Spina Bifida Information for Fetal Diagnostics
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
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.
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. ,,,,,,
*Sweden, 6.1 = 2.4/10,000 newborns plus 3.7/10,000 termination of pregnancy.
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.
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. 
A separate classification includes abnormalities of the vertebral arches (dysraphism) and includes open defects such as meningocele and spina bifida cystica.  Spina bifida occulta represents a closed spinal defect. 
Above. A separate classification for Spinal Dysraphism (spinal defects which affect the vertebra arches) has been proposed.  This classification divides the spinal lesions into open and closed defects and suggests certain associations with each.
Above. Neural tube defects can broadly be described as syndromic and non-syndromic.  In the non-syndromic multifactorial group, a number of specific risk factors have been reported.
Above are risk factors reported for spina bifida. 
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.
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 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.  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.
Above. Williams  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.
Above. Neural tube defects are due to multiple environmental and genetic factors. 
Above. These gene-gene factors and gene-environmental factors are operable through a variety of maternal conditions. 
Above. With respect to genetic risk factors, multiple genes are responsible.
Above. Among fetuses with open neural tube defects, a rate of chromosomal abnormalities of 7% has been reported.  Among 10 fetuses: 3/21 (14%) were encephalocele defects, 6/66 (9%) were spina bifida abnormalities and 1/57 (2%) were lethal defects. 
Above. Specific chromosomal abnormalities have been reported with neural tube defects and are variable , while the risk factors for a chromosomal abnormality vary with:
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. 
Above. Both chromosomal structural deletions and duplications have been associated with NTDs. 
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. 
Above. Genetically detectable human chromosome abnormalities were studied to identify patients with 14 brain malformations including 542 with deletions, and 290 carrying duplications.  Among CNS malformations many chromosomal deletions and duplications were identified among associated bands in various regions.
Many folate metabolism related genes have been reported.  The gene VANGL-1 and its mutations have been implicated as risk factors for the development of neural tube defects.  Other specify VANGL-1 mutations have been reported.  The endothelial nitric oxide synthase gene has been implicated as a risk factor in women with impaired homocysteine metabolism.  Some deletion allele may be a protective NTD genetic factor  but these effects remain under investigation.  Specific maternal genotypes such as MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low. 
Prevention of 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. 
Above. Note the pre- and post-Folic acid fortification in Canada.
Above. Folic acid fortification programs demonstrate a positive but variable influence on the prevention of defects.
Outcome of 33 Infants Studied for Spina Bifida
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.  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. 
Muscle echogenicity is increased in fetuses with open spina bifida.  In utero leg movements are present only to disappear within one week after birth. The initial presence of neonatal leg movements does not indicate functional lower motor neuron innervations.  Additional neuromuscular damage after the prenatal period may account for the neonatal loss of leg movements. 
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. 
Above. The likelihood for a neural tube defect increases with the degree of maternal obesity,  and through a shared mechanism, maternal obesity and gestational diabetes may increase the risk for central nerve system birth defects. 
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.  In spina bifida patients, epilepsy correlates with coexisting cerebral abnormalities and appears to be multfactorial in origin. ,
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