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Intrauterine surgery in myelomeningocele
Seminars in Fetal & Neonatal Medicine (2007) 12, 471e476
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Intrauterine surgery in myelomeningocele Joseph P. Bruner* The Perinatal Center, Fort Sanders Regional Medical Center, 501 19th Street, Suite 304, Knoxville, TN 37916, USA
KEYWORDS Intrauterine surgery; Myelomeningocele; Spina bifida; Hysterotomy
Summary Intrauterine surgery for repair of fetal myelomeningocele has been performed since 1994. Open repair through a hysterotomy has been performed since 1997. Although much has been published about diagnosis, counseling, case selection, pre-, intra-, and postoperative management, delivery and long-term sequelae for both mother and baby, and associated ethical issues, several questions have yet to be openly discussed in a public forum. ª 2007 Published by Elsevier Ltd.
Introduction Intrauterine surgery for treatment of fetal myelomeningocele was first performed in humans at Vanderbilt University Medical Center in Nashville, Tennessee, USA, in 1994.1 J. Bruner, a perinatologist, W. Richards, a general surgeon, and N. Tulipan, a pediatric neurosurgeon used a fetoscopic approach through a maternal laparotomy with multiple uterine ports to attach a maternal split-thickness skin patch over the dissected lesion with autologous fibrin glue. Four cases were performed until the technique was abandoned in 1997 due to frustration with the limitations of the standard fetoscopic approach and disappointing outcomes.2 At that time, standard multiplayer neonatal repair through a hysterotomy was adopted, and 178 cases were completed until the start of the MOMS (Management of Myelomeningocele Study) trial in 2003.3
What is the MOMS trial? The MOMS trial is a multicenter randomized trial funded in the USA for 5 years by the National Institute of Child Health
* Tel.: þ1 865 541 2020; fax: þ1 865 541 2019. E-mail address: [email protected] 1744-165X/$ - see front matter ª 2007 Published by Elsevier Ltd. doi:10.1016/j.siny.2007.06.011
and Human Development (NICHD).4 The goal of the trial is to compare the safety and efficacy of intrauterine repair of myelomeningocele with standard postnatal repair. The study is necessarily unblinded, with 100 candidates scheduled to be randomized to intrauterine repair and 100 to postnatal repair of the myelomeningocele lesion. The three participating clinical centers, in alphabetical order, are the Children’s Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, the University of California at San Francisco (UCSF), San Francisco, California, and Vanderbilt University Medical Center, Nashville, Tennessee. After initial screening by the study coordinating center at George Washington University, Washington, District of Columbia, candidates are assigned to a participating MOMS clinical center based on geography. Candidates in the Eastern USA are assigned to CHOP, those in the Western USA are assigned to UCSF, and those in the Midwest are assigned to Vanderbilt. After extensive evaluation and counseling, families who choose to participate are randomized to either intrauterine microsurgical repair between 19 0/7 and 25 6/7 weeks’ gestation or to standard care. Patients randomized to intrauterine repair of myelomeningocele stay at the participating center until delivery. Patients randomized to postnatal repair are allowed to return to their home communities temporarily, with plans to go back to the participating center for delivery as well. Thus, it is hoped that all study babies will deliver and receive initial neonatal care at one of the three
472 MOMS centers. Follow-up currently includes comprehensive neurological, urological, orthopedic, psychosocial and reproductive evaluations of mothers and babies, respectively, at 12 and 30 months postpartum, although continued funding to allow for extended follow-up of this unique cohort through young adulthood is anticipated. As of August 2007, 119 maternalefetal pairs have been randomized.
Will the MOMS trial demonstrate whether intrauterine surgery for myelomeningocele ‘works’? Prior to the start of the MOMS trial, more than 270 cases of myelomeningocele were repaired by intrauterine surgery at various centers around the world. The outcomes of most of these cases have been published in a number of observational and unrandomized controlled studies.3,5e8 As a result, much is already known about the potential risks and benefits of intrauterine repair of myelomeningocele. For example, in almost every case, intrauterine surgery for myelomeningocele improves the hindbrain herniation associated with the Arnold Chiari II malformation.9,10 Hindbrain herniation is downward displacement of the cerebellar tonsils through the foramen magnum, and is best appreciated in a sagittal view of the craniocervical junction. Using standard neurological scoring systems, hindbrain herniation has been shown to improve within 3 weeks of intrauterine repair of the spinal defect, probably due to normalization of CSF flow.11 So far, decompression surgery for relief of brainstem compression has been extremely rare in children after intrauterine repair of myelomeningocele. Furthermore, intrauterine surgery for myelomeningocele reduces the need for ventriculoperitoneal shunt placement before 1 year of age by about 50%.6 If the upper margin of the myelomeningocele lesion is at L1 or above, based on prenatal ultrasonography, virtually all babies will still require a shunt. If the lesion is at L4 or below, however, and repaired at 25 weeks’ gestation, as few as 25% will receive a shunt.12 Those that do require ventriculoperitoneal drainage are typically shunted later, at an average of 3 months of age, rather than during the newborn period. Cognitive development in children after intrauterine repair of myelomeningocele has been difficult to interpret, because pregnant women with significant psychosocial problems are typically excluded from such treatment. In addition, virtually all pregnancies deliver prematurely after performance of hysterotomy. In spite of these limitations, there has been no suggestion of systematic cognitive impairment in children treated in utero.6 Following the same theme, fewer urinary tract infections (UTIs) and less reflux was noted in infants undergoing urological assessment after intrauterine repair of myelomeningocele, but this beneficial effect could not be separated from the exceptionally good medical care provided by the families of the children studied.13 Gastrointestinal function has not yet been systematically evaluated in any cohort of children whose lesions were repaired in utero. Improvement in lower-extremity function could not be demonstrated in two unrandomized controlled studies of children after intrauterine surgery for myelomeningocele at
J.P. Bruner Vanderbilt.14,15 Importantly, candidates for in-utero repair at Vanderbilt were not excluded on the basis of absence of lower-extremity movement during preoperative assessment. At CHOP, by contrast, only fetuses with documented lower-extremity movement were accepted for intrauterine repair. In this selected group, leg function after delivery was better than expected by at least two spinal levels.16 It appears, therefore, that intrauterine surgery for myelomeningocele can preserve lower-extremity function still present at the time of repair, but cannot recover function already lost. The major risk of intrauterine surgery for myelomeningocele is preterm delivery. Almost all patients deliver preterm after open fetal surgery, although the mean gestational age at delivery is 34 weeks.3,6 Approximately 10% of patients deliver before 30 weeks’ gestation. In the Vanderbilt series, only four patients (2.2%) had uterine scar dehiscence at the time of delivery, and three of these were asymptomatic.3 The perinatal mortality rate reported after intrauterine surgery for myelomeningocele is 3e5%.3,8 Presumably, all of the perinatal deaths would have been avoided if standard care had been chosen. It is not likely that the published outcomes listed above will differ significantly from findings of the MOMS trial. Clearly, intrauterine surgery for myelomeningocele offers improved neurological functioning in some cases, but also incurs significant risks. The major revelation of the MOMS trial is expected to be the outcomes of the control group.
