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Eur J Pediatr Surg 2013; 23(02): 103-109
DOI: 10.1055/s-0033-1343082
Review
Georg Thieme Verlag KG Stuttgart · New York

Fetal Surgery for Myelomeningocele: A Critical Appraisal

Martin Meuli
1   Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland
2   The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland
,
Ueli Moehrlen
1   Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland
2   The Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland
› Institutsangaben
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Publikationsverlauf

11. März 2013

11. März 2013

Publikationsdatum:
09. April 2013 (online)

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Abstract

This article narrates the thrilling story of how the pathogenetic understanding of myelomeningocele was fundamentally revised during the last decades and how these new insights, in particular the “two-hit hypothesis,” have prepared the terrain for human fetal surgery. Formerly, the devastating cluster of neurologic and neurogenic problems was mainly attributed to the primary malformation, that is, failure of neurulation. At present, there is solid evidence that in early gestation the nonneurulated spinal cord functions well, but suffers from progressive traumatic and degenerative damage in later gestation because it is openly exposed to the amniotic cavity. There is no doubt that the secondary, in utero acquired spinal cord destruction is mainly responsible for the disastrous and irreversible peripheral neurologic deficit present at birth, and there is no doubt either that timely prenatal protective coverage can potentially arrest these deleterious dynamics and preserve neurologic function. Also, tethering of the cord within and constant outflow of cerebrospinal fluid from the lesion are seen as the driving forces behind the Chiari II malformation and consequent ventriculomegaly. Untethering and watertight sealing of the lesion reverses hindbrain herniation and lowers the risk for a relevant hydrocephalus. This article then details how human fetal surgery started in the late 1990s and follows the evolution from the pioneer case studies via the first case series providing encouraging results to the ground breaking Management of Myelomeningocele Study Trial, published in The New England Journal of Medicine in February 2011 by Adzick et al, that has, for the first time, generated unequivocal evidence that patients with prenatal repair do significantly better than those with postnatal care only. Finally, this review looks at several other critical issues, including the hitherto immature endoscopic approach to fetal repair, some future directions of research and clinical practice, and also utters a plea for concentration of these equally rare and complex cases to a few truly qualified centers worldwide. The conclusion derived from all data existing today is that maternal–fetal surgery, although not a cure and not free of risks, represents a novel standard of care for select mothers and their fetuses suffering from one of the most ruinous nonlethal congenital malformations.

