iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://www.nature.com/articles/nrdp20157
Spina bifida | Nature Reviews Disease Primers
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Spina bifida

Nature Reviews Disease Primers volume 1, Article number: 15007 (2015) Cite this article

Subjects

Abstract

Spina bifida is a birth defect in which the vertebral column is open, often with spinal cord involvement. The most clinically significant subtype is myelomeningocele (open spina bifida), which is a condition characterized by failure of the lumbosacral spinal neural tube to close during embryonic development. The exposed neural tissue degenerates in utero, resulting in neurological deficit that varies with the level of the lesion. Occurring in approximately 1 per 1,000 births worldwide, myelomeningocele is one of the most common congenital malformations, but its cause is largely unknown. The genetic component is estimated at 60–70%, but few causative genes have been identified to date, despite much information from mouse models. Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity. Primary prevention by periconceptional supplementation with folic acid has been demonstrated in clinical trials, leading to food fortification programmes in many countries. Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy. Individuals who survive to birth have their lesions closed surgically, with subsequent management of associated defects, including the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae. Fetal surgical repair of myelomeningocele has been associated with improved early neurological outcome compared with postnatal operation. Myelomeningocele affects quality of life during childhood, adolescence and adulthood, posing a challenge for individuals, families and society as a whole. For an illustrated summary of this Primer, visit: http://go.nature.com/fK9XNa

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of neural tube defects.
Figure 2: Neurulation and the origin of open and closed spinal bifida.
Figure 3: MRI appearance of brain dysmorphology in myelomeningocele.
Figure 4: Myelomeningocele and associated cranial signs on ultrasonography.
Figure 5: Fetal surgery for spina bifida.
Figure 6: Quality-of-life concerns across developmental stages in patients with spina bifida.
Figure 7: Folate metabolism and possible interventions.

Similar content being viewed by others

References

  1. Meuli, M. et al. The spinal cord lesion in human fetuses with myelomeningocele: Implications for fetal surgery. J. Pediatr. Surg. 32, 448–452 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Oakeshott, P., Hunt, G. M., Poulton, A. & Reid, F. Open spina bifida: birth findings predict long-term outcome. . Arch. Dis. Child. 97, 474–476 (2012).

    Article  PubMed  Google Scholar 

  3. Yi, Y., Lindemann, M., Colligs, A. & Snowball, C. Economic burden of neural tube defects and impact of prevention with folic acid: a literature review. Eur. J. Pediatr. 170, 1391–1400 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Elwood, J. M., Little, J. & Elwood, J. H. Epidemiology and Control of Neural Tube Defects (Oxford Univ. Press, 1992).

    Google Scholar 

  5. International Center on Birth Defects. International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS), Annual Report 2011 with Data for 2009 (International Center on Birth Defects, 2011).

  6. Li, Z. et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res. A Clin. Mol. Teratol. 76, 237–240 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Moore, C. A. et al. Elevated rates of severe neural tube defects in a high-prevalence area in northern China. Am. J. Med. Genet. 73, 113–118 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Canfield, M. A. et al. Anencephaly and spina bifida among Hispanics: maternal, sociodemographic, and acculturation factors in the National Birth Defects Prevention Study. Birth Defects Res. A Clin. Mol. Teratol. 85, 637–646 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Cragan, J. D. et al. Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis – United States, 1985–1994. MMWR CDC Surveill. Summ. 44, 1–13 (1995).

    CAS  PubMed  Google Scholar 

  10. Velie, E. M. & Shaw, G. M. Impact of prenatal diagnosis and elective termination on prevalence and risk estimates of neural tube defects in California, 1989–1991. Am. J. Epidemiol. 144, 473–479 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Dolk, H., Loane, M. & Garne, E. The prevalence of congenital anomalies in Europe. Adv. Exp. Med. Biol. 686, 349–364 (2010).

    Article  PubMed  Google Scholar 

  12. Carter, C. O. & Evans, K. A. Spina bifida and anencephalus in Greater London. J. Med. Genet. 10, 209–234 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rampersaud, E., Melvin, E. C. & Speer, M. C. in Neural Tube Defects: From Origin to Treatment (ed. Wyszynski, D. F. ) 165–175 (Oxford Univ. Press, 2006).

    Google Scholar 

  14. Juriloff, D. M. & Harris, M. J. Hypothesis: the female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating X chromosome on the molecular mechanisms of neural fold elevation. Birth Defects Res. A Clin. Mol. Teratol. 94, 849–855 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Leck, I. Causation of neural tube defects: clues from epidemiology. Br. Med. Bull. 30, 158–163 (1974).

    Article  CAS  PubMed  Google Scholar 

  16. Stothard, K. J., Tennant, P. W., Bell, R. & Rankin, J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 301, 636–650 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Waller, D. K. et al. Prepregnancy obesity as a risk factor for structural birth defects. Arch. Pediatr. Adolesc. Med. 161, 745–750 (2007).

    Article  PubMed  Google Scholar 

  18. Carmichael, S. L., Rasmussen, S. A. & Shaw, G. M. Prepregnancy obesity: a complex risk factor for selected birth defects. Birth Defects Res. A Clin. Mol. Teratol. 88, 804–810 (2010). This paper provides a critical synoptic view of the importance and complexity of obesity as a risk factor for human birth defects.

    Article  CAS  PubMed  Google Scholar 

  19. Parker, S. E., Yazdy, M. M., Tinker, S. C., Mitchell, A. A. & Werler, M. M. The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida. Am. J. Obstet. Gynecol. 209, 239–238 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Agopian, A. J., Tinker, S. C., Lupo, P. J., Canfield, M. A. & Mitchell, L. E. Proportion of neural tube defects attributable to known risk factors. Birth Defects Res. A Clin. Mol. Teratol. 97, 42–46 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stiefel, D., Copp, A. J. & Meuli, M. Fetal spina bifida: loss of neural function in utero. J. Neurosurg. 106, 213–221 (2007).

    PubMed  PubMed Central  Google Scholar 

  22. Harris, M. J. & Juriloff, D. M. An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res. A Clin. Mol. Teratol. 88, 653–669 (2010). This article gives an overview of >200 genes in mice that when mutated or knocked out, give rise to a range of NTDs, confirming that various pathways are involved in neurulation.

    Article  CAS  PubMed  Google Scholar 

  23. Copp, A. J. & Greene, N. D. E. Genetics and development of neural tube defects. J. Pathol. 220, 217–230 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Harris, M. J. & Juriloff, D. M. Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects. Birth Defects Res. A Clin. Mol. Teratol. 79, 187–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Juriloff, D. M. & Harris, M. J. A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. Birth Defects Res. A Clin. Mol. Teratol. 94, 824–840 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Murdoch, J. N. et al. Interactions between planar cell polarity genes cause diverse neural tube defects. Dis. Model. Mech. 7, 1153–1163 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Amorim, M. R., Lima, M. A., Castilla, E. E. & Orioli, I. M. Non-Latin European descent could be a requirement for association of NTDs and MTHFR variant 677C > T: a meta-analysis. Am. J. Med. Genet. A 143A, 1726–1732 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Pickell, L. et al. Methylenetetrahydrofolate reductase deficiency and low dietary folate increase embryonic delay and placental abnormalities in mice. Birth Defects Res. A Clin. Mol. Teratol. 85, 531–541 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Narisawa, A. et al. Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. Hum. Mol. Genet. 21, 1496–1503 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Pai, Y. J. et al. Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. Nat. Commun. 6, 6388 (2015).