What will the control group of the MOMS trial reveal? Between 1997 and the start of the MOMS trial in 2003, the fetal surgery team at Vanderbilt averaged one case of intrauterine repair of myelomeningocele every other week. Since the average tertiary-care center of comparable size may only encounter several cases per year, it soon became impossible to find a suitable control group for comparison. Attempts included historical institutional controls, contemporaneous unrandomized controls, controls from other institutions, and historical databases. To complicate matters, it became apparent during this time that the standard management of myelomeningocele in newborns was changing. For example, whereas placement of a ventriculoperitoneal shunt in newborns with spina bifida had been standard care for a generation of neurosurgeons, the benefits of selective shunt placement based on predetermined criteria were being discovered.17 Therefore, historical controls of more than just a few years of age became suspect. It became obvious that there was a great need for a rigorously selected control group of children with myelomeningocele, whose medical care even before birth was provided by institutions with special expertise in the management of the disease. Careful documentation of various neurological, urological, orthopedic, and developmental milestones could provide a robust database that could contribute to a better understanding of the disease process for many years. Only a large, comprehensive, multi-institutional randomized clinical trial could produce
Intrauterine surgery in myelomeningocele such a cohort. This realization was the conception of the MOMS trial. While those involved in the performance of intrauterine surgery for myelomeningocele prior to the start of the MOMS Trial have considerable experience with expected outcomes in the surgery arm of the study, no one has a good grasp on what the control group might reveal. Conceivably, aggressive management of newborns with spina bifida at selected centers of excellence could result in outcomes comparable to those seen after intrauterine surgery.
If Intrauterine surgery for myelomeningocele continues, who will have it? Based on our current understanding of the potential risks and benefits associated with intrauterine surgery for myelomeningocele, almost all the fetuses will experience an improved appearance of the brain on neuroimaging studies, and many of these will not require a shunt. On the other hand, almost all the fetuses will be born preterm. Using this model, there is a clear trade-off of risks and benefits that must be balanced. In some cases, the upper limit of the myelomeningocele lesion will be so low that any expected benefit will probably not justify the significant risk of prematurity. Conversely, some lesions will be so severe that the small anticipated benefit of surgery will also not be worth the risk. Specifically, lesions confined to the fetal sacrum with absence of hindbrain herniation may never require a shunt and may result only in ankle weakness; such cases are probably poor candidates for intrauterine surgery. At the other end of the spectrum, virtually all fetuses with a lesion at L1 or above will require a shunt, even after intrauterine surgery, and may never ambulate without the use of braces and crutches, and so are probably also poor candidates. Therefore, it appears that ideal candidates for intrauterine surgery for myelomeningocele in the future will be in the middle of the road. In helping patients to understand the trade-off of risks and benefits, it may be helpful to construct concrete examples based on published outcomes.3,12 For example, if the parents believe that their child’s quality of life will be improved if it delivers after 30 weeks’ gestation and does not require a ventriculoperitoneal shunt, then the likelihood of this outcome can currently be calculated. If the only expected benefit is reversal of hindbrain herniation, then the likelihood of delivery after, say, 32 weeks’ gestation can be similarly figured.
If intrauterine surgery for myelomeningocele continues, who should perform it? Any institution with the resources available to establish a fetal treatment center may be sufficiently qualified to perform intrauterine surgery for myelomeningocele. Specific needs include: (1) an experienced perinatologist with prenatal imaging expertise in both ultrasound and ultrafast magnetic resonance imaging (MRI); (2) an experienced operating-room team, including an anesthesiologist knowledgeable about the specific techniques used during maternalefetal surgery for maternal and fetal monitoring and
473 uterine quiescence; (3) an experienced pediatric neurosurgeon knowledgeable about the specific techniques used during intrauterine repair of myelomeningocele and neonatal care; (4) a neonatal ICU with the capability of treating severely preterm newborns; (5) social workers, obstetrical and neonatal case managers, and ethicists experienced in the unique needs of this population; and (6) an institutional commitment to oversight and excellence in care.18 A number of centers in the USA have already performed intrauterine surgery for myelomeningocele, and others are sufficiently qualified to begin once the MOMS trial is successfully concluded. Many medical centers around the world have adequate resources, including personnel, and institutional commitment, but lack specific skills necessary for the performance of this procedure. These institutions are encouraged to partner with established centers in the USA in order to acquire the techniques required to perform intrauterine surgery for myelomeningocele in the safest manner possible. Aspiring institutions must remember that intrauterine repair of myelomeningocele is elective surgery and does not save lifedeven under the best of conditions, it can only threaten life.
