Spina Bifida Information for Fetal Diagnostics
Spina Bifida Information for Fetal Diagnostics

Page Links on Spina Bifida Topics: Definition, Prevalence, Classification, Risk Factors, Etiology, Genetics,  Prevention, Outcome, Differential Diagnosis,  References

Definition of Spina Bifida

The following definitions are from National Library of Medicine – Medical Subject Headings, 2008 MeSH.

Meningocele: A congenital or acquired protrusion of the meninges, unaccompanied by neural tissue, through a bony defect in the skull or vertebral column.

Meningomyelocele: Congenital, or rarely acquired, herniation of meningeal and spinal cord tissue through a bony defect in the vertebral column.

Spinal dysraphism: Congenital defects of closure of one or more vertebral arches, which may be associated with malformations of the spinal cord, nerve roots, congenital fibrous bands, lipomas, and congenital cysts. These malformations range from mild (spina bifida occulta) to severe, including rachischisis where there is complete failure of neural tube and spinal cord fusion, resulting in exposure of the spinal cord at the surface. Spinal dysraphism includes all forms of spina bifida. The open form is called spina bifida cystica and the closed form is spina bifida occulta.

Fetal Prevalence of Spina Bifida

prevalence of neural tube defects

Above. United States data show the prevalence of neural tube defects has declined due to: preconceptual supplementation with folic acid and, prenatal diagnoses with resultant selective termination of pregnancies.

rate of spina bifida and anencephaly

Above. There is significant geographic variations in the rates of spina bifida and anencephaly. The rates (per 10,000 population) for neural tube defects are twice in certain areas of Russia compared to Norway, for example. [1],[2],[3],[4],[5],[6],[7]

*Sweden, 6.1 = 2.4/10,000 newborns plus 3.7/10,000 termination of pregnancy.

Spina bifida incidence of neural tube defect
NTDs which are not related to a syndrome

In summary, the incidence of neural tube defect is affected by racial, geographic and seasonal variations as well as the risk factors listed above. Most NTDs which are not related to a syndrome are multifactorial in origin.

There is also an increased frequency in: maternal hyperthermia valproate ingestion.

No Mendelian inheritance pattern is noted.

Genetic contribution evidence is present due to the following: single gene defects, recurrence among siblings, and higher likelihood in twins.

Classification

Neural tube defects can be classified as either abnormalities of the skull or brain. Those of the skull and brain include Arnold Chiari malformation, which represents secondary changes within the fetal brain associated with spinal defects. [8]

A separate classification includes abnormalities of the vertebral arches (dysraphism) and includes open defects such as meningocele and spina bifida cystica. [8] Spina bifida occulta represents a closed spinal defect. [9]

neural tube defect classification abnormalities of fetal skull and brain
Neural tube defect classification abnormalities of fetal spine

fetal spinal dysraphism classification

Above. A separate classification for Spinal Dysraphism (spinal defects which affect the vertebra arches) has been proposed. [10] This classification divides the spinal lesions into open and closed defects and suggests certain associations with each.

Risk Factors

neural tube defects associated with spina bifida

Above. Neural tube defects can broadly be described as syndromic and non-syndromic. [11] In the non-syndromic multifactorial group, a number of specific risk factors have been reported.

risk factors with fetal spina bifida

Above are risk factors reported for spina bifida. [11]

Exposure to agricultural pesticides and to fumonisin, a mycotoxin that often contaminates corn, appear as causative links for the occurrence of neural tube defects. [12],[13]

Retinoid acid (RA) plays a role in the development of the spinal cord while genetic polymorphism of the human retinoic acid-metabolizing enzyme is being explored for its role in the development of spina bifida.

[14],[15]

Etiology

spina bifida environmental and genetic factors

Above. The etiology of neural tube defects is related to environmental and genetic factors and may be considered heterogeneous and multifactorial. The genetic component is discussed separately.

Congenital spinal defects are associated with intracranial changes

Congenital spinal defects are associated with intracranial changes and the Arnold Chiari malformation. The Chiari malformation, associated with hindbrain herniation, is related to low spinal pressure relative to cranial pressure, and results in hindbrain-related symptoms caused by cerebellar and brainstem compression. [16] Increased CNS volume, with any space occupying lesion, compresses veins and raises venous pressure which in turn raises the volume of cerebrospinal fluid (CSF).  When blood enters the CNS during fetal movement,  the compressed posterior fossa prevents spine-to-head flow of CSF. These movement induced pressure events may result in spinal cord injury.

hypothesis for spinal lesions and hydrocephalus

Above. Williams [17] proposes a venous hypothesis for spinal lesions and hydrocephalus related to the overall pressure in the CNS, which is dependent upon all of the volume within the closed CNS space. Arterial supply is maintained normally because of venous outflow from the CNS. Increased CNS volume with any space occupying lesion compresses veins and raises venous pressure, which in turn raises the volume of cerebrospinal fluid (CSF). These changes affect hydrocephalus and the associated spinal lesions, while the Chiari malformation leads to reductions in CSF flow that can occur intermittently.