Keywords

fetal surgery - myelomeningocele - spina bifida - prenatal diagnosis
 

  • References

  • 1 Harrison MR, Golbus MS, Filly RA , et al. Fetal surgery for congenital hydronephrosis. N Engl J Med 1982; 306 (10) 591-593
    CrossrefPubMedGoogle Scholar
  • 2 Patten BM. Embryological stages in the establishing of myeloschisis with spina bifida. Am J Anat 1953; 93 (3) 365-395
    CrossrefPubMedGoogle Scholar
  • 3 Cameron AH. The spinal cord lesion in spina bifida cystica. Lancet 1956; 271 (6935) 171-174
    PubMedGoogle Scholar
  • 4 Hutchins GM, McGowan KD, Blakemore KJ. Spinal dysraphia: not a neural tube defect?. Am J Hum Genet 1992; 1: A319
    PubMedGoogle Scholar
  • 5 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 (5) 701-712
    CrossrefPubMedGoogle Scholar
  • 6 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 (6) 987-992
    CrossrefPubMedGoogle Scholar
  • 7 Heffez DS, Aryanpur J, Rotellini NA, Hutchins GM, Freeman JM. Intrauterine repair of experimental surgically created dysraphism. Neurosurgery 1993; 32 (6) 1005-1010
    CrossrefPubMedGoogle Scholar
  • 8 Jordan MA, Heffez DS, Hutchins GM. The relationships of the spinal cord and meninges in meningocele, meningomyelocele and iniencephaly. Teratology 1991; 43: 472
    PubMedGoogle Scholar
  • 9 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 (3) 448-452
    CrossrefPubMedGoogle Scholar
  • 10 Michejda M. Intrauterine treatment of spina bifida: primate model. Z Kinderchir 1984; 39 (4) 259-261
    PubMedGoogle Scholar
  • 11 Housley HT, Graf JL, Lipshultz GS , et al. Creation of myelomeningocele in the fetal rabbit. Fetal Diagn Ther 2000; 15 (5) 275-279
    CrossrefPubMedGoogle Scholar
  • 12 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 (4) 342-347
    CrossrefPubMedGoogle Scholar
  • 13 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 (7) 1028-1032 , discussion 1032–1033
    CrossrefPubMedGoogle Scholar
  • 14 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 (3) 397-402
    CrossrefPubMedGoogle Scholar
  • 15 Stiefel D, Copp AJ, Meuli M. Fetal spina bifida in a mouse model: loss of neural function in utero. J Neurosurg 2007; 106 (3, Suppl): 213-221
    PubMedGoogle Scholar
  • 16 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 (1) F197-F206
    PubMedGoogle Scholar
  • 17 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 (2) 157-162
    CrossrefPubMedGoogle Scholar
  • 18 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 (2) e1-e11
    PubMedGoogle Scholar
  • 19 Encinas JL, García-Cabezas MA, Barkovich J , et al. Maldevelopment of the cerebral cortex in the surgically induced model of myelomeningocele: implications for fetal neurosurgery. J Pediatr Surg 2011; 46 (4) 713-722
    CrossrefPubMedGoogle Scholar
  • 20 Stiefel D, Meuli M. Scanning electron microscopy of fetal murine myelomeningocele reveals growth and development of the spinal cord in early gestation and neural tissue destruction around birth. J Pediatr Surg 2007; 42 (9) 1561-1565
    CrossrefPubMedGoogle Scholar
  • 21 Stiefel D, Shibata T, Meuli M, Duffy PG, Copp AJ. Tethering of the spinal cord in mouse fetuses and neonates with spina bifida. J Neurosurg 2003; 99 (2, Suppl): 206-213
    PubMedGoogle Scholar
  • 22 Stiefel D, Meuli M. The dysraphic levels of skin and vertebrae are different in mouse fetuses and neonates with myelomeningocele. J Pediatr Surg 2008; 43 (4) 683-690
    CrossrefPubMedGoogle Scholar
  • 23 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 (3) 451-458 , discussion 451–458
    CrossrefPubMedGoogle Scholar
  • 24 Paek BW, Farmer DL, Wilkinson CC , et al. Hindbrain herniation develops in surgically created myelomeningocele but is absent after repair in fetal lambs. Am J Obstet Gynecol 2000; 183 (5) 1119-1123
    CrossrefPubMedGoogle Scholar
  • 25 Bruner JP, Tulipan NE, Richards WO. Endoscopic coverage of fetal open myelomeningocele in utero. Am J Obstet Gynecol 1997; 176 (1 Pt 1) 256-257
    PubMedGoogle Scholar
  • 26 Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina bifida. Lancet 1998; 352 (9141) 1675-1676
    CrossrefPubMedGoogle Scholar