What is the most dangerous part of intrauterine surgery for myelomeningocele? The single most dangerous moment in intrauterine surgery for myelomeningocele is the creation of the hysterotomy. After induction of adequate anesthesia and uterine quiescence, using both general and regional techniques, after confirmation of fetal well-being, after creation of maternal laparotomy and exteriorization of the gravid uterus, placental location is carefully mapped and clearly marked on the uterine surface. The location of the 6e8-cm hysterotomy site is selected and also marked, and the fetus is positioned for easy access to the myelomeningocele sac. The presence of polyhydramnios or any suspicion of fetal stress are contraindications to continuing. Under continuous direct ultrasonographic guidance, full-thickness stay sutures are placed approximately two finger-breadths apart on either side of the initial entry site. The use of an atraumatic trocar, such as the TulipaneBruner trocar (Cook Inc., Bloomington, IN),19 is used to achieve initial entry into the amniotic space. A uterine autostapling device (US Surgical CS-57; US Surgical Corp., Norwalk, CT) is carefully positioned, and a final check is made to exclude the entrapment of fetal parts or the proximity of myometrial vessels. The autostapling device is engaged and fired, and care taken to remove the device, searching diligently for evidence of a partial misfiring. The staples will not occlude the trocar entry site, and after removal of the device the edge of this apex is quickly but carefully sutured with a full-thickness continuous interlocking stitch of absorbable suture material. After completion of the hysterotomy, the fetal myelomeningocele sac should be visible just inside the uterine incision, and the uterine wall should be completely soft and compliant. If so, the single most dangerous step in the performance of intrauterine surgery for myelomeningocele has been concluded. At this point, however, a developing subchorionic hematoma may be visualized adjacent to the hysterotomy site,
474 and blood may be seen oozing from beneath the fetal membranes through the staple line. This is a surgical emergency, and demands a prompt and definitive response lest fetal well-being is jeopardized. Left untreated, the spreading hematoma will dissect the entire surface of the fetal membranes from the uterine wall and cause membrane collapse. The source of the hematoma is a subchorionic venous injury near the edge of the hysterotomy, and initial control can be achieved by digitally elevating and tamponading the involved area. Fetal well-being must be continuously confirmed. Unfortunately, the exact location of the vessel injury cannot be determined because it lies beneath the membrane surface and is not directly visible. If the hematoma is small, however, one or more well-placed absorbable full-thickness mattress sutures should control the bleeding and contain the dissection. Control of the emergency is confirmed by direct observation of the hematoma to document the absence of further expansion. If the uterus remains quiescent and fetal well-being preserved, the intrauterine myelomeningocele repair may proceed. If the hematoma cannot be successfully contained, the surgery team must abandon further attempts at repair and direct their efforts at salvage of the pregnancy. The hysterotomy must be quickly closed in standard fashion, and amniotic volume increased by the liberal addition of sterile warmed saline solution. Overdistention of the uterus in this manner will increase intrauterine pressure and tamponade the leaking vessel. Although mother and fetus will incur all the risks of intrauterine surgery with none of the potential benefits, disaster will still have been averted.
What is the most frustrating complication of intrauterine repair of myelomeningocele? The most vexing postoperative complication after intrauterine surgery for myelomeningocele is imperfect healing of the chorioamniotic membranes, manifesting as either persistent amniotic fluid leakage through the hysterotomy or membrane collapse. While these two problems are not mutually exclusive, the particular presentation may be dependent upon the technique used for hysterotomy closure. At Vanderbilt, the polyglycolic acid staples placed during creation of the hysterotomy are incorporated into the wound closure. Each staple is square, with a needle aperture in the center. During closure, the suture needle is placed through the uterine surface adjacent to the staple line, through the staple aperture into the wound, into the aperture of the opposing staple, and out through the opposing uterine surface. In this manner, a continuous running suture is placed. When tied, each staple face directly opposes the one opposite. This is followed by an imbricating suture, and the hysterotomy wound is covered with either a commercially available barrier fabric or omentum. Using this technique, up to 20% of patients may develop oligohydramnios,6 presumably due to leakage of amniotic fluid at the hysterotomy site. The number of affected patients decreases with time, secondary to hysterotomy scar formation. By the time the maternal abdominal wound is well healed, however, any remaining oligohydramnios is likely to be persistent. The presence of
J.P. Bruner oligohydramnios frequently leads to readmission to the hospital for bed-rest, intravenous fluid administration, and aggressive antepartum surveillance. Early elective delivery is often undertaken, contributing to the overall problem of preterm delivery after intrauterine surgery for myelomeningocele. In at least one case, neonatal death was attributed to pulmonary hypoplasia resulting from prolonged postoperative oligohydramnios. Patients with postoperative oligohydramnios after intrauterine surgery for myelomeningocele rarely experience amniorhexis, especially if the membranes appear intact during ultrasonographic examination. Fluid is rarely seen in the cul-de-sac more than a few days postoperatively, due to the low intrauterine fluid volume and peritoneal absorption of leaked fluid. At the time of delivery, the hysterotomy invariably appears to be well healed, both by palpation and by direct visual inspection of the site. Thus, fluid leakage hypothetically occurs via a tiny fistula at the hysterotomy site, too small to be seen or felt, but large enough to cause persistent oligohydramnios. Attempts to prevent or correct this problem have been unsuccessful. The use of a fibrin sealant to achieve watertight closure of the hysterotomy did not affect the incidence of oligohydramnios, and is no longer used at most centers in the USA. Conservative measures, such as bedrest and fluid hydration, are similarly ineffective. Creation of an amniopatch by injection of maternal platelets and cryoprecipitate into the amniotic space20 has not yet been attempted. Other centers have experimented with alternative means of hysterotomy closure, including removal of the staples followed by mass closure of the wound. While this technique appears to decrease the incidence of postoperative oligohydramnios, membrane disruption has been reported with equal frequency. It seems that altering the technique of hysterotomy closure does not eliminate problems of membrane healing, but substitutes one type of complication for another. The ideal method of hysterotomy closure after intrauterine surgery for myelomeningocele has not yet been developed.
Will intrauterine surgery for myelomeningocele become ‘minimally invasive’? As noted above, the initial approach to intrauterine surgery for myelomeningocele was endoscopic. In part, this was due to the fact that most of the published literature in the early 1990s cited unacceptably high incidences of maternal morbidity and fetal mortality and morbidity when surgery through a hysterotomy was attempted. After four laparoscopic attempts at repair, however, the technique was abandoned at Vanderbilt because of the inherent limitations of the approach. Instead, open surgery was introduced for myelomeningocele, and the complication rate was surprisingly low compared to that of earlier surgeries. The difference lies in the reason open maternal fetal surgery is performed. Before 1997, the only cases attempted were for lethal fetal malformations. As these surgeries were lifesaving, the fetus was usually very sick, and the mother was often in suboptimal condition as well. By contrast,
Intrauterine surgery in myelomeningocele intrauterine repair of myelomeningocele is elective surgery. If any maternal or fetal medical or surgical problems are present, surgery is not performed. Therefore, aside from the myelomeningocele, the fetus is healthy, and the mother is too. As a result, life-threatening complications of intrauterine surgery for myelomeningocele are uncommon. Still, the complications that do occur are serious enough: almost certain prematurity of the fetus, and a lifelong need for cesarean delivery in the mother. A return to the endoscopic approach to intrauterine surgery for myelomeningocele could potentially allow patients the option of delivering vaginally at term. While conventional laparoscopy is still not a practical choice, new robotic endoscopic technologies may allow a return of intrauterine surgery for myelomeningocele to the minimally invasive arena. A Da Vinci robotic operating system (Intuitive Surgical, Sunnyvale, CA) at Vanderbilt was used to create and repair a spina-bifida-like lesion in six midgestation fetal lambs.21 The average case length was 90 min, and the mean operating time after port placement was only 30 min. All lesions were repaired satisfactorily, and the only complication was postoperative membrane collapse in one fetal lamb. While intrauterine repair of a myelomeningocele-like lesion using a robotic fetoscope was successful in the ovine model, a number of obstacles to human surgery still remain. First and foremost, the 5- and 10-mm ports used for robotic surgery are too large for application in a pregnant uterus, where 1- and 2-mm ports are the rule. Second, unresolved issues of fetal positioning, fetal monitoring, and operating in an amniotic fluid environment bar the immediate application of this promising technology in the human patient. If solutions to these surgical dilemmas can be developed, then theoretically future intrauterine surgery for myelomeningocele will be safer, and most patients will deliver vaginally at term gestation. The potential benefits for all types of intrauterine surgery on fetuses would be immeasurable.