  31. Robert, E. & Guidbaud, P. Maternal valproic acid and congenital neural tube defects. Lancet 320, 937 (1982).

  32. Phiel, C. J. et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276, 36734–36741 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Hendricks, K. A., Simpson, J. S. & Larsen, R. D. Neural tube defects along the Texas-Mexico border, 1993–1995. Am. J. Epidemiol. 149, 1119–1127 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Marasas, W. F. O. et al. Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. J. Nutr. 134, 711–716 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Phelan, S. A., Ito, M. & Loeken, M. R. Neural tube defects in embryos of diabetic mice: role of the Pax-3gene and apoptosis. Diabetes 46, 1189–1197 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Müller, F. & O'Rahilly, R. The development of the human brain, the closure of the caudal neuropore, and the beginning of secondary neurulation at stage 12. Anat. Embryol. 176, 413–430 (1987).

    Article  PubMed  Google Scholar 

  37. Ybot-Gonzalez, P. et al. Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development 134, 789–799 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ybot-Gonzalez, P. et al. Neural plate morphogenesis during mouse neurulation is regulated by antagonism of BMP signalling. Development 134, 3203–3211 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Van Straaten, H. W. M. & Copp, A. J. Curly tail: a 50-year history of the mouse spina bifida model. Anat. Embryol. 203, 225–237 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schoenwolf, G. C. Histological and ultrastructural studies of secondary neurulation of mouse embryos. Am. J. Anat. 169, 361–374 (1984).

    Article  CAS  PubMed  Google Scholar 

  41. Wilson, V., Olivera-Martinez, I. & Storey, K. G. Stem cells, signals and vertebrate body axis extension. Development 136, 1591–1604 (2009). This paper reviews the important studies that have shown the existence of multipotent progenitor cells at the caudal extremity of the embryo, and that have determined the signalling pathways involved in secondary neurulation and formation of the lower body axis.

    Article  CAS  PubMed  Google Scholar 

  42. Finn, M. A. & Walker, M. L. Spinal lipomas: clinical spectrum, embryology, and treatment. Neurosurg. Focus 23, E10 (2007).

    Article  PubMed  Google Scholar 

  43. Barkovich, A. J. & Raybaud, C. Pediatric Neuroimaging (Lippincott Williams & Wilkins, 2011).

    Google Scholar 

  44. McLone, D. G. & Knepper, P. A. The cause of Chiari II malformation: a unified theory. Pediatr. Neurosci. 15, 1–12 (1989).

    Article  CAS  PubMed  Google Scholar 

  45. Juranek, J., Dennis, M., Cirino, P. T., El-Messidi, L. & Fletcher, J. M. The cerebellum in children with spina bifida and Chiari II malformation: quantitative volumetrics by region. Cerebellum 9, 240–248 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Fletcher, J. M. et al. Spinal lesion level in spina bifida: a source of neural and cognitive heterogeneity. J. Neurosurg. 102, 268–279 (2005).

    PubMed  Google Scholar 

  47. Ware, A. L. et al. Anatomical and diffusion MRI of deep gray matter in pediatric spina bifida. Neuroimage Clin. 5, 120–127 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Treble-Barna, A. et al. Prospective and episodic memory in relation to hippocampal volume in adults with spina bifida myelomeningocele. Neuropsychology 29, 92–101 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Barkovich, A. J. & Norman, D. Anomalies of the corpus callosum: correlation with further anomalies of the brain. Am. J. Roentgenol. 151, 171–179 (1988).

    Article  CAS  Google Scholar 

  50. Crawley, J. T. et al. Structure, integrity, and function of the hypoplastic corpus callosum in spina bifida myelomeningocele. Brain Connect. 4, 608–618 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Herweh, C. et al. DTI of commissural fibers in patients with Chiari II-malformation. Neuroimage 44, 306–311 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Erol, F. S., Ozturk, S., Akgun, B., Cakin, H. & Kaplan, M. How innocent is corpus callosum dysgenesis? Pediatr. Neurosurg. 49, 24–28 (2013).

    Article  PubMed  Google Scholar 

  53. Juranek, J. et al. Neocortical reorganization in spina bifida. Neuroimage 40, 1516–1522 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Del Bigio, M. R. Neuropathology and structural changes in hydrocephalus. Dev. Disabil. Res. Rev. 16, 16–22 (2010). This report integrates the results of animal and human studies to further our understanding of the effects of hydrocephalus on the brain.

    Article  PubMed  Google Scholar 

  55. Hasan, K. M. et al. White matter microstructural abnormalities in children with spina bifida myelomeningocele and hydrocephalus: a diffusion tensor tractography study of the association pathways. J. Magn. Reson. Imaging 27, 700–709 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ou, X., Glasier, C. M. & Snow, J. H. Diffusion tensor imaging evaluation of white matter in adolescents with myelomeningocele and Chiari II malformation. Pediatr. Radiol. 41, 1407–1415 (2011).

    Article  PubMed  Google Scholar 

  57. Williams, V. J. et al. Examination of frontal and parietal tectocortical attention pathways in spina bifida meningomyelocele using probabilistic diffusion tractography. Brain Connect. 3, 512–522 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hampton, L. E. et al. Hydrocephalus status in spina bifida: an evaluation of variations in neuropsychological outcomes. J. Neurosurg. Pediatr. 8, 289–298 (2011).

    Article  PubMed  Google Scholar 

  59. Treble, A., Juranek, J., Stuebing, K. K., Dennis, M. & Fletcher, J. M. Functional significance of atypical cortical organization in spina bifida myelomeningocele: relations of cortical thickness and gyrification with IQ and fine motor dexterity. Cereb. Cortex 23, 2357–2369 (2013).

    Article  PubMed  Google Scholar 

  60. Dennis, M., Salman, M. S., Juranek, J. & Fletcher, J. M. Cerebellar motor function in spina bifida meningomyelocele. Cerebellum 9, 484–498 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Treble-Barna, A., Kulesz, P. A., Dennis, M. & Fletcher, J. M. Covert orienting in three etiologies of congenital hydrocephalus: the effect of midbrain and posterior fossa dysmorphology. J. Int. Neuropsychol. Soc. 20, 268–277 (2014).

