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Fetal Diagn Ther 2011;30:163–173

Fetal Surgery for Myelomeningocele: Patient Selection, Perioperative Management and Outcomes

Danzer E. · Adzick N.S.
The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Penn., USA
email Corresponding Author

 goto top of outline Key Words

  • Myelomeningocele
  • Spina bifida
  • Hydrocephalus
  • Hindbrain herniation
  • Prenatal diagnosis
  • Fetal surgery
  • Management of Myelomeningocele Study

 goto top of outline Abstract

Myelomeningocele (MMC), one of the most common congenital malformations, can result in severe lifelong disabilities, including paraplegia, hydrocephalus, Chiari II malformation (CM-II), incontinence, sexual dysfunction, skeletal deformations and mental impairment. MMC was the first nonlethal anomaly to be treated by fetal surgery. Experimental and clinical evidence suggests that the primary cause of the neurologic deficit associated with MMC is not simply incomplete neurulation but rather chronic mechanical injury and amniotic fluid-induced chemical trauma that progressively damages the exposed neural tissue during gestation. Case series and a prospective, randomized study show that fetal surgery for MMC before 26 weeks’ gestation may preserve neurologic function, reverse the hindbrain herniation of the CM-II and obviate the need for postnatal placement of a ventriculoperitoneal shunt. However, these studies also demonstrate that fetal surgery is associated with significant maternal and fetal risks. Consequently, further research is warranted to further expand our understanding of the pathophysiology of MMC, to evaluate the long-term impact of in utero intervention and to refine the timing and technique of fetal MMC surgery.