475
Thus, future candidates for intrauterine surgery are likely to have ‘average’ lesions with a middle-of-the-road prognosis. Any institution with sufficient resources, commitment, and experience can develop a fetal treatment center. Established centers are available for consultation and collaboration. The single most dangerous moment in intrauterine surgery for myelomeningocele is creation of the hysterotomy. Special techniques and instruments have been devised to minimize this risk. Development of a subchorionic hematoma adjacent to the hysterotomy is a surgical emergency. The most frustrating complication of intrauterine repair of myelomeningocele is imperfect healing of the chorioamniotic membranes, manifesting as either oligohydramnios or postoperative membrane separation. No known prophylaxis is effective for these problems, which affect up to 20% of cases. The particular presentation of the complication is probably technique-specific. Robotic operating technology may allow a minimally invasive approach to intrauterine repair of myelomeningocele. Instrument size, management of the amniotic fluid environment, and fetal positioning and monitoring are still unresolved issues.
Research directions Robotic endoscopic repair of fetal myelomeningocele has been performed in sheep, but has not yet been attempted in humans. Currently available 5and 10-mm ports are too large for clinical use, and 1- to 3-mm tools must be developed. Techniques for fetal positioning, dealing with the amniotic fluid environment, and fetal monitoring during intrauterine surgery must be refined.
Practice points The MOMS (Management of Myelomeningocele Study) trial is a multicenter randomized trial comparing intrauterine repair of myelomeningocele with standard care. Intrauterine repair of myelomeningocele is not performed outside the trial in the USA. Although much is already known about the potential risks and benefits of intrauterine repair of myelomeningocele, long-term outcomes of a contemporaneous rigorously managed control group are currently unknown. The MOMS trial will supply this information. Some fetuses with mild disease have a favorable prognosis that probably does not justify the risk of intrauterine repair of myelomeningocele; other fetuses have severe disease that will not be improved significantly with any known treatment.
References 1. Bruner JP, Richards WO, Tulipan NB, Arney TL. Endoscopic coverage of fetal myelomeningocele in utero. Am J Obstet Gynecol 1999;180:153e8. 2. Bruner JP, Tulipan N, Richards WO, Walsh WF, Boehm FH, Vrabchak EK. In utero repair of myelomeningocele: A comparison of endoscopy and hysterotomy. Fetal Diagn Ther 2000;15:83e8. 3. Bruner JP, Tulipan N. Intrauterine repair of spina bifida. In: Bruner JP, ed. Clin Obstet Gynecol 2005;48:942e55. 4. National Institute of Child Health and Human Development. Management of myelomeningocele study, Available from: http://www.spinabifidamoms.com; 2003. 5. Tulipan N. Intrauterine myelomeningocele repair. In: Bruner JP, ed. Clin Perinatol 2003;30:521e30. 6. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh WF, Silva SR, et al. Fetal surgery for myelomeningocele and the
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J.P. Bruner incidence of shunt-dependent hydrocephalus. JAMA 1999;282: 1819e25. Walsh WF, Bruner JP, Tulipan N. Neonatal outcome of the first 50 infants treated with in utero repair of spina bifida. Pediatr Res 2000;47:439. Tulipan N, Sutton LN, Bruner JP, Cohen BM, Johnson M, Adzick NS. The effect of intrauterine myelomeningocele repair on the incidence of shunt-dependent hydrocephalus. Pediatr Neurosurg 2003;38:27e33. Tulipan N, Schulman M, Bruner JP. Reduced hindbrain herniation after intrauterine myelomeningocele repair: A report of four cases. Pediatr Neurosurg 1998;29:274e8. Tulipan N, Hernanz-Schulman M, Bruner JP. Intrauterine myelomeningocele repair reverses preexisting hindbrain herniation. Pediatr Neurosurg 1999;31:137e42. Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999;282:1826e31. Bruner JP, Tulipan N, Reed G, Davis GH, Bennett K, Luker KS, et al. Intrauterine repair of spina bifida: Preoperative predictors of shunt-dependent hydrocephalus. Am J Obstet Gynecol 2004;190:1305e12. Holzbeierlein J, Pope JC IV, Adams MC, Bruner J, Tulipan N, Brock 3rd JW. The urodynamic profile of myelodysplasia in childhood with spinal closure during gestation. J Urol 2000; 164:1336e9.