Genetics

genetic basis for spina bifida

Above. Neural tube defects are due to multiple environmental and genetic factors. [18]

gene-gene factors and gene-environmental factors

Above. These gene-gene factors and gene-environmental factors are operable through a variety of maternal conditions. [23]

multiple genes are responsible in spina bifida

Above. With respect to genetic risk factors, multiple genes are responsible.

fetal open neutral tube defects

Above. Among fetuses with open neural tube defects, a rate of chromosomal abnormalities of 7% has been reported. [19] Among 10 fetuses: 3/21 (14%) were encephalocele defects, 6/66 (9%) were spina bifida abnormalities and 1/57 (2%) were lethal defects. [24]

risk factors for a chromosomal abnormality vary

Above. Specific chromosomal abnormalities have been reported with neural tube defects and are variable [20], while the risk factors for a chromosomal abnormality vary with:

maternal age,
gestational age at diagnosis and,
the presence of other malformations family history of chromosomal abnormalities.

In 587 women, when central nervous system malformations were isolated, specific associations were noted with Trisomy 21, Trisomy 13, and Trisomy 18. [21]

spina bifida chromosomal structural deletions and duplications

Above. Both chromosomal structural deletions and duplications have been associated with NTDs. [22]

fetuses with open NTD underwent prenatal chromosome analysis

Above. Over a 6-year period, 144 fetuses with open NTD underwent prenatal chromosome analysis between 12 and 37 weeks of gestation as part of a prospective, multicenter prenatal diagnosis and counseling program. The prevalence of chromosomal abnormality varied with the defect, with a 14% (3/21) prevalence among those with cephalocele, a 9%  prevalence (6/66) among those with spina bifida and a 2% (1/57) prevalence among those with lethal defects such as acrania, anencephaly or iniencephaly. [24]

Genetically detectable human chromosome abnormalities

Above. Genetically detectable human chromosome abnormalities were studied to identify patients with 14 brain malformations including 542 with deletions, and 290 carrying duplications. [23] Among CNS malformations many chromosomal deletions and duplications were identified among associated bands in various regions.

folate metabolism related genes found in spina bifida

Many folate metabolism related genes have been reported. [24] The gene VANGL-1 and its mutations have been implicated as risk factors for the development of neural tube defects. [25] Other specify VANGL-1 mutations have been reported. [26] The endothelial nitric oxide synthase gene has been implicated as a risk factor in women with impaired homocysteine metabolism. [27] Some deletion allele may be a protective NTD genetic factor [28] but these effects remain under investigation. [29] Specific maternal genotypes such as MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low. [30]

Prevention of Spina Bifida

mandatory folic acid fortification has resulted in a significant decline in spina bifida

Above. In the United States, mandatory folic acid fortification has resulted in a significant decline in spina bifida.

United States data. Change in Spina bifida prevalence among all particpating systems. Prevalence per 10,000. [31]

pre- and post-Folic acid fortification in Canada

Above. Note the pre- and post-Folic acid fortification in Canada.[32]

Folic acid fortification programs

Above. Folic acid fortification programs demonstrate a positive but variable influence on the prevention of defects.

Outcome of 33 Infants Studied for Spina Bifida

spinal defects predict ambulatory status after birth

Above. In an effort to determine whether prenatal ultrasound findings in fetuses with open spinal defects predict ambulatory status after birth, 33 infants were studied. [33] All infants with L4 lesions and below were ambulatory while no infants with thoracic lesions were ambulatory.

The site of the spinal lesion is the most significant predictor of intellectual outcome followed by the presence and degree of ventriculomegaly. The presence of a foot abnormality had no significant effect on outcome while high spinal lesions and the degree of ventriculomegaly correlated with adverse outcome measures. [34]

Muscle echogenicity is increased in fetuses with open spina bifida

Muscle echogenicity is increased in fetuses with open spina bifida. [35] In utero leg movements are present only to disappear within one week after birth.[40] The initial presence of neonatal leg movements does not indicate functional lower motor neuron innervations. [36] Additional neuromuscular damage after the prenatal period may account for the neonatal loss of leg movements. [37]