    Article  PubMed  Google Scholar 

  62. Hannay, H. J. et al. Auditory interhemispheric transfer in relation to patterns of partial agenesis and hypoplasia of the corpus callosum in spina bifida meningomyelocele. J. Int. Neuropsychol. Soc. 14, 771–781 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Taylor, H. B. et al. Motor contingency learning and infants with spina bifida. J. Int. Neuropsychol. Soc. 19, 206–215 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Dennis, M., Landry, S. H., Barnes, M. & Fletcher, J. M. A model of neurocognitive function in spina bifida over the life span. J. Int. Neuropsychol. Soc. 12, 285–296 (2006). This work provides a framework for understanding the variability in cognitive and motor outcomes for people with myelomeningocele, based on genetic, neurological and environmental factors.

    Article  PubMed  Google Scholar 

  65. Brock, D. J. H. & Sutcliffe, R. G. Early prenatal diagnosis of anencephaly. Lancet 300, 1252–1253 (1972).

    Article  Google Scholar 

  66. Seller, M. J., Campbell, S., Coltart, T. M. & Singer, J. D. Early termination of anencephalic pregnancy after detection by raised alpha-fetoprotein levels. Lancet 302, 73 (1973).

  67. [No authors listed.] Amniotic fluid acetylcholinesterase electrophoresis as a secondary test in the diagnosis of anencephaly and open spina bifida in early pregnancy. Report of the Collaborative Acetylcholinesterase Study. Lancet 318, 321–324 (1981).

  68. Wald, N. J. et al. Maternal serum-alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Report of UK collaborative study on alpha-fetoprotein in relation to neural-tube defects. Lancet 309, 1323 (1977).

  69. Wald, N. J. Prenatal screening for open neural tube defects and Down syndrome: three decades of progress. Prenat. Diag. 30, 619–621 (2010).

    Article  Google Scholar 

  70. Campbell, S., Pryse-Davies, J., Coltart, T. M., Seller, M. J. & Singer, J. D. Ultrasound in the diagnosis of spina bifida. Lancet 305, 1065–1068 (1975).

    Article  Google Scholar 

  71. Wald, N., Cuckle, H., Boreham, J. & Stirrat, G. Small biparietal diameter of fetuses with spina bifida: implications for antenatal screening. Br. J. Obstet. Gynaecol. 87, 219–221 (1980).

    Article  CAS  PubMed  Google Scholar 

  72. Biggio, J. R. Jr., Owen, J., Wenstrom, K. D. & Oakes, W. J. Can prenatal ultrasound findings predict ambulatory status in fetuses with open spina bifida? Am. J. Obstet. Gynecol. 185, 1016–1020 (2001).

    Article  PubMed  Google Scholar 

  73. Nicolaides, K. H., Gabbe, S. G., Campbell, S. & Guidetti, R. Ultrasound screening for spina bifida: cranial and cerebellar signs. Lancet 328, 72–74 (1986).

    Article  Google Scholar 

  74. Nyberg, D. A., Mack, L. A., Hirsch, J. & Mahony, B. S. Abnormalities of fetal cranial contour in sonographic detection of spina bifida: evaluation of the “lemon” sign. Radiology 167, 387–392 (1988).

    Article  CAS  PubMed  Google Scholar 

  75. Penso, C., Redline, R. W. & Benacerraf, B. R. A sonographic sign which predicts which fetuses with hydrocephalus have an associated neural tube defect. J. Ultrasound Med. 6, 307–311 (1987).

    Article  CAS  PubMed  Google Scholar 

  76. Thiagarajah, S. et al. Early diagnosis of spina bifida: the value of cranial ultrasound markers. Obstet. Gynecol. 76, 54–57 (1990).

    CAS  PubMed  Google Scholar 

  77. Bahlmann, F. et al. Cranial and cerebral signs in the diagnosis of spina bifida between 18 and 22 weeks of gestation: a German multicenter study. Prenat. Diag. 35, 228–235 (2014).

    Article  Google Scholar 

  78. Blumenfeld, Z., Siegler, E. & Bronshtein, M. The early diagnosis of neural tube defects. Prenat. Diag. 13, 863–871 (1993).

    Article  CAS  Google Scholar 

  79. Van den Hof, M. C., Nicolaides, K. H., Campbell, J. & Campbell, S. Evaluation of the lemon and banana signs in one hundred thirty fetuses with open spina bifida. Am. J. Obstet. Gynecol. 162, 322–327 (1990). This investigation demonstrates the importance of the cranial signs in prenatal ultrasonography screening for spina bifida.

    Article  CAS  PubMed  Google Scholar 

  80. Chitty, L. S. Ultrasound screening for fetal abnormalities. Prenat. Diag. 15, 1241–1257 (1995).

    Article  CAS  Google Scholar 

  81. Rankin, J., Glinianaia, S., Brown, R. & Renwick, M. The changing prevalence of neural tube defects: a population-based study in the north of England, 1984–1996. Paediatr. Perinat. Epidemiol. 14, 104–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. [No authors listed.] NHS Fetal Anomaly Screening Programme Standards. UK National Screening Committee[online], (2015).

  83. Kennedy, D., Chitayat, D., Winsor, E. J. T., Silver, M. & Toi, A. Prenatally diagnosed neural tube defects: ultrasound, chromosome, and autopsy or postnatal findings in 212 cases. Am. J. Med. Genet. 77, 317–321 (1998). This work studies the underlying aetiology of NTDs and demonstrates the benefit of autopsy and other investigations in determining aetiology.

    Article  CAS  PubMed  Google Scholar 

  84. Buyukkurt, S. et al. Prenatal determination of the upper lesion level of spina bifida with three-dimensional ultrasound. Fetal Diagn. Ther. 33, 36–40 (2013).

    Article  PubMed  Google Scholar 

  85. Van Der Vossen, S. et al. Role of prenatal ultrasound in predicting survival and mental and motor functioning in children with spina bifida. Ultrasound Obstet. Gynecol. 34, 253–258 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Obican, S. G., Finnell, R. H., Mills, J. L., Shaw, G. M. & Scialli, A. R. Folic acid in early pregnancy: a public health success story. FASEB J. 24, 4167–4174 (2010). This paper nicely summarizes the very extensive literature on folic acid and NTDs, including data obtained from human genetic studies and from animal experiments.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Smithells, R. W., Sheppard, S. & Schorah, C. J. Vitamin deficiencies and neural tube defects. Arch. Dis. Child. 51, 944–950 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Smithells, R. W. et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch. Dis. Child. 56, 911–918 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131–137 (1991). This is the randomized clinical trial on which primary prevention of spina bifida by folic acid is based.

    Article  Google Scholar 

  90. Czeizel, A. E. & Dudás, I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 327, 1832–1835 (1992).

    Article  CAS  PubMed  Google Scholar 

  91. Canfield, M. A. et al. Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study. Birth Defects Res. A Clin. Mol. Teratol. 73, 679–689 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Cortes, F., Mellado, C., Pardo, R. A., Villarroel, L. A. & Hertrampf, E. Wheat flour fortification with folic acid: changes in neural tube defects rates in Chile. Am. J. Med. Genet. A 158A, 1885–1890 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Chen, L. T. & Rivera, M. A. The Costa Rican experience: reduction of neural tube defects following food fortification programs. Nutr. Rev. 62, S40–S43 (2004).