14. Tulipan N, Bruner JP, Hernanz-Schulman M, Lowe LH, Walsh WF, Nickolaus D, Oakes WJ. The effect of intrauterine myelomeningocele repair on central nervous system structure and neurologic function. Pediatr Neurosurg 1999;31:183e8. 15. Tubbs RS, Chambers MR, Smyth MD, Bartolucci AA, Bruner JP, Tulipan N, et al. Late gestational intrauterine myelomeningocele repair does not improve lower extremity function. Pediatr Neurosurg 2003;38:128e32. 16. Johnson MP, Sutton LN, Rintoul N. Fetal myelomeningocele repair: short-term clinical outcomes. Am J Obstet Gynecol 2003; 189:482e7. 17. Rintoul N, Sutton LN, Hubbard AM, Cohen B, Melchionni J, Pasquariello PS. A new look at myelomeningoceles: functional level, vertebral level, shunting and the implications for fetal intervention. Pediatrics 2002;109:409e13. 18. Bruner JP, Paschall RL. Cirugia fetal abierta. In: Gratacos E, Gomez R, Nicolaides K, Romero R, Cabero L, eds. Medicina fetal. Madrid: Medica Panamerica; 2007. 19. Bruner JP, Boehm FH, Tulipan N. The Tulipan-Bruner trocar for uterine entry during fetal surgery. Am J Obstet Gynecol 1999; 181:1188e91. 20. Quintero RA. Treatment of previable premature ruptured membranes. In: Bruner JP, ed. Clin Perinatol 2003;30:573e89. 21. Aaronson OS, Tulipan NB, Cywes R, Sundell HW, Davis GH, Bruner JP, et al. Robot-assisted endoscopic intrauterine myelomeningocele repair: A feasibility study. Pediatr Neurosurg 2002;36:85e9.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Intrauterine surgery in myelomeningocele Joseph P. Bruner* The Perinatal Center, Fort Sanders Regional Medical Center, 501 19th Street, Suite 304, Knoxville, TN 37916, USA
KEYWORDS Intrauterine surgery; Myelomeningocele; Spina bifida; Hysterotomy
Summary Intrauterine surgery for repair of fetal myelomeningocele has been performed since 1994. Open repair through a hysterotomy has been performed since 1997. Although much has been published about diagnosis, counseling, case selection, pre-, intra-, and postoperative management, delivery and long-term sequelae for both mother and baby, and associated ethical issues, several questions have yet to be openly discussed in a public forum. ª 2007 Published by Elsevier Ltd.
Introduction Intrauterine surgery for treatment of fetal myelomeningocele was first performed in humans at Vanderbilt University Medical Center in Nashville, Tennessee, USA, in 1994.1 J. Bruner, a perinatologist, W. Richards, a general surgeon, and N. Tulipan, a pediatric neurosurgeon used a fetoscopic approach through a maternal laparotomy with multiple uterine ports to attach a maternal split-thickness skin patch over the dissected lesion with autologous fibrin glue. Four cases were performed until the technique was abandoned in 1997 due to frustration with the limitations of the standard fetoscopic approach and disappointing outcomes.2 At that time, standard multiplayer neonatal repair through a hysterotomy was adopted, and 178 cases were completed until the start of the MOMS (Management of Myelomeningocele Study) trial in 2003.3
What is the MOMS trial? The MOMS trial is a multicenter randomized trial funded in the USA for 5 years by the National Institute of Child Health
* Tel.: þ1 865 541 2020; fax: þ1 865 541 2019. E-mail address: [email protected] 1744-165X/$ - see front matter ª 2007 Published by Elsevier Ltd. doi:10.1016/j.siny.2007.06.011
and Human Development (NICHD).4 The goal of the trial is to compare the safety and efficacy of intrauterine repair of myelomeningocele with standard postnatal repair. The study is necessarily unblinded, with 100 candidates scheduled to be randomized to intrauterine repair and 100 to postnatal repair of the myelomeningocele lesion. The three participating clinical centers, in alphabetical order, are the Children’s Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, the University of California at San Francisco (UCSF), San Francisco, California, and Vanderbilt University Medical Center, Nashville, Tennessee. After initial screening by the study coordinating center at George Washington University, Washington, District of Columbia, candidates are assigned to a participating MOMS clinical center based on geography. Candidates in the Eastern USA are assigned to CHOP, those in the Western USA are assigned to UCSF, and those in the Midwest are assigned to Vanderbilt. After extensive evaluation and counseling, families who choose to participate are randomized to either intrauterine microsurgical repair between 19 0/7 and 25 6/7 weeks’ gestation or to standard care. Patients randomized to intrauterine repair of myelomeningocele stay at the participating center until delivery. Patients randomized to postnatal repair are allowed to return to their home communities temporarily, with plans to go back to the participating center for delivery as well. Thus, it is hoped that all study babies will deliver and receive initial neonatal care at one of the three
472 MOMS centers. Follow-up currently includes comprehensive neurological, urological, orthopedic, psychosocial and reproductive evaluations of mothers and babies, respectively, at 12 and 30 months postpartum, although continued funding to allow for extended follow-up of this unique cohort through young adulthood is anticipated. As of August 2007, 119 maternalefetal pairs have been randomized.
Will the MOMS trial demonstrate whether intrauterine surgery for myelomeningocele ‘works’? Prior to the start of the MOMS trial, more than 270 cases of myelomeningocele were repaired by intrauterine surgery at various centers around the world. The outcomes of most of these cases have been published in a number of observational and unrandomized controlled studies.3,5e8 As a result, much is already known about the potential risks and benefits of intrauterine repair of myelomeningocele. For example, in almost every case, intrauterine surgery for myelomeningocele improves the hindbrain herniation associated with the Arnold Chiari II malformation.9,10 Hindbrain herniation is downward displacement of the cerebellar tonsils through the foramen magnum, and is best appreciated in a sagittal view of the craniocervical junction. Using standard neurological scoring systems, hindbrain herniation has been shown to improve within 3 weeks of intrauterine repair of the spinal defect, probably due to normalization of CSF flow.11 So far, decompression surgery for relief of brainstem compression has been extremely rare in children after intrauterine repair of myelomeningocele. Furthermore, intrauterine surgery for myelomeningocele reduces the need for ventriculoperitoneal shunt placement before 1 year of age by about 50%.6 If the upper margin of the myelomeningocele lesion is at L1 or above, based on prenatal ultrasonography, virtually all babies will still require a shunt. If the lesion is at L4 or below, however, and repaired at 25 weeks’ gestation, as few as 25% will receive a shunt.12 Those that do require ventriculoperitoneal drainage are typically shunted later, at an average of 3 months of age, rather than during the newborn period. Cognitive development in children after intrauterine repair of myelomeningocele has been difficult to interpret, because pregnant women with significant psychosocial problems are typically excluded from such treatment. In addition, virtually all pregnancies deliver prematurely after performance of hysterotomy. In spite of these limitations, there has been no suggestion of systematic cognitive impairment in children treated in utero.6 Following the same theme, fewer urinary tract infections (UTIs) and less reflux was noted in infants undergoing urological assessment after intrauterine repair of myelomeningocele, but this beneficial effect could not be separated from the exceptionally good medical care provided by the families of the children studied.13 Gastrointestinal function has not yet been systematically evaluated in any cohort of children whose lesions were repaired in utero. Improvement in lower-extremity function could not be demonstrated in two unrandomized controlled studies of children after intrauterine surgery for myelomeningocele at
J.P. Bruner Vanderbilt.14,15 Importantly, candidates for in-utero repair at Vanderbilt were not excluded on the basis of absence of lower-extremity movement during preoperative assessment. At CHOP, by contrast, only fetuses with documented lower-extremity movement were accepted for intrauterine repair. In this selected group, leg function after delivery was better than expected by at least two spinal levels.16 It appears, therefore, that intrauterine surgery for myelomeningocele can preserve lower-extremity function still present at the time of repair, but cannot recover function already lost. The major risk of intrauterine surgery for myelomeningocele is preterm delivery. Almost all patients deliver preterm after open fetal surgery, although the mean gestational age at delivery is 34 weeks.3,6 Approximately 10% of patients deliver before 30 weeks’ gestation. In the Vanderbilt series, only four patients (2.2%) had uterine scar dehiscence at the time of delivery, and three of these were asymptomatic.3 The perinatal mortality rate reported after intrauterine surgery for myelomeningocele is 3e5%.3,8 Presumably, all of the perinatal deaths would have been avoided if standard care had been chosen. It is not likely that the published outcomes listed above will differ significantly from findings of the MOMS trial. Clearly, intrauterine surgery for myelomeningocele offers improved neurological functioning in some cases, but also incurs significant risks. The major revelation of the MOMS trial is expected to be the outcomes of the control group.