Copyright © 2011 S. Karger AG, Basel

 goto top of outline References
  1. Adzick NS: Fetal myelomeningocele: natural history, pathophysiology, and in-utero intervention. Semin Fetal Neonatal Med 2010;15:9–14.
  2. McLone DG, Dias MS: The Chiari II malformation: cause and impact. Childs Nerv Syst 2003;19:540–550.
  3. McLone DG, Knepper PA: The cause of Chiari II malformation: a unified theory. Pediatr Neurosci 1989;15:1–12.
  4. Bell WO, Charney EB, Bruce DA, Sutton LN, Schut L: Symptomatic Arnold-Chiari malformation: review of experience with 22 cases. J Neurosurg 1987;66:812–816.
  5. Charney EB, Rorke LB, Sutton LN, Schut L: Management of Chiari II complications in infants with myelomeningocele. J Pediatr 1987;111:364–371.
  6. Worley G, Schuster JM, Oakes WJ: Survival at 5 years of a cohort of newborn infants with myelomeningocele. Dev Med Child Neurol 1996;38:816–822.
  7. Hoffman HJ, Neill J, Crone KR, Hendrick EB, Humphreys RP: Hydrosyringomyelia and its management in childhood. Neurosurgery 1987;21:347–351.
  8. Rintoul NE, Sutton LN, Hubbard AM, et al: A new look at myelomeningoceles: functional level, vertebral level, shunting, and the implications for fetal intervention. Pediatrics 2002;109:409–413.
  9. 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;38:27–33.
  10. Beeker TW, Scheers MM, Faber JA, Tulleken CA: Prediction of independence and intelligence at birth in meningomyelocele. Childs Nerv Syst 2006;22:33–37.
  11. Dennis M, Landry SH, Barnes M, Fletcher JM: A model of neurocognitive function in spina bifida over the life span. J Int Neuropsychol Soc 2006;12:285–296.
  12. Pooh RK, Shiota K, Kurjak A: Imaging of the human embryo with magnetic resonance imaging microscopy and high-resolution transvaginal 3-dimensional sonography: human embryology in the 21st century. Am J Obstet Gynecol 2011;204:77.e1–77.e16.
  13. Botto LD, Moore CA, Khoury MJ, Erickson JD: Neural-tube defects. N Engl J Med 1999;341:1509–1519.
  14. Danzer E, Rintoul NE, Crombleholme TM, Adzick NS: Pathophysiology of neural tube defects; in Pollin R, Fox WW, Abman SH (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 2003, pp 1772–1785.
  15. Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, Sutton LN, Whitehead AS: Spina bifida. Lancet 2004;364:1885–1895.
  16. Williams LJ, Rasmussen SA, Flores A, Kirby RS, Edmonds LD: Decline in the prevalence of spina bifida and anencephaly by race/ethnicity: 1995–2002. Pediatrics 2005;116:580–586.
  17. De Wals P, Tairou F, Van Allen MI, et al: Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 2007;357:135–142.
  18. Hunt GM, Oakeshott P: Outcome in people with open spina bifida at age 35: prospective community based cohort study. BMJ 2003;326:1365–1366.
  19. Waitzman NJ, Romano PS, Scheffler RM: Estimates of the economic costs of birth defects. Inquiry 1994;31:188–205.
  20. Adzick NS, Thom EA, Spong CY, et al: A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364:993–1004.
  21. Patten BM: Embryological stages in the establishing of myeloschisis with spina bifida. Am J Anat 1953;93:365–395.
  22. Osaka K, Tanimura T, Hirayama A, Matsumoto S: Myelomeningocele before birth. J Neurosurg 1978;49:711–724.
  23. Osaka K, Matsumoto S, Tanimura T: Myeloschisis in early human embryos. Childs Brain 1978;4:347–359.
  24. Meuli M, Meuli-Simmen C, Hutchins GM, Seller MJ, Harrison MR, Adzick NS: The spinal cord lesion in human fetuses with myelomeningocele: implications for fetal surgery. J Pediatr Surg 1997;32:448–452.
  25. Hutchins GM, Meuli M, Meuli-Simmen C, Jordan MA, Heffez DS, Blakemore KJ: Acquired spinal cord injury in human fetuses with myelomeningocele. Pediatr Pathol Lab Med 1996;16:701–712.
  26. Danzer E, Ernst LM, Rintoul NE, Johnson MP, Adzick NS, Flake AW: In utero meconium passage in fetuses and newborns with myelomeningocele. J Neurosurg Pediatr 2009;3:141–146.
  27. Correia-Pinto J, Reis JL, Hutchins GM, et al: In utero meconium exposure increases spinal cord necrosis in a rat model of myelomeningocele. J Pediatr Surg 2002;37:488–492.
  28. Drewek MJ, Bruner JP, Whetsell WO, Tulipan N: Quantitative analysis of the toxicity of human amniotic fluid to cultured rat spinal cord. Pediatr Neurosurg 1997;27:190–193.
  29. Sival DA, Guerra M, den Dunnen WF, et al: Neuroependymal denudation is in progress in full-term human foetal spina bifida aperta. Brain Pathol 2011;21:163–179.
  30. de Wit OA, den Dunnen WF, Sollie KM, et al: Pathogenesis of cerebral malformations in human fetuses with meningomyelocele. Cerebrospinal Fluid Res 2008;5:4.
  31. Sival DA, Verbeek RJ, Brouwer OF, Sollie KM, Bos AF, den Dunnen WF: Spinal hemorrhages are associated with early neonatal motor function loss in human spina bifida aperta. Early Hum Dev 2008;84:423–431.
  32. Sarnat HB: Ependymal reactions to injury. A review. J Neuropathol Exp Neurol 1995;54:1–15.
  33. Korenromp MJ, van Gool JD, Bruinese HW, Kriek R: Early fetal leg movements in myelomeningocele. Lancet 1986;i:917–918.

    External Resources

  34. Sival DA, Begeer JH, Staal-Schreinemachers AL, Vos-Niel JM, Beekhuis JR, Prechtl HF: Perinatal motor behaviour and neurological outcome in spina bifida aperta. Early Hum Dev 1997;50:27–37.
  35. Bannister CM, Russell SA, Rimmer S, Arora A: Pre-natal ventriculomegaly and hydrocephalus. Neurol Res 2000;22:37–42.
  36. Bannister CM, Russell SA, Rimmer S: Pre-natal brain development of fetuses with a myelomeningocele. Eur J Pediatr Surg 1998;8(suppl 1):15–17.
  37. Babcook CJ, Goldstein RB, Barth RA, Damato NM, Callen PW, Filly RA: Prevalence of ventriculomegaly in association with myelomeningocele: correlation with gestational age and severity of posterior fossa deformity. Radiology 1994;190:703–707.
  38. Merrill DC, Goodwin P, Burson JM, Sato Y, Williamson R, Weiner CP: The optimal route of delivery for fetal meningomyelocele. Am J Obstet Gynecol 1998;179:235–240.
  39. Luthy DA, Wardinsky T, Shurtleff DB, et al: Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med 1991;324:662–666.
  40. Thevenet A, Sengel P: Naturally occurring wounds and wound healing in chick embryo wings. Roux Arch Dev Biol 1986;195:345–354.