    Article  PubMed  Google Scholar 

  94. De Wals, P. et al. Reduction in neural-tube defects after folic acid fortification in Canada. N. Engl. J. Med. 357, 135–142 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Sayed, A. R., Bourne, D., Pattinson, R., Nixon, J. & Henderson, B. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa. Birth Defects Res. A Clin. Mol. Teratol. 82, 211–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Safdar, O. Y., Al-Dabbagh, A. A., Abuelieneen, W. A. & Kari, J. A. Decline in the incidence of neural tube defects after the national fortification of flour (1997–2005). Saudi Med. J. 28, 1227–1229 (2007).

    PubMed  Google Scholar 

  97. Pacheco, S. S., Braga, C., Souza, A. I. & Figueiroa, J. N. Effects of folic acid fortification on the prevalence of neural tube defects. Rev. Saude Publica 43, 565–571 (2009).

    Article  PubMed  Google Scholar 

  98. Ricks, D. J. et al. Peru's national folic acid fortification program and its effect on neural tube defects in Lima. Rev. Panam. Salud Pubica 32, 391–398 (2012).

    Article  Google Scholar 

  99. Bower, C., D'Antoine, H. & Stanley, F. J. Neural tube defects in Australia: trends in encephaloceles and other neural tube defects before and after promotion of folic acid supplementation and voluntary food fortification. Birth Defects Res. A Clin. Mol. Teratol. 85, 269–273 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Oakley, G. P. Jr. Folic acid-preventable spina bifida: a good start but much to be done. Am. J. Prev. Med. 38, 569–570 (2010).

    Article  PubMed  Google Scholar 

  101. Heseker, H. B., Mason, J. B., Selhub, J., Rosenberg, I. H. & Jacques, P. F. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid. Br. J. Nutr. 102, 173–180 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Osterhues, A., Ali, N. S. & Michels, K. B. The role of folic acid fortification in neural tube defects: a review. Crit. Rev. Food Sci. Nutr. 53, 1180–1190 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Rintoul, N. E. et al. A new look at myelomeningoceles: functional level, vertebral level, shunting, and the implications for fetal intervention. Pediatrics 109, 409–413 (2002).

    Article  PubMed  Google Scholar 

  104. Kulkarni, A. V. et al. Endoscopic third ventriculostomy and choroid plexus cauterization in infants with hydrocephalus: a retrospective Hydrocephalus Clinical Research Network study. J. Neurosurg. Pediatr. 14, 224–229 (2014).

    Article  PubMed  Google Scholar 

  105. McComb, J. G. Spinal and cranial neural tube defects. Semin. Pediatr. Neurol. 4, 156–166 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Bauer, S. B. The management of the myelodysplastic child: a paradigm shift. BJU Int. 92, (Suppl. 1), 23–28 (2003).

    Article  PubMed  Google Scholar 

  107. Leibold, S., Ekmark, E. & Adams, R. C. Decision-making for a successful bowel continence program. Eur. J. Pediatr. Surg. 10, (Suppl. 1), 26–30 (2000).

    Article  PubMed  Google Scholar 

  108. Perez, M., Lemelle, J. L., Barthelme, H., Marquand, D. & Schmitt, M. Bowel management with antegrade colonic enema using a Malone or a Monti conduit – clinical results. Eur. J. Pediatr. Surg. 11, 315–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Adzick, N. S. Fetal surgery for myelomeningocele: trials and tribulations. Isabella Forshall Lecture. J. Pediatr. Surg. 47, 273–281 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Sutton, L. N. et al. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 282, 1826–1831 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Bruner, J. P. et al. Fetal surgery for myelomeningocele and the incidence of shunt- dependent hydrocephalus. JAMA 282, 1819–1825 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Bouchard, S. et al. Correction of hindbrain herniation and anatomy of the vermis after in utero repair of myelomeningocele in sheep. J. Pediatr. Surg. 38, 451–458 (2003).

    Article  PubMed  Google Scholar 

  113. Quinn, T. M., Hubbard, A. M. & Adzick, N. S. Prenatal magnetic resonance imaging enhances fetal diagnosis. J. Pediatr. Surg. 33, 553–558 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Adzick, N. S. et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N. Engl. J. Med. 364, 993–1004 (2011). This prospective randomized clinical trial shows that prenatal repair reduces the need for a ventriculoperitoneal shunt and improves motor outcomes when compared with postnatal repair. Fetal and maternal risks relating to fetal surgery are quantified.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rychik, J. et al. Acute cardiovascular effects of fetal surgery in the human. Circulation 110, 1549–1556 (2004).

    Article  PubMed  Google Scholar 

  116. Adzick, N. S., Sutton, L. N., Crombleholme, T. M. & Flake, A. W. Successful fetal surgery for spina bifida. Lancet 352, 1675–1676 (1998). This is the first report of successful fetal surgery for spina bifida in an early-gestation human fetus.

    Article  CAS  PubMed  Google Scholar 

  117. Tulipan, N., Hernanz-Schulman, M. & Bruner, J. P. Reduced hindbrain herniation after intrauterine myelomeningocele repair: a report of four cases. Pediatr. Neurosurg. 29, 274–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Black, M. M. & Matula, K. Essentials of Bayley Scales of Infant Development (Wiley, 1999).

    Google Scholar 

  119. Werner, E. F. et al. Evaluating the cost-effectiveness of prenatal surgery for myelomeningocele: a decision analysis. Ultrasound Obstet. Gynecol. 40, 158–164 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Moldenhauer, J. S. et al. Fetal myelomeningocele repair: the post-MOMS experience at the Children's Hospital of Philadelphia. Fetal Diagn. Ther. 37, 235–240 (2014).

    Article  PubMed  Google Scholar 

  121. Cohen, A. R. et al. Position statement on fetal myelomeningocele repair. Am. J. Obstet. Gynecol. 210, 107–111 (2014).

    Article  PubMed  Google Scholar 

  122. Greenley, R. N., Holmbeck, G. N., Zukerman, J. & Buck, C. F. in Neural Tube Defects: From Origin to Treatment (ed. Wyszynski, D. F. ) 307–324 (Oxford Univ. Press, 2006).

    Google Scholar 

  123. Kelly, L. M., Zebracki, K., Holmbeck, G. N. & Gershenson, L. Adolescent development and family functioning in youth with spina bifida. J. Pediatr. Rehabil. Med. 1, 291–302 (2008).

    PubMed  Google Scholar 

  124. Singh, D. K. Families of children with spina bifida: a review. J. Dev. Phys. Disabil. 15, 37–55 (2003).

    Article  Google Scholar 

  125. Murray, C. B. et al. A longitudinal examination of health-related quality of life in children and adolescents with spina bifida. J. Pediatr. Psychol.http://dx.doi.org/10.1093/jpepsy/jsu098 (2014).

  126. Sawin, K. J. & Bellin, M. H. Quality of life in individuals with spina bifida: a research update. Dev. Disabil. Res. Rev. 16, 47–59 (2010). This report provides an up-to-date review of the research literature on quality of life in individuals with spina bifida.