  • 27 Bruner JP, Tulipan N, Paschall RL , et al. Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999; 282 (19) 1819-1825
    CrossrefPubMedGoogle Scholar
  • 28 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 (19) 1826-1831
    CrossrefPubMedGoogle Scholar
  • 29 Johnson MP, Sutton LN, Rintoul N , et al. Fetal myelomeningocele repair: short-term clinical outcomes. Am J Obstet Gynecol 2003; 189 (2) 482-487
    CrossrefPubMedGoogle Scholar
  • 30 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 (3) 409-413
    CrossrefPubMedGoogle Scholar
  • 31 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) 1-6
    CrossrefPubMedGoogle Scholar
  • 32 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 (6) 359-362
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 33 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 (1) 47-53
    CrossrefPubMedGoogle Scholar
  • 34 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 (5) e1-e9
    PubMedGoogle Scholar
  • 35 Johnson MP, Gerdes M, Rintoul N , et al. Maternal-fetal surgery for myelomeningocele: neurodevelopmental outcomes at 2 years of age. Am J Obstet Gynecol 2006; 194 (4) 1145-1150 , discussion 1150–1152
    CrossrefPubMedGoogle Scholar
  • 36 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 (6) 406-413
    CrossrefPubMedGoogle Scholar
  • 37 Clayton DB, Tanaka ST, Trusler L , et al. Long-term urological impact of fetal myelomeningocele closure. J Urol 2011; 186 (4, Suppl): 1581-1585
    CrossrefPubMedGoogle Scholar
  • 38 Wilson RD, Johnson MP, Flake AW , et al. Reproductive outcomes after pregnancy complicated by maternal-fetal surgery. Am J Obstet Gynecol 2004; 191 (4) 1430-1436
    CrossrefPubMedGoogle Scholar
  • 39 Wilson RD, Lemerand K, Johnson MP , et al. Reproductive outcomes in subsequent pregnancies after a pregnancy complicated by open maternal-fetal surgery (1996-2007). Am J Obstet Gynecol 2010; 203 (3) e1-e6
    CrossrefPubMedGoogle Scholar
  • 40 Adzick NS, Thom EA, Spong CY , et al; MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011; 364 (11) 993-1004
    CrossrefPubMedGoogle Scholar
  • 41 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 (8) 872-878
    CrossrefPubMedGoogle Scholar
  • 42 Kohl T, Gembruch U. Current status and prospects of fetoscopic surgery for spina bifida in human fetuses. Response to Fichter et al: Fetal spina bifida repair—current trends and prospects of intrauterine neurosurgery (Fetal Diagn Ther 2008;23:271-286). Fetal Diagn Ther 2008; 24 (3) 318-320
    CrossrefPubMedGoogle Scholar
  • 43 Verbeek RJ, Heep A, Maurits NM. Does fetal endoscopic closure of the myelomeningocele prevent loss of neurologic function in spina bifida aperta?. Cerebrospinal Fluid Res 2010; 7 (Suppl. 01) S18
    CrossrefPubMedGoogle Scholar
  • 44 Verbeek RJ, Heep A, Maurits NM , et al. Fetal endoscopic myelomeningocele closure preserves segmental neurological function. Dev Med Child Neurol 2012; 54 (1) 15-22
    CrossrefPubMedGoogle Scholar
  • 45 Shurtleff D. Fetal endoscopic myelomeningocele repair. Dev Med Child Neurol 2012; 54 (1) 4-5
    PubMedGoogle Scholar
  • 46 Hisaba WJ, Cavalheiro S, Almodim CG , et al. Intrauterine myelomeningocele repair postnatal results and follow-up at 3.5 years of age—initial experience from a single reference service in Brazil. Childs Nerv Syst 2012; 28 (3) 461-467
    CrossrefPubMedGoogle Scholar
  • 47 Zamłyńiski J, Olejek A, Bohosiewicz J , et al. [Perinatal results of intrauterine open fetal surgery of fetuses diagnosed with myelomeningocoele—the clinical report of ten cases]. Ginekol Pol 2007; 78 (8) 647-651
    PubMedGoogle Scholar
  • 48 Meuli M, Moehrlen U, Flake A , et al. Fetal surgery in Zurich: key features of our first open in utero repair of myelomeningocele. Eur J Pediatr Surg 2012; ; November 19 (Epub ahead of print)
    PubMedGoogle Scholar
  • 49 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 (5) 1645-1655
    CrossrefPubMedGoogle Scholar
  • 50 Watanabe M, Li H, Roybal J , et al. A tissue engineering approach for prenatal closure of myelomeningocele: comparison of gelatin sponge and microsphere scaffolds and bioactive protein coatings. Tissue Eng Part A 2011; 17 (7-8) 1099-1110
    CrossrefPubMedGoogle Scholar