What will the control group of the MOMS trial reveal? Between 1997 and the start of the MOMS trial in 2003, the fetal surgery team at Vanderbilt averaged one case of intrauterine repair of myelomeningocele every other week. Since the average tertiary-care center of comparable size may only encounter several cases per year, it soon became impossible to find a suitable control group for comparison. Attempts included historical institutional controls, contemporaneous unrandomized controls, controls from other institutions, and historical databases. To complicate matters, it became apparent during this time that the standard management of myelomeningocele in newborns was changing. For example, whereas placement of a ventriculoperitoneal shunt in newborns with spina bifida had been standard care for a generation of neurosurgeons, the benefits of selective shunt placement based on predetermined criteria were being discovered.17 Therefore, historical controls of more than just a few years of age became suspect. It became obvious that there was a great need for a rigorously selected control group of children with myelomeningocele, whose medical care even before birth was provided by institutions with special expertise in the management of the disease. Careful documentation of various neurological, urological, orthopedic, and developmental milestones could provide a robust database that could contribute to a better understanding of the disease process for many years. Only a large, comprehensive, multi-institutional randomized clinical trial could produce
Intrauterine surgery in myelomeningocele such a cohort. This realization was the conception of the MOMS trial. While those involved in the performance of intrauterine surgery for myelomeningocele prior to the start of the MOMS Trial have considerable experience with expected outcomes in the surgery arm of the study, no one has a good grasp on what the control group might reveal. Conceivably, aggressive management of newborns with spina bifida at selected centers of excellence could result in outcomes comparable to those seen after intrauterine surgery.
If Intrauterine surgery for myelomeningocele continues, who will have it? Based on our current understanding of the potential risks and benefits associated with intrauterine surgery for myelomeningocele, almost all the fetuses will experience an improved appearance of the brain on neuroimaging studies, and many of these will not require a shunt. On the other hand, almost all the fetuses will be born preterm. Using this model, there is a clear trade-off of risks and benefits that must be balanced. In some cases, the upper limit of the myelomeningocele lesion will be so low that any expected benefit will probably not justify the significant risk of prematurity. Conversely, some lesions will be so severe that the small anticipated benefit of surgery will also not be worth the risk. Specifically, lesions confined to the fetal sacrum with absence of hindbrain herniation may never require a shunt and may result only in ankle weakness; such cases are probably poor candidates for intrauterine surgery. At the other end of the spectrum, virtually all fetuses with a lesion at L1 or above will require a shunt, even after intrauterine surgery, and may never ambulate without the use of braces and crutches, and so are probably also poor candidates. Therefore, it appears that ideal candidates for intrauterine surgery for myelomeningocele in the future will be in the middle of the road. In helping patients to understand the trade-off of risks and benefits, it may be helpful to construct concrete examples based on published outcomes.3,12 For example, if the parents believe that their child’s quality of life will be improved if it delivers after 30 weeks’ gestation and does not require a ventriculoperitoneal shunt, then the likelihood of this outcome can currently be calculated. If the only expected benefit is reversal of hindbrain herniation, then the likelihood of delivery after, say, 32 weeks’ gestation can be similarly figured.
If intrauterine surgery for myelomeningocele continues, who should perform it? Any institution with the resources available to establish a fetal treatment center may be sufficiently qualified to perform intrauterine surgery for myelomeningocele. Specific needs include: (1) an experienced perinatologist with prenatal imaging expertise in both ultrasound and ultrafast magnetic resonance imaging (MRI); (2) an experienced operating-room team, including an anesthesiologist knowledgeable about the specific techniques used during maternalefetal surgery for maternal and fetal monitoring and
473 uterine quiescence; (3) an experienced pediatric neurosurgeon knowledgeable about the specific techniques used during intrauterine repair of myelomeningocele and neonatal care; (4) a neonatal ICU with the capability of treating severely preterm newborns; (5) social workers, obstetrical and neonatal case managers, and ethicists experienced in the unique needs of this population; and (6) an institutional commitment to oversight and excellence in care.18 A number of centers in the USA have already performed intrauterine surgery for myelomeningocele, and others are sufficiently qualified to begin once the MOMS trial is successfully concluded. Many medical centers around the world have adequate resources, including personnel, and institutional commitment, but lack specific skills necessary for the performance of this procedure. These institutions are encouraged to partner with established centers in the USA in order to acquire the techniques required to perform intrauterine surgery for myelomeningocele in the safest manner possible. Aspiring institutions must remember that intrauterine repair of myelomeningocele is elective surgery and does not save lifedeven under the best of conditions, it can only threaten life.