    Article  PubMed  Google Scholar 

  127. Freeman, K. A., Smith, K., Adams, E., Mizokawa, S. & Neville-Jan, A. Is continence status associated with quality of life in young children with spina bifida? J. Pediatr. Rehabil. Med. 6, 215–223 (2013).

    PubMed  Google Scholar 

  128. Cope, H. et al. Outcome and life satisfaction of adults with myelomeningocele. Disabil. Health J. 6, 236–243 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Dicianno, B. E., Gaines, A., Collins, D. M. & Lee, S. Mobility, assistive technology use, and social integration among adults with spina bifida. Am. J. Phys. Med. Rehabil. 88, 533–541 (2009).

    Article  PubMed  Google Scholar 

  130. Bellin, M. H. et al. Family satisfaction, pain, and quality-of-life in emerging adults with spina bifida: a longitudinal analysis. Am. J. Phys. Med. Rehabil. 92, 641–655 (2013).

    Article  PubMed  Google Scholar 

  131. Holmbeck, G. N. et al. A multimethod, multi-informant, and multidimensional perspective on psychosocial adjustment in preadolescents with spina bifida. J. Consult. Clin. Psychol. 71, 782–796 (2003).

    Article  PubMed  Google Scholar 

  132. Holmbeck, G. N. et al. Trajectories of psychosocial adjustment in adolescents with spina bifida: a 6-year, four-wave longitudinal follow-up. J. Consult. Clin. Psychol. 78, 511–525 (2010).This longitudinal study of young people with spina bifida reveals areas of psychological adjustment difficulties as well as areas of psychosocial resilience.

    Article  PubMed  Google Scholar 

  133. Shields, N., Taylor, N. F. & Dodd, K. J. Self-concept in children with spina bifida compared with typically developing children. Dev. Med. Child Neurol. 50, 733–743 (2008).

    Article  PubMed  Google Scholar 

  134. Blum, R. W., Resnick, M. D., Nelson, R. & St Germaine, A. Family and peer issues among adolescents with spina bifida and cerebral palsy. Pediatrics 88, 280–285 (1991).

    CAS  PubMed  Google Scholar 

  135. Ellerton, M. L., Stewart, M. J., Ritchie, J. A. & Hirth, A. M. Social support in children with a chronic condition. Can. J. Nurs. Res. 28, 15–36 (1996).

    CAS  PubMed  Google Scholar 

  136. Davis, B. E., Shurtleff, D. B., Walker, W. O., Seidel, K. D. & Duguay, S. Acquisition of autonomy skills in adolescents with myelomeningocele. Dev. Med. Child Neurol. 48, 253–258 (2006).

    Article  PubMed  Google Scholar 

  137. Friedman, D., Holmbeck, G. N., DeLucia, C., Jandasek, B. & Zebracki, K. Trajectories of autonomy development across the adolescent transition in children with spina bifida. Rehabil. Psychol. 54, 16–27 (2009).

    Article  PubMed  Google Scholar 

  138. Holmbeck, G. N. et al. Observed and perceived parental overprotection in relation to psychosocial adjustment in preadolescents with a physical disability: the mediational role of behavioral autonomy. J. Consult. Clin. Psychol. 70, 96–110 (2002).

    Article  PubMed  Google Scholar 

  139. Holmbeck, G. N., Greenley, R. N., Coakley, R. M., Greco, J. & Hagstrom, J. Family functioning in children and adolescents with spina bifida: an evidence-based review of research and interventions. J. Dev. Behav. Pediatr. 27, 249–277 (2006). This literature review focuses on basic psychosocial research and interventions that reveal the lack of interventions for individuals with spina bifida and their families, as compared with the number of interventions that are available for individuals with other chronic health conditions.

    Article  PubMed  Google Scholar 

  140. Costigan, C. L., Floyd, F. J., Harter, K. S. M. & McClintock, J. C. Family process and adaptation to children with mental retardation: Disruption and resilience in family problems-solving interactions. J. Fam. Psychol. 11, 515–529 (1997).

    Article  Google Scholar 

  141. Ammerman, R. et al. Psychiatric symptomatology and family functioning in children and adolescents with spina bifida. J. Clin. Psychol. Med. Settings 5, 449–465 (1998).

    Article  Google Scholar 

  142. Wiegner, S. & Donders, J. Predictors of parental distress after congenital disabilities. J. Dev. Behav. Pediatr. 21, 271–277 (2000).

    Article  CAS  PubMed  Google Scholar 

  143. Holmbeck, G. N., Coakley, R. M., Hommeyer, J. S., Shapera, W. E. & Westhoven, V. C. Observed and perceived dyadic and systemic functioning in families of preadolescents with spina bifida. J. Pediatr. Psychol. 27, 177–189 (2002).

    Article  PubMed  Google Scholar 

  144. Cappelli, M., McGarth, P. J., Daniels, T., Manion, I. & Schillinger, J. Marital quality of parents of children with spina bifida: a case-comparison study. J. Dev. Behav. Pediatr. 15, 320–326 (1994).

    Article  CAS  PubMed  Google Scholar 

  145. Holmbeck, G. N. et al. Maternal, paternal, and marital functioning in families of preadolescents with spina bifida. J. Pediatr. Psychol. 22, 167–181 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Spaulding, B. R. & Morgan, S. B. Spina bifida children and their parents: a population prone to family dysfunction? J. Pediatr. Psychol. 11, 359–374 (1986).

    Article  CAS  PubMed  Google Scholar 

  147. Vermaes, I. P., Janssens, J. M., Bosman, A. M. & Gerris, J. R. Parents’ psychological adjustment in families of children with spina bifida: a meta-analysis. BMC Pediatr. 5, 32–44 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Vermaes, I. P., Gerris, J. R. & Janssens, J. M. Parents’ social adjustment in families of children with spina bifida: a theory-driven review. J. Pediatr. Psychol. 32, 1214–1226 (2007).

    Article  PubMed  Google Scholar 

  149. Grosse, S., Flores, A., Ouyang, L., Robbins, J. & Tilford, J. Impact of spina bifida on parental caregivers: findings from a survey of Arkansas families. J. Child Fam. Stud. 18, 574–581 (2009).

    Article  Google Scholar 

  150. Sawin, K. J. et al. The experience of parenting an adolescent with spina bifida. Rehabil. Nurs. 28, 173–185 (2003).

    Article  PubMed  Google Scholar 

  151. Macias, M., Clifford, S., Saylor, C. & Kreh, S. Predictors of parenting stress in families of children with spina bifida. Child. Health Care 30, 57–65 (2001).

    Article  Google Scholar 

  152. Bellin, M. H., Bentley, K. J. & Sawin, K. J. Factors associated with the psychological and behavioral adjustment of siblings of youths with spina bifida. Fam. Syst. Health 27, 1–15 (2009).