10% of Diabetics have some form of fetal malformation

Above. Diabetics comprise 2% to 6% of all pregnancies. Overall 10% of Diabetics have some form of fetal malformation involving a variety of organ systems, while NTDs are commonly represented among CNS malformations. [38]

increased risk of CNS birth defects

Above. A number of mechanisms may be responsible for the increased risk of CNS birth defects among women with diabetes and maternal obesity. [43],[39],[40],[41],[42]

central nerve system birth defects

Above. The likelihood for a neural tube defect increases with the degree of maternal obesity, [43] and through a shared mechanism, maternal obesity and gestational diabetes may increase the risk for central nerve system birth defects. [44]

offspring of women with epilepsy was observed in spina bifida

Above. In women with epilepsy, congenital malformations are increased. The highest relative risk for malformations in the offspring of women with epilepsy was observed in spina bifida. [45] In spina bifida patients, epilepsy correlates with coexisting cerebral abnormalities and appears to be multfactorial in origin. [46],[47]

References


 

    1
  1. Garca Lpez E, Rodrguez Dehli C, Ariza Hevia F, Rodrguez Fernndez A, Fernndez Toral J, Riao Galn I, Mosquera Tenreiro C.  Prevalence of neural tube defects in Asturias (Spain): impact of prenatal diagnosis.  Gac Sanit.  2009 Nov-Dec;23(6):506-11.

    Abstract: PMID: 19406531

     

  2. 2
  3. Abstract: PMID: 19353336

    3
  4. Abd El Ghani A, El Ansarry K.  Embryological summary.  A Neural Tube Defects.  [Note: Article defines Spina Bifida, Anencephaly, Encephalocele, and Iniencephaly].  ASJOG.  2006 Feb;3:38-48.
     

  5. 4
  6. Racial/ethnic differences in the birth prevalence of spina bifida: United States, 1995-2005.  Centers for Disease Control and Prevention (CDC).  MMWR Morb Mortal Wkly Rep.  2009 Jan 9;57(53):1409-13.

    Abstract: PMID: 19129744

     

  7. 5
  8. Abstract: PMID: 19228313

    6
  9. Abstract: PMID: 19412801

    7
  10. Abstract: PMID: 16575897

    8
  11. Neural Tube Defects Classification: abnormalities of the skull and brain.  National Library of Medicine – Medical Subject Headings, 2008 MeSH, MeSH Descriptor Data
     

  12. 9
  13. Neural Tube Defects Classification: abnormalities of the spine.  National Library of Medicine – Medical Subject Headings, 2008 MeSH, MeSH Descriptor Data
     

  14. 10
  15. Abstract: PMID: 10952179

    11
  16. Abstract: PMID: 18935989

    12
  17. Abstract: PMID: 16495467

    13
  18. Abstract: PMID: 16451860

    14
  19. Abstract: PMID: 16688770

    15
  20. Abstract: PMID: 16933217

    16
  21. Abstract: PMID: 18405364

    17
  22. Abstract: PMID: 17919832

    18
  23. Abstract: PMID: 19808787

    19
  24. Abstract: PMID: 15065184

    20
  25. Abstract: PMID: 18182338

    21
  26. Abstract: PMID: 18771985

    22
  27. Abstract: PMID: 18182339

    23
  28. Abstract: PMID: 18563447

    24
  29. Franke B, Vermeulen S, Steegers-Theunissen R, Coenen M, Schijvenaars M, Scheffer H, den Heijer M, Blom H.  An association study of 45 folate-related genes in spina bifida: involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1).  Birth Defects Research (Part A).  2009;85(3):216-26.
     

  30. 25
  31. Abstract: PMID: 19319979

    26
  32. Abstract: PMID: 17409324

    27
  33. Abstract: PMID: 17479212

    28
  34. Abstract: PMID: 17486595

    29
  35. Abstract: PMID: 17336564

    30
  36. Abstract: PMID: 17024475

    31
  37. Centers for Disease Control and Prevention (CDC).  Racial/ethnic differences in the birth prevalence of spina bifida: United States, 1995-2005.  MMWR Morb Mortal Wkly Rep.  2009 Jan 9;57(53):1409-13.

    Abstract: PMID: 19129744

     

  38. 32
  39. Abstract: PMID: 18655127

    33
  40. Abstract: PMID: 11717624

    34
  41. Abstract: PMID: 12673636

    35
  42. Verbeek EJ, vd Hoeven JH, Maurits NM, Sollie KM, Bos AF, Brouwer OF, den Dunnen WF, Sival DA.  Muscle echogenicity is increased in fetuses with spina bifida aperta.  Cerebrospinal Fluid Research.  2007 Dec;4(Suppl 1):S11.
     

  43. 36
  44. Abstract: PMID: 15286226

    37
  45. Abstract: PMID: 19447572

    38
  46. Abstract: PMID: 19519395

    39
  47. Abstract: PMID: 14710103

    40
  48. Abstract: PMID: 12614945

    41
  49. Abstract: PMID: 18212354

    42
  50. Abstract: PMID: 15172003

    43
  51. Abstract: PMID: 18538144

    44
  52. Abstract: PMID: 15613950

    45
  53. Abstract: PMID: 16280367

    46
  54. Abstract: PMID: 16933125

    47
  55. Abstract: PMID: 19228313