    External Resources

  41. Copp AJ, Greene ND, Murdoch JN: The genetic basis of mammalian neurulation. Nat Rev Genet 2003;4:784–793.
  42. Greene ND, Stanier P, Copp AJ: Genetics of human neural tube defects. Hum Mol Genet 2009;18:R113–R129.
  43. Ehlers K, Sturje H, Merker HJ, Nau H: Spina bifida aperta induced by valproic acid and by all-trans-retinoic acid in the mouse: distinct differences in morphology and periods of sensitivity. Teratology 1992;46:117–130.
  44. Ehlers K, Sturje H, Merker HJ, Nau H: Valproic acid-induced spina bifida: a mouse model. Teratology 1992;45:145–154.
  45. Heffez DS, Aryanpur J, Hutchins GM, Freeman JM: The paralysis associated with myelomeningocele: clinical and experimental data implicating a preventable spinal cord injury. Neurosurgery 1990;26:987–992.
  46. Heffez DS, Aryanpur J, Rotellini NA, Hutchins GM, Freeman JM: Intrauterine repair of experimental surgically created dysraphism. Neurosurgery 1993;32:1005–1010.
  47. Meuli M, Meuli-Simmen C, Hutchins GM, et al: In utero surgery rescues neurological function at birth in sheep with spina bifida. Nat Med 1995;1:342–347.
  48. Meuli M, Meuli-Simmen C, Yingling CD, et al: Creation of myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep. J Pediatr Surg 1995;30:1028–1032, discussion 1032–1033.
  49. Meuli M, Meuli-Simmen C, Yingling CD, et al: In utero repair of experimental myelomeningocele saves neurological function at birth. J Pediatr Surg 1996;31:397–402.
  50. Michejda M: Intrauterine treatment of spina bifida: primate model. Z Kinderchir 1984;39:259–261.
  51. Paek BW, Farmer DL, Wilkinson CC, Albanese CT, Peacock W, Harrison MR, Jennings RW: Hindbrain herniation develops in surgically created myelomeningocele but is absent after repair in fetal lambs. Am J Obstet Gynecol 2000;183:1119–1123.
  52. Bouchard S, Davey MG, Rintoul NE, Walsh DS, Rorke LB, Adzick NS: Correction of hindbrain herniation and anatomy of the vermis after in utero repair of myelomeningocele in sheep. J Pediatr Surg 2003;38:451–458, discussion 451–458.
  53. McLone DG, Naidich TP: Developmental morphology of the subarachnoid space, brain vasculature, and contiguous structures, and the cause of the Chiari II malformation. AJNR Am J Neuroradiol 1992;13:463–482.
  54. Danzer E, Schwarz U, Wehrli S, Radu A, Adzick NS, Flake AW: Retinoic acid induced myelomeningocele in fetal rats: characterization by histopathological analysis and magnetic resonance imaging. Exp Neurol 2005;194:467–475.
  55. Danzer E, Kiddoo DA, Redden RA, et al: Structural and functional characterization of bladder smooth muscle in fetal rats with retinoic acid-induced myelomeningocele. Am J Physiol Renal Physiol 2007;292:F197–F206.
  56. Danzer E, Radu A, Robinson LE, Volpe MV, Adzick NS, Flake AW: Morphologic analysis of the neuromuscular development of the anorectal unit in fetal rats with retinoic acid induced myelomeningocele. Neurosci Lett 2008;430:157–162.
  57. Danzer E, Zhang L, Radu A, et al: Amniotic fluid levels of glial fibrillary acidic protein in fetal rats with retinoic acid induced myelomeningocele: a potential marker for spinal cord injury. Am J Obstet Gynecol 2011;204:178 e1–e11.
  58. Adzick NS, Harrison MR: Fetal surgical therapy. Lancet 1994;343:897–902.
  59. Danzer E, Sydorak RM, Harrison MR, Albanese CT: Minimal access fetal surgery. Eur J Obstet Gynecol Reprod Biol 2003;108:3–13.
  60. Husler MR, Danzer E, Johnson MP, et al: Prenatal diagnosis and postnatal outcome of fetal spinal defects without Arnold-Chiari II malformation. Prenat Diagn 2009;29:1050–1057.
  61. Schwarz U, Galinkin JL: Anesthesia for fetal surgery. Semin Pediatr Surg 2003;12:196–201.
  62. Bruner JP, Tulipan NE, Richards WO: Endoscopic coverage of fetal open myelomeningocele in utero. Am J Obstet Gynecol 1997;176:256–257.