    Article  PubMed  Google Scholar 

  153. Bowman, R. M., McLone, D. G., Grant, J. A., Tomita, T. & Ito, J. A. Spina bifida outcome: a 25-year prospective. Pediatr. Neurosurg. 34, 114–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Oakeshott, P., Hunt, G. M., Poulton, A. & Reid, F. Expectation of life and unexpected death in open spina bifida: a 40-year complete, non-selective, longitudinal cohort study. Dev. Med. Child Neurol. 52, 749–753 (2010).

    Article  PubMed  Google Scholar 

  155. Holmbeck, G. N., Bauman, L., Essner, B., Kelly, L. & Zebracki, K. in Launching into Adulthood: An Integrated Response to Support Transition of Youth with Chronic Health Conditions and Disabilities (ed. Lollar, D. ) 21–47 (Brookes, 2010).

    Google Scholar 

  156. Liptak, G. S., Kennedy, J. A. & Dosa, N. P. Youth with spina bifida and transitions: health and social participation in a nationally represented sample. J. Pediatr. 157, 584–588 (2010).

    Article  PubMed  Google Scholar 

  157. Sawyer, S. M. et al. Young people with spina bifida: transfer from paediatric to adult health care. J. Paediatr. Child Health 34, 414–417 (1998).

    Article  CAS  PubMed  Google Scholar 

  158. Bellin, M. H. et al. Correlates of depressive and anxiety symptoms in young adults with spina bifida. J. Pediatr. Psychol. 35, 778–789 (2010).

    Article  PubMed  Google Scholar 

  159. Murray, C. B. et al. The influence of social adjustment on normative and risky health behaviors in emerging adults with spina bifida. Health Psychol. 33, 1153–1163 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Cohen, P., Kasen, S., Chen, H., Hartmark, C. & Gordon, K. Variations in patterns of developmental transitions in the emerging adulthood period. Dev. Psychol. 39, 657–669 (2003).

    Article  PubMed  Google Scholar 

  161. Zukerman, J. M., Devine, K. A. & Holmbeck, G. N. Adolescent predictors of emerging adulthood milestones in youth with spina bifida. J. Pediatr. Psychol. 36, 265–276 (2011).

    Article  PubMed  Google Scholar 

  162. McDonnell, G. V. & McCann, J. P. Link between the CSF shunt and achievement in adults with spina bifida. J. Neurol. Neurosurg. Psychiatry 68, 800 (2000).

  163. Roach, J. W., Short, B. F. & Saltzman, H. M. Adult consequences of spina bifida: a cohort study. Clin. Orthop. Relat. Res. 469, 1246–1252 (2011).

    Article  PubMed  Google Scholar 

  164. Hamilton, S. & Hamilton, M. in Emerging Adults in America: Coming of Age in the 21st Century (eds Arnett, J. & Tanner, J. ) 257–277 (American Psychological Association, 2006).

    Book  Google Scholar 

  165. Gerhardt, C. A. et al. Educational and occupational outcomes among survivors of childhood cancer during the transition to emerging adulthood. J. Dev. Behav. Pediatr. 28, 448–455 (2007).

    Article  PubMed  Google Scholar 

  166. Verhoef, M. et al. Sex education, relationships, and sexuality in young adults with spina bifida. Arch. Phys. Med. Rehabil. 86, 979–987 (2005).

    Article  PubMed  Google Scholar 

  167. Sawin, K. J., Buran, C. F., Brei, T. J. & Fastenau, P. S. Sexuality issues in adolescents with a chronic neurological condition. J. Perinat. Educ. 11, 22–34 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Sawyer, S. M. & Roberts, K. V. Sexual and reproductive health in young people with spina bifida. Dev. Med. Child Neurol. 41, 671–675 (1999).

    Article  CAS  PubMed  Google Scholar 

  169. Shurtleff, D. B., Walker, W. O., Duguay, S., Peterson, D. & Cardenas, D. Obesity and myelomeningocele: anthropometric measures. J. Spinal Cord. Med. 33, 410–419 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Dosa, N. P., Foley, J. T., Eckrich, M., Woodall-Ruff, D. & Liptak, G. S. Obesity across the lifespan among persons with spina bifida. Disabil. Rehabil. 31, 914–920 (2009).

    Article  PubMed  Google Scholar 

  171. Boudos, R. M. & Mukherjee, S. Barriers to community participation: teens and young adults with spina bifida. J. Pediatr. Rehabil. Med. 1, 303–310 (2008).

    PubMed  Google Scholar 

  172. Kelly, E. H., Altiok, H., Gorzkowski, J. A., Abrams, J. R. & Vogel, L. C. How does participation of youth with spina bifida vary by age? Clin. Orthop. Relat. Res. 469, 1236–1245 (2011).

    Article  PubMed  Google Scholar 

  173. Barf, H. A. et al. Restrictions in social participation of young adults with spina bifida. Disabil. Rehabil. 31, 921–927 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Park, M., Mulye, T., Adams, S., Brindis, C. & Irwin, C. E. Jr. The health status of young adults in the United States. J. Adolesc. Health 39, 305–317 (2006).

    Article  PubMed  Google Scholar 

  175. Dicianno, B. E. et al. Rehabilitation and medical management of the adult with spina bifida. Am. J. Phys. Med. Rehabil. 87, 1027–1050 (2008).

    Article  PubMed  Google Scholar 

  176. Schriner, K. F., Roessler, R. T. & Johnson, P. Identifying the employment concerns of people with spina bifida. J. Appl. Rehabil. Counsel. 24, 32 (1993).

  177. Krupp, D. R. et al. Missing genetic risk in neural tube defects: can exome sequencing yield an insight?. Birth Defects Res. A Clin. Mol. Teratol. 100, 642–646 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Greene, N. D., Stanier, P. & Moore, G. E. The emerging role of epigenetic mechanisms in the aetiology of neural tube defects. Epigenetics. 6, 875–883 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Wilde, J. J., Petersen, J. R. & Niswander, L. Genetic, epigenetic, and environmental contributions to neural tube closure. Annu. Rev. Genet. 48, 583–611 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Chen, R. et al. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 148, 1293–1307 (2012). This paper provides the first description of a method for providing a personal health profile based on a variety of computational and omics techniques, including genomic, gene expression, protein, metabolic and autoantibody data.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Copp, A. J., Greene, N. D. E. & Murdoch, J. N. The genetic basis of mammalian neurulation. Nat. Rev. Genet. 4, 784–793 (2003).

    Article  PubMed  Google Scholar 

  182. Hook, E. B. & Czeizel, A. E. Can terathanasia explain the protective effect of folic-acid supplementation on birth defects? Lancet 350, 513–515 (1997).