What is the most dangerous part of intrauterine surgery for myelomeningocele? The single most dangerous moment in intrauterine surgery for myelomeningocele is the creation of the hysterotomy. After induction of adequate anesthesia and uterine quiescence, using both general and regional techniques, after confirmation of fetal well-being, after creation of maternal laparotomy and exteriorization of the gravid uterus, placental location is carefully mapped and clearly marked on the uterine surface. The location of the 6e8-cm hysterotomy site is selected and also marked, and the fetus is positioned for easy access to the myelomeningocele sac. The presence of polyhydramnios or any suspicion of fetal stress are contraindications to continuing. Under continuous direct ultrasonographic guidance, full-thickness stay sutures are placed approximately two finger-breadths apart on either side of the initial entry site. The use of an atraumatic trocar, such as the TulipaneBruner trocar (Cook Inc., Bloomington, IN),19 is used to achieve initial entry into the amniotic space. A uterine autostapling device (US Surgical CS-57; US Surgical Corp., Norwalk, CT) is carefully positioned, and a final check is made to exclude the entrapment of fetal parts or the proximity of myometrial vessels. The autostapling device is engaged and fired, and care taken to remove the device, searching diligently for evidence of a partial misfiring. The staples will not occlude the trocar entry site, and after removal of the device the edge of this apex is quickly but carefully sutured with a full-thickness continuous interlocking stitch of absorbable suture material. After completion of the hysterotomy, the fetal myelomeningocele sac should be visible just inside the uterine incision, and the uterine wall should be completely soft and compliant. If so, the single most dangerous step in the performance of intrauterine surgery for myelomeningocele has been concluded. At this point, however, a developing subchorionic hematoma may be visualized adjacent to the hysterotomy site,
474 and blood may be seen oozing from beneath the fetal membranes through the staple line. This is a surgical emergency, and demands a prompt and definitive response lest fetal well-being is jeopardized. Left untreated, the spreading hematoma will dissect the entire surface of the fetal membranes from the uterine wall and cause membrane collapse. The source of the hematoma is a subchorionic venous injury near the edge of the hysterotomy, and initial control can be achieved by digitally elevating and tamponading the involved area. Fetal well-being must be continuously confirmed. Unfortunately, the exact location of the vessel injury cannot be determined because it lies beneath the membrane surface and is not directly visible. If the hematoma is small, however, one or more well-placed absorbable full-thickness mattress sutures should control the bleeding and contain the dissection. Control of the emergency is confirmed by direct observation of the hematoma to document the absence of further expansion. If the uterus remains quiescent and fetal well-being preserved, the intrauterine myelomeningocele repair may proceed. If the hematoma cannot be successfully contained, the surgery team must abandon further attempts at repair and direct their efforts at salvage of the pregnancy. The hysterotomy must be quickly closed in standard fashion, and amniotic volume increased by the liberal addition of sterile warmed saline solution. Overdistention of the uterus in this manner will increase intrauterine pressure and tamponade the leaking vessel. Although mother and fetus will incur all the risks of intrauterine surgery with none of the potential benefits, disaster will still have been averted.
What is the most frustrating complication of intrauterine repair of myelomeningocele? The most vexing postoperative complication after intrauterine surgery for myelomeningocele is imperfect healing of the chorioamniotic membranes, manifesting as either persistent amniotic fluid leakage through the hysterotomy or membrane collapse. While these two problems are not mutually exclusive, the particular presentation may be dependent upon the technique used for hysterotomy closure. At Vanderbilt, the polyglycolic acid staples placed during creation of the hysterotomy are incorporated into the wound closure. Each staple is square, with a needle aperture in the center. During closure, the suture needle is placed through the uterine surface adjacent to the staple line, through the staple aperture into the wound, into the aperture of the opposing staple, and out through the opposing uterine surface. In this manner, a continuous running suture is placed. When tied, each staple face directly opposes the one opposite. This is followed by an imbricating suture, and the hysterotomy wound is covered with either a commercially available barrier fabric or omentum. Using this technique, up to 20% of patients may develop oligohydramnios,6 presumably due to leakage of amniotic fluid at the hysterotomy site. The number of affected patients decreases with time, secondary to hysterotomy scar formation. By the time the maternal abdominal wound is well healed, however, any remaining oligohydramnios is likely to be persistent. The presence of
J.P. Bruner oligohydramnios frequently leads to readmission to the hospital for bed-rest, intravenous fluid administration, and aggressive antepartum surveillance. Early elective delivery is often undertaken, contributing to the overall problem of preterm delivery after intrauterine surgery for myelomeningocele. In at least one case, neonatal death was attributed to pulmonary hypoplasia resulting from prolonged postoperative oligohydramnios. Patients with postoperative oligohydramnios after intrauterine surgery for myelomeningocele rarely experience amniorhexis, especially if the membranes appear intact during ultrasonographic examination. Fluid is rarely seen in the cul-de-sac more than a few days postoperatively, due to the low intrauterine fluid volume and peritoneal absorption of leaked fluid. At the time of delivery, the hysterotomy invariably appears to be well healed, both by palpation and by direct visual inspection of the site. Thus, fluid leakage hypothetically occurs via a tiny fistula at the hysterotomy site, too small to be seen or felt, but large enough to cause persistent oligohydramnios. Attempts to prevent or correct this problem have been unsuccessful. The use of a fibrin sealant to achieve watertight closure of the hysterotomy did not affect the incidence of oligohydramnios, and is no longer used at most centers in the USA. Conservative measures, such as bedrest and fluid hydration, are similarly ineffective. Creation of an amniopatch by injection of maternal platelets and cryoprecipitate into the amniotic space20 has not yet been attempted. Other centers have experimented with alternative means of hysterotomy closure, including removal of the staples followed by mass closure of the wound. While this technique appears to decrease the incidence of postoperative oligohydramnios, membrane disruption has been reported with equal frequency. It seems that altering the technique of hysterotomy closure does not eliminate problems of membrane healing, but substitutes one type of complication for another. The ideal method of hysterotomy closure after intrauterine surgery for myelomeningocele has not yet been developed.
