme prematurity" with the infants delivered at less than 30 weeks.

This limitation is improving. The challenge, he said, is the incision and closure of the uterus. Dr. Tulipan and his colleagues have recently given increased attention to suturing the amniotic membranes to prevent them from separating from the uterine wall "With this change, our results have gotten substantially better. We’re getting to a rate that could make it mainstream. If the [extreme] prematurity rate was less than 5%, it would be hard to argue against this surgery."

Fetal MMC repair "will continue to grow, but not by an order of magnitude until there is a new technique that could be offered earlier in gestation and in a minimally-invasive way," said Dr. N. Scott Adzick, surgeon in chief and director of the Center for Fetal Diagnosis and Treatment at CHOP. Currently, MMC repairs are done at 20 weeks’-25 weeks’ 6 days gestation. His group at CHOP, as well as others, is also trying to perfect less-invasive approaches. "We are working on a tissue-engineering approach to seal the MMC defect before birth, and thus prevent exposure of the spinal cord to damaging amniotic fluid, and also prevent leakage of the cerebrospinal fluid from the spina bifida. CSF leakage is the underlying cause of hindbrain herniation and hydrocephalus seen with spina bifida. The goal is for this tissue-engineered component to be introduced through a single fetoscopic port or through an amniocentesis needle under sonographic guidance," Dr. Adzick said.

The risk of prematurity, as well as potential complications for the mother, means that centers offering fetal MMC repair provide extensive counseling for potential parents. "We are proud of the fact that over half of our families decide not to have prenatal surgery after the counseling," said Dr. Hanmin Lee, professor and chief of pediatric surgery at UCSF, and one of the leaders of that center’s MMC fetal repair program.

At CHOP, during the first year after the MOMS publication 238 pregnancies underwent evaluation, with 137 making it to a more extensive stage of assessment. Of these, 40 mothers (29%) underwent fetal MMC repair, Dr. Adzick said.

At Cincinnati Children’s Hospital, which began offering fetal MMC repairs following publication of the MOMS results, the winnowing was about as sharp as at CHOP. Since the program began, the Cincinnati team evaluated 53 pregnancies and performed 10 repairs, said Dr. Foong-Yen Lim, surgical director of the Fetal Care Center there. A handful of these patients who were first seen at Cincinnati decided to travel to Vanderbilt or CHOP instead for the surgery and thereby take advantage of the greater experience those centers offered.

That sentiment underscores a challenge faced by the programs that are trying to establish themselves as new options for fetal MMC repair, as the procedure rolls out post-MOMS.

"There is nothing wrong with patients going to a higher-volume center; they know that their outcome will be close to what is available today, compared with new centers that have not done as many of these procedures," Dr. Lim said in an interview. "Patients should hear the options and pick what’s best for them, not just whether to choose the procedure, but also to decide where to go. The reason why MOMS had such difficulty recruiting patients was that they had to uproot themselves to go to a MMC repair center, and a lot of patients decided not to go.

"Regionalization is the future. Spina bifida is one of the most common birth defects, so there is a large number of cases that could benefit" from fetal repair. But what does it mean to be a fetal surgery center, and what does it require," said CHOP’s Dr. Johnson. "These are the ideas that the fetal surgery community is struggling with and trying to address. The big question is which will be the centers of excellence. The first step toward answering this will be to see whether the new centers can replicate the MOMS results, he added.

Spreading the Word About Fetal Surgery

Another key element in growing fetal MMC repair, and fetal surgeries of all types, is boosting awareness of repair options among primary care obstetrical providers and making referrals more timely.

"The market is controlled by the number of physicians who are aware of surgical interventions," said Dr. Mark I. Evans, a clinical professor of obstetrics, gynecology, and reproductive services at Mount Sinai Medical Center in New York. "The number of anomalies that are potentially amenable to treatment is a small percent of all pregnancies, but with more than 4 million U.S. births per year, it adds up to a fairly substantial number."

Fetal interventions "are accepted therapies; in the fetal community, I don’t think anyone thinks they are still investigational. But the number of cases is small, and a lot of the people who are diagnosing these may not be aware of how successful a lot of the procedures are," said Dr. Johnson.

"Obstetricians and maternal-fetal medicine physicians need to be more aware of what we can do. Our biggest challenge is to disseminate the information. The treatments are safe and effective, and families should at least have the option of going to centers to get more information and make informed decisions."

In addition, "screening ultrasound at between 18 to 20 weeks would be a great thing," he added.

"In the United States, ultrasound screening is becoming more the standard of care, but a lot of screening is not done until 22 or 23 weeks, often too late for patients to be referred to fetal treatment centers for evaluations before 24 weeks so that the option of termination is often no longer available to them. Also, with some anomalies irreversible damage has already occurred by 24 weeks so that fetal therapy would not help. In cases of lower urinary tract obstructions, well over half the cases we see are too late to offer therapy. It is recognized that screening at 19-20 weeks won’t pick up all anomalies, but it would pick up a lot of major anomalies," Dr. Johnson said.

A Fetal Surgery Checklist

Aside from myelomeningocele repair, placental laser ablation in cases of severe twin-twin transfusion syndrome is the fetal surgery with the best evidence base and, for now, it’s also the most frequently performed fetal surgery, although experts say it’s also underused.

"The success story of fetal surgery is laser ablation for TTTS," said Dr. Francois I. Luks, director of the Fetal Treatment Program at Hasbro Children’s Hospital in Providence, R.I. "Left untreated, severe TTTS leads to greater than 80% dual mortality. With laser surgery, survival of at least one twin is in excess of 80%."

First established as a good alternative to standard amnioreduction therapy in a 2004 randomized trial (N. Engl. J. Med. 2004;351:136-44), placental laser ablation has since become standard-of-care for TTTS.

"More and more groups are taking [laser ablation for TTTS] on because they believe they should provide it to patients," and it currently is available at about 30 U.S. centers, said Dr. Lim. "The maternal risk [from placental laser ablation] is acceptable and the outcomes are quite good. But some cases [of TTTS] are still being misdiagnosed," he said.

"Awareness is more widespread, but not at the rate it should be. We still have patients who are not referred until something bad happens," Dr. Lim said in an interview.

In Cincinnati alone, the program does more than 100 placental laser ablations each year, he added.

About 80 per year are performed at CHOP, and roughly 300-400 per year total at the 24 U.S. and Canadian centers that form the North American Fetal Therapy Network (NAFTNet), said Dr. Luks. (CHOP and Cincinnati Children’s are members of NAFTNet.) At least two other U.S. centers not in NAFTNet do more than 100 laser ablations each annually, and several other hospitals outside of NAFTNet do smaller numbers yearly, which means that while the current annual U.S. volume of these cases is uncertain it easily exceeds 500, Dr. Luks said.

All the other fetal surgeries each occur in fewer than about 50 U.S. cases a year, are available at fewer U.S. centers and, in some cases, have a checkered history of success and failure although today several are considered effective, relatively safe, and standard therapy.

The third most-common fetal surgery, based on NAFTNet records, are various types of selective umbilical cord occlusions in twin pregnancies, for reasons such as intrauterine growth retardation, placental insufficiency, and other situations in which problems with one twin puts a healthy twin at risk, said Dr. Johnson.

Dr. Johnson, Dr. Hirose, Dr. Adzick, Dr. Moldenhauer, Dr. Lee, Dr. Tulipan, Dr. Lim, and Dr. Evans all said that they had no relevant financial disclosures.

* This story was updated on 10/3/1012.