    Article  CAS  PubMed  Google Scholar 

  183. Marean, A., Graf, A., Zhang, Y. & Niswander, L. Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival. Hum. Mol. Genet. 20, 3678–3683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Burren, K. A. et al. Gene–environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function. Hum. Mol. Genet. 17, 3675–3685 (2008). This study in a well-defined mouse model of NTDs confirms that severe folate deficiency during pregnancy is not sufficient to cause neural tube defects, but that it is a risk factor in the presence of a genetic predisposition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Molloy, A. M. et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics 123, 917–923 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Czeizel, A. E., Dudas, I., Paput, L. & Banhidy, F. Prevention of neural-tube defects with periconceptional folic acid, methylfolate, or multivitamins? Ann. Nutr. Metab. 58, 263–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Leung, K. Y., de Castro, S. C., Savery, D., Copp, A. J. & Greene, N. D. Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse. Brain 136, 2836–2841 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Greene, N. D. E. & Copp, A. J. Inositol prevents folate-resistant neural tube defects in the mouse. Nat. Med. 3, 60–66 (1997).

    Article  CAS  PubMed  Google Scholar 

  189. Cavalli, P., Tonni, G., Grosso, E. & Poggiani, C. Effects of inositol supplementation in a cohort of mothers at risk of producing an NTD pregnancy. Birth Defects Res. A Clin. Mol. Teratol. 91, 962–965 (2011). This is the first study showing that inositol supplementation is safe in mothers at high risk of pregnancy complicated by NTDs.

    Article  CAS  PubMed  Google Scholar 

  190. Copp, A. J., Greene, N. D. & Chitty, L. S. Prevention of Neural Tube Defects by Inositol in Conjunction With Folic Acid (PONTI Study). [online], (2015).

  191. Fauza, D. O., Jennings, R. W., Teng, Y. D. & Snyder, E. Y. Neural stem cell delivery to the spinal cord in an ovine model of fetal surgery for spina bifida. Surgery 144, 367–373 (2008).

    Article  PubMed  Google Scholar 

  192. Li, H. et al. Therapeutic potential of in utero mesenchymal stem cell (MSCs) transplantation in rat foetuses with spina bifida aperta. J. Cell. Mol. Med. 16, 1606–1617 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Saadai, P. et al. Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele. J. Pediatr. Surg. 48, 158–163 (2013).

    Article  PubMed  Google Scholar 

  194. Hosper, N. A., Bank, R. A. & van den Berg, P. P. Human amniotic fluid-derived mesenchymal cells from fetuses with a neural tube defect do not deposit collagen type I protein after TGF-ß1 stimulation in vitro. Stem Cells Dev. 23, 555–562 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Stubberud, J., Langenbahn, D., Levine, B., Stanghelle, J. & Schanke, A. K. Emotional health and coping in spina bifida after goal management training: a randomized controlled trial. Rehabil. Psychol. 60, 1–16 (2014).

    Article  PubMed  Google Scholar 

  196. O'Mahar, K., Holmbeck, G. N., Jandasek, B. & Zukerman, J. A camp-based intervention targeting independence among individuals with spina bifida. J. Pediatr. Psychol. 35, 848–856 (2010).

    Article  PubMed  Google Scholar 

  197. Holbein, C. E. et al. A camp-based psychosocial intervention to promote independence and social function in individuals with spina bifida: moderators of treatment effectiveness. J. Pediatr. Psychol. 38, 412–424 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Grewal, J., Carmichael, S. L., Ma, C., Lammer, E. J. & Shaw, G. M. Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies. Birth Defects Res. A Clin. Mol. Teratol. 82, 519–526 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Schmidt, R. J. et al. Maternal caffeine consumption and risk of neural tube defects. Birth Defects Res. A Clin. Mol. Teratol. 85, 879–889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Kirke, P. N. et al. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q. J. Med. 86, 703–708 (1993).

    CAS  PubMed  Google Scholar 

  201. Carmichael, S. L. et al. Reduced risks of neural tube defects and orofacial clefts with higher diet quality. Arch. Pediatr. Adolesc. Med. 166, 121–126 (2012).

    Article  PubMed  Google Scholar 

  202. Yazdy, M. M., Mitchell, A. A., Liu, S. & Werler, M. M. Maternal dietary glycaemic intake during pregnancy and the risk of birth defects. Paediatr. Perinat. Epidemiol. 25, 340–346 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Shaw, G. M., Velie, E. M. & Schaffer, D. M. Is dietary intake of methionine associated with a reduction in risk for neural tube defect-affected pregnancies. Teratology. 56, 295–299 (1997).

    Article  CAS  PubMed  Google Scholar 

  204. Shaw, G. M. et al. Choline and risk of neural tube defects in a folate-fortified population. Epidemiology 20, 714–719 (2009).

    Article  PubMed  Google Scholar 

  205. Ray, J. G. & Blom, H. J. Vitamin B12 insufficiency and the risk of fetal neural tube defects. Q. J. Med. 96, 289–295 (2003).

    Article  CAS  Google Scholar 

  206. Schorah, C. J., Wild, J., Hartley, R., Sheppard, S. & Smithells, R. W. The effect of periconceptional supplementation on blood vitamin concentrations in women at recurrence risk for neural tube defect. Br. J. Nutr. 49, 203–211 (1983).

    Article  CAS  PubMed  Google Scholar 

  207. Velie, E. M. et al. Maternal supplemental and dietary zinc intake and the occurrence of neural tube defects in California. Am. J. Epidemiol. 150, 605–616 (1999).

    Article  CAS  PubMed  Google Scholar 

  208. Moretti, M. E., Bar-Oz, B., Fried, S. & Koren, G. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology 16, 216–219 (2005).

    Article  PubMed  Google Scholar 

  209. Wasserman, C. R., Shaw, G. M., Selvin, S., Gould, J. B. & Syme, S. L. Socioeconomic status, neighborhood social conditions, and neural tube defects. Am. J. Publ. Health 88, 1674–1680 (1998).

    Article  CAS  Google Scholar 

  210. Shaw, G. M., Todoroff, K., Velie, E. M. & Lammer, E. J. Maternal illness, including fever, and medication use as risk factors for neural tube defects. Teratology. 57, 1–7 (1998).

    Article  CAS  PubMed  Google Scholar 

  211. Becerra, J. E., Khoury, M. J., Cordero, J. F. & Erickson, J. D. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics 85, 1–9 (1990).

    CAS  PubMed  Google Scholar 

  212. Carmichael, S. L. & Shaw, G. M. Maternal life event stress and congenital anomalies. Epidemiology 11, 30–35 (2000).

    Article  CAS  PubMed  Google Scholar 

  213. Suarez, L., Cardarelli, K. & Hendricks, K. Maternal stress, social support, and risk of neural tube defects among Mexican Americans. Epidemiology 14, 612–616 (2003).

    Article  PubMed  Google Scholar 

  214. Vajda, F. J., O'Brien, T. J., Graham, J. E., Lander, C. M. & Eadie, M. J. Dose dependence of fetal malformations associated with valproate. Neurology 81, 999–1003 (2013).

    Article  CAS  PubMed  Google Scholar 

  215. Lupo, P. J. et al. Maternal exposure to ambient levels of benzene and neural tube defects among offspring: Texas, 1999–2004. Environ. Health Perspect. 119, 397–402 (2011).