  63. Kohl T, Hering R, Heep A, et al: Percutaneous fetoscopic patch coverage of spina bifida aperta in the human – early clinical experience and potential. Fetal Diagn Ther 2006;21:185–193.
  64. Farmer DL, von Koch CS, Peacock WJ, et al: In utero repair of myelomeningocele: experimental pathophysiology, initial clinical experience, and outcomes. Arch Surg 2003;138:872–878.
  65. Adzick NS, Sutton LN, Crombleholme TM, Flake AW: Successful fetal surgery for spina bifida. Lancet 1998;352:1675–1676.
  66. 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;282:1826–1831.
  67. Bruner JP, Tulipan N, Paschall RL, et al: Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999;282:1819–1825.
  68. Danzer E, Johnson MP, Bebbington M, et al: Fetal head biometry assessed by fetal magnetic resonance imaging following in utero myelomeningocele repair. Fetal Diagn Ther 2007;22:1–6.
  69. Danzer E, Johnson MP, Wilson RD, et al: Fetal head biometry following in-utero repair of myelomeningocele. Ultrasound Obstet Gynecol 2004;24:606–611.
  70. Danzer E, Finkel R, Gerdes M, et al: The relationship of seizure activity and chronic epilepsy in early infancy and short-term neurodevelopmental outcome following fetal myelomeningocele closure. Neuropediatrics 2010;41:140–143.
  71. Danzer E, Finkel RS, Rintoul NE, et al: Reversal of hindbrain herniation after maternal-fetal surgery for myelomeningocele subsequently impacts on brain stem function. Neuropediatrics 2008;39:359–362.
  72. Danzer E, Gerdes M, Bebbington MW, et al: Lower extremity neuromotor function and short-term ambulatory potential following in utero myelomeningocele surgery. Fetal Diagn Ther 2009;25:47–53.
  73. Danzer E, Adzick NS, Rintoul NE, et al: Intradural inclusion cysts following in utero closure of myelomeningocele: clinical implications and follow-up findings. J Neurosurg Pediatr 2008;2:406–413.
  74. Danzer E, Gerdes M, Bebbington MW, Zarnow DM, Adzick NS, Johnson MP: Preschool neurodevelopmental outcome of children following fetal myelomeningocele closure. Am J Obstet Gynecol 2010;202:450.e1– 450.e9.
  75. Danzer E, Gerdes M, Bebbington MW, Koh J, Adzick SN, Johnson MP: Fetal myelomeningocele surgery: preschool functional status using the Functional Independence Measure for children (WeeFIM). Childs Nerv Syst 2011;27:1083–1088.
  76. Holmes NM, Nguyen HT, Harrison MR, Farmer DL, Baskin LS: Fetal intervention for myelomeningocele: effect on postnatal bladder function. J Urol 2001;166:2383–2386.
  77. Holzbeierlein J, Pope JI, Adams MC, Bruner J, Tulipan N, Brock JW 3rd: The urodynamic profile of myelodysplasia in childhood with spinal closure during gestation. J Urol 2000;164:1336–1339.
  78. Watanabe M, Jo J, Radu A, Kaneko M, Tabata Y, Flake AW: A tissue engineering approach for prenatal closure of myelomeningocele with gelatin sponges incorporating basic fibroblast growth factor. Tissue Eng Part A 2010;16:1645–1655.

 goto top of outline Author Contacts

N. Scott Adzick, MD
The Center for Fetal Diagnosis and Treatment, 5th Floor Wood Center
The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard
Philadelphia, PA 19104-4388 (USA)
Tel. +1 215 590 2727, E-Mail

 goto top of outline Article Information

Received: May 22, 2011
Accepted after revision: May 31, 2011
Published online: August 18, 2011
Number of Print Pages : 11
Number of Figures : 3, Number of Tables : 1, Number of References : 78

 goto top of outline Publication Details

Fetal Diagnosis and Therapy (Clinical Advances and Basic Research)

Vol. 30, No. 3, Year 2011 (Cover Date: November 2011)

Journal Editor: Gratacós E. (Barcelona)
ISSN: 1015-3837 (Print), eISSN: 1421-9964 (Online)

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