Will intrauterine surgery for myelomeningocele become ‘minimally invasive’? As noted above, the initial approach to intrauterine surgery for myelomeningocele was endoscopic. In part, this was due to the fact that most of the published literature in the early 1990s cited unacceptably high incidences of maternal morbidity and fetal mortality and morbidity when surgery through a hysterotomy was attempted. After four laparoscopic attempts at repair, however, the technique was abandoned at Vanderbilt because of the inherent limitations of the approach. Instead, open surgery was introduced for myelomeningocele, and the complication rate was surprisingly low compared to that of earlier surgeries. The difference lies in the reason open maternal fetal surgery is performed. Before 1997, the only cases attempted were for lethal fetal malformations. As these surgeries were lifesaving, the fetus was usually very sick, and the mother was often in suboptimal condition as well. By contrast,
Intrauterine surgery in myelomeningocele intrauterine repair of myelomeningocele is elective surgery. If any maternal or fetal medical or surgical problems are present, surgery is not performed. Therefore, aside from the myelomeningocele, the fetus is healthy, and the mother is too. As a result, life-threatening complications of intrauterine surgery for myelomeningocele are uncommon. Still, the complications that do occur are serious enough: almost certain prematurity of the fetus, and a lifelong need for cesarean delivery in the mother. A return to the endoscopic approach to intrauterine surgery for myelomeningocele could potentially allow patients the option of delivering vaginally at term. While conventional laparoscopy is still not a practical choice, new robotic endoscopic technologies may allow a return of intrauterine surgery for myelomeningocele to the minimally invasive arena. A Da Vinci robotic operating system (Intuitive Surgical, Sunnyvale, CA) at Vanderbilt was used to create and repair a spina-bifida-like lesion in six midgestation fetal lambs.21 The average case length was 90 min, and the mean operating time after port placement was only 30 min. All lesions were repaired satisfactorily, and the only complication was postoperative membrane collapse in one fetal lamb. While intrauterine repair of a myelomeningocele-like lesion using a robotic fetoscope was successful in the ovine model, a number of obstacles to human surgery still remain. First and foremost, the 5- and 10-mm ports used for robotic surgery are too large for application in a pregnant uterus, where 1- and 2-mm ports are the rule. Second, unresolved issues of fetal positioning, fetal monitoring, and operating in an amniotic fluid environment bar the immediate application of this promising technology in the human patient. If solutions to these surgical dilemmas can be developed, then theoretically future intrauterine surgery for myelomeningocele will be safer, and most patients will deliver vaginally at term gestation. The potential benefits for all types of intrauterine surgery on fetuses would be immeasurable.
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Thus, future candidates for intrauterine surgery are likely to have ‘average’ lesions with a middle-of-the-road prognosis. Any institution with sufficient resources, commitment, and experience can develop a fetal treatment center. Established centers are available for consultation and collaboration. The single most dangerous moment in intrauterine surgery for myelomeningocele is creation of the hysterotomy. Special techniques and instruments have been devised to minimize this risk. Development of a subchorionic hematoma adjacent to the hysterotomy is a surgical emergency. The most frustrating complication of intrauterine repair of myelomeningocele is imperfect healing of the chorioamniotic membranes, manifesting as either oligohydramnios or postoperative membrane separation. No known prophylaxis is effective for these problems, which affect up to 20% of cases. The particular presentation of the complication is probably technique-specific. Robotic operating technology may allow a minimally invasive approach to intrauterine repair of myelomeningocele. Instrument size, management of the amniotic fluid environment, and fetal positioning and monitoring are still unresolved issues.
Research directions Robotic endoscopic repair of fetal myelomeningocele has been performed in sheep, but has not yet been attempted in humans. Currently available 5and 10-mm ports are too large for clinical use, and 1- to 3-mm tools must be developed. Techniques for fetal positioning, dealing with the amniotic fluid environment, and fetal monitoring during intrauterine surgery must be refined.
Practice points The MOMS (Management of Myelomeningocele Study) trial is a multicenter randomized trial comparing intrauterine repair of myelomeningocele with standard care. Intrauterine repair of myelomeningocele is not performed outside the trial in the USA. Although much is already known about the potential risks and benefits of intrauterine repair of myelomeningocele, long-term outcomes of a contemporaneous rigorously managed control group are currently unknown. The MOMS trial will supply this information. Some fetuses with mild disease have a favorable prognosis that probably does not justify the risk of intrauterine repair of myelomeningocele; other fetuses have severe disease that will not be improved significantly with any known treatment.
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J.P. Bruner incidence of shunt-dependent hydrocephalus. JAMA 1999;282: 1819e25. Walsh WF, Bruner JP, Tulipan N. Neonatal outcome of the first 50 infants treated with in utero repair of spina bifida. Pediatr Res 2000;47:439. Tulipan N, Sutton LN, Bruner JP, Cohen BM, Johnson M, Adzick NS. The effect of intrauterine myelomeningocele repair on the incidence of shunt-dependent hydrocephalus. Pediatr Neurosurg 2003;38:27e33. Tulipan N, Schulman M, Bruner JP. Reduced hindbrain herniation after intrauterine myelomeningocele repair: A report of four cases. Pediatr Neurosurg 1998;29:274e8. Tulipan N, Hernanz-Schulman M, Bruner JP. Intrauterine myelomeningocele repair reverses preexisting hindbrain herniation. Pediatr Neurosurg 1999;31:137e42. Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999;282:1826e31. Bruner JP, Tulipan N, Reed G, Davis GH, Bennett K, Luker KS, et al. Intrauterine repair of spina bifida: Preoperative predictors of shunt-dependent hydrocephalus. Am J Obstet Gynecol 2004;190:1305e12. Holzbeierlein J, Pope JC IV, Adams MC, Bruner J, Tulipan N, Brock 3rd JW. The urodynamic profile of myelodysplasia in childhood with spinal closure during gestation. J Urol 2000; 164:1336e9.
14. Tulipan N, Bruner JP, Hernanz-Schulman M, Lowe LH, Walsh WF, Nickolaus D, Oakes WJ. The effect of intrauterine myelomeningocele repair on central nervous system structure and neurologic function. Pediatr Neurosurg 1999;31:183e8. 15. Tubbs RS, Chambers MR, Smyth MD, Bartolucci AA, Bruner JP, Tulipan N, et al. Late gestational intrauterine myelomeningocele repair does not improve lower extremity function. Pediatr Neurosurg 2003;38:128e32. 16. Johnson MP, Sutton LN, Rintoul N. Fetal myelomeningocele repair: short-term clinical outcomes. Am J Obstet Gynecol 2003; 189:482e7. 17. Rintoul N, Sutton LN, Hubbard AM, Cohen B, Melchionni J, Pasquariello PS. A new look at myelomeningoceles: functional level, vertebral level, shunting and the implications for fetal intervention. Pediatrics 2002;109:409e13. 18. Bruner JP, Paschall RL. Cirugia fetal abierta. In: Gratacos E, Gomez R, Nicolaides K, Romero R, Cabero L, eds. Medicina fetal. Madrid: Medica Panamerica; 2007. 19. Bruner JP, Boehm FH, Tulipan N. The Tulipan-Bruner trocar for uterine entry during fetal surgery. Am J Obstet Gynecol 1999; 181:1188e91. 20. Quintero RA. Treatment of previable premature ruptured membranes. In: Bruner JP, ed. Clin Perinatol 2003;30:573e89. 21. Aaronson OS, Tulipan NB, Cywes R, Sundell HW, Davis GH, Bruner JP, et al. Robot-assisted endoscopic intrauterine myelomeningocele repair: A feasibility study. Pediatr Neurosurg 2002;36:85e9.