    Article  PubMed  Google Scholar 

  216. Padula, A. M. et al. The association of ambient air pollution and traffic exposures with selected congenital anomalies in the San Joaquin Valley of California. Am. J. Epidemiol. 177, 1074–1085 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Righi, E. et al. Trihalomethanes, chlorite, chlorate in drinking water and risk of congenital anomalies: a population-based case-control study in Northern Italy. Environ. Res. 116, 66–73 (2012).

    Article  CAS  PubMed  Google Scholar 

  218. Li, Z. et al. Indoor air pollution from coal combustion and the risk of neural tube defects in a rural population in Shanxi Province, China. Am. J. Epidemiol. 174, 451–458 (2011).

    Article  PubMed  Google Scholar 

  219. Brender, J. D. et al. Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the national birth defects prevention study. Environ. Health Perspect. 121, 1083–1089 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Cordier, S. et al. Congenital malformations and maternal occupational exposure to glycol ethers. Epidemiology 8, 355–363 (1997).

    Article  CAS  PubMed  Google Scholar 

  221. Brender, J. D., Felkner, M., Suarez, L., Canfield, M. A. & Henry, J. P. Maternal pesticide exposure and neural tube defects in Mexican Americans. Ann. Epidemiol. 20, 16–22 (2010).

    Article  PubMed  Google Scholar 

  222. Yang, W. et al. Residential agricultural pesticide exposures and risk of neural tube defects and orofacial clefts among offspring in the San Joaquin Valley of California. Am. J. Epidemiol. 179, 740–748 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Ren, A. et al. Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects. Proc. Natl Acad. Sci. USA 138, 12770–12775 (2011).

    Article  Google Scholar 

  224. Hutchins, G. M. et al. Acquired spinal cord injury in human fetuses with myelomeningocele. Pediatr. Pathol. Lab. Med. 16, 701–712 (1996).

    Article  CAS  PubMed  Google Scholar 

  225. Korenromp, M. J., Van Gool, J. D., Bruinese, H. W. & Kriek, R. Early fetal leg movements in myelomeningocele. Lancet 327, 917–918 (1986).

    Article  Google Scholar 

  226. Sival, D. A. et al. Perinatal motor behaviour and neurological outcome in spina bifida aperta. Early Hum. Dev. 50, 27–37 (1997).

    Article  CAS  PubMed  Google Scholar 

  227. Duckworth, T., Sharrard, W. J., Lister, J. & Seymour, N. Hemimyelocele. Dev. Med. Child Neurol. 10, (Suppl. 16), 69–75 (1968).

    Google Scholar 

  228. Meuli, M. et al. In utero surgery rescues neurological function at birth in sheep with spina bifida. Nat. Med. 1, 342–347 (1995). This investigation in sheep fetuses shows that amniotic fluid exposure accounts for the neural tissue destruction in the sheep model of spina bifida and that timely in utero repair of myelomeningocele lesions might rescue neurological function in humans.

    Article  CAS  PubMed  Google Scholar 

  229. Drewek, M. J., Bruner, J. P., Whetsell, W. O. & Tulipan, N. Quantitative analysis of the toxicity of human amniotic fluid to cultured rat spinal cord. Pediatr. Neurosurg. 27, 190–193 (1997).

    Article  CAS  PubMed  Google Scholar 

  230. Campbell, J., Gilbert, W. M., Nicolaides, K. H. & Campbell, S. Ultrasound screening for spina bifida: cranial and cerebellar signs in a high-risk population. Obstet. Gynecol. 70, 247–250 (1987).

    CAS  PubMed  Google Scholar 

  231. Smith, N. C. & Hau, C. A six year study of the antenatal detection of fetal abnormality in six Scottish health boards. Br. J. Obstet. Gynaecol. 106, 206–212 (1999).

    Article  CAS  PubMed  Google Scholar 

  232. Boyd, P. A., Chamberlain, P. & Hicks, N. R. 6-year experience of prenatal diagnosis in an unselected population in Oxford, UK. Lancet 352, 1577–1581 (1998).

    Article  CAS  PubMed  Google Scholar 

  233. Shirley, I. M., Bottomley, F. & Robinson, V. P. Routine radiographer screening for fetal abnormalities by ultrasound in an unselected low risk population. Br. J. Radiol. 65, 564–569 (1992).

    Article  CAS  PubMed  Google Scholar 

  234. Chitty, L. S., Hunt, G. H., Moore, J. & Lobb, M. O. Effectiveness of routine ultrasonography in detecting fetal structural abnormalities in a low risk population. Br. Med. J. 303, 1165–1169 (1991).

    Article  CAS  Google Scholar 

  235. Luck, C. A. Value of routine ultrasound scanning at 19 weeks: a four year study of 8849 deliveries. Br. Med. J. 304, 1474–1478 (1992).

    Article  CAS  Google Scholar 

  236. Papp, Z. et al. Impact of prenatal mid-trimester screening on the prevalence of fetal structural anomalies: a prospective epidemiological study. Ultrasound Obstet. Gynecol. 6, 320–326 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge grants from The Wellcome Trust (grant 087525 to A.J.C.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health (grants U10 HD041666 to N.S.A., P01 HD35946 to J.M.F. and R01-HD048629 to G.N.H.) and the March of Dimes Foundation (grant 12-FY13-271 to G.N.H.). Images of human embryonic material are provided by the Joint Medical Research Council–Wellcome Trust Human Developmental Biology Resource (www.hdbr.org; grant 099175).

Author information

Authors and Affiliations

  1. Newlife Birth Defects Research Centre, University College London Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    Andrew J. Copp

  2. Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    N. Scott Adzick

  3. Genetics and Genomic Medicine, University College London (UCL) Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust and UCL Hospitals NHS Foundation Trust, London, UK

    Lyn S. Chitty

  4. Department of Psychology, University of Houston, Houston, Texas, USA

    Jack M. Fletcher

  5. Department of Psychology, Loyola University Chicago, Chicago, Illinois, USA

    Grayson N. Holmbeck

  6. Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA

    Gary M. Shaw

Authors
  1. Andrew J. Copp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Scott Adzick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lyn S. Chitty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jack M. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Grayson N. Holmbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gary M. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (A.J.C.); Epidemiology (G.M.S.); Mechanisms/pathophysiology (A.J.C. and J.M.F.); Diagnosis, screening and prevention (G.M.S. and L.S.C.); Management (N.S.A.); Quality of life (G.N.H.); Outlook (A.J.C. and G.N.H.); overview of Primer (A.J.C.).

Corresponding author

Correspondence to Andrew J. Copp.

Ethics declarations

Competing interests

G.M.S. has received consulting fees from: Advanced Micro Devices and NXP Semiconductors for semiconductor employment and birth defects; GlaxoSmithKline for paroxetine use and birth defects; and Vivus, Inc. for topiramate use and oral clefts. A.J.C., N.S.A., L.S.C., J.M.F. and G.N.H. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Copp, A., Adzick, N., Chitty, L. et al. Spina bifida. Nat Rev Dis Primers 1, 15007 (2015). https://doi.org/10.1038/nrdp.2015.7

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2015.7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing