Neural Tube Defects



Neural tube defects (NTDs): CNS malformations due to abnormalities of neural tube closure during early embryonic development that can be either open or closed defects. Spina bifida (SB) is a term referring to a subset of NTDs involving the spinal cord and means “spine split in two.”

  • Anencephaly: due to failed closure of rostral neural tube with total or partial absence of cranial vault and cerebral hemispheres
  • Encephalocele: partial failure of rostral neural tube closure
    • Abnormal brain tissue protrudes through a skull defect usually covered by skin.
    • 70–80% are occipital; 20% are frontal.
    • 10–20% of occipital defects are meningoceles and contain no brain tissue.
  • Open SB: Exposed neural tissue and membranes protrude through a bony defect.
    • Due to failure of primary neural tube closure during the 3rd and 4th weeks after fertilization
    • Includes myelomeningocele (MMC) and myeloschisis
    • MMC: open NTD of the spine, most common type of SB, and characterized by herniation of dysplastic spinal cord and meninges through a posterior vertebral column defect
  • Closed SB: Often referred to as occult spinal dysraphism (OSD). Theorized to be due to defects of secondary neurulation; less common than open NTDs
    • Often not diagnosed at birth
    • Skin-covered lesions
    • Wide spectrum of defects including lipomyelomeningocele, dermal sinus tracts, diastematomyelia (split cord malformations), myelocystocele, other tumors and cysts of the cord, and congenital spinal cord tethering


  • NTDs affect ~1 in 1,000 established pregnancies worldwide, with significant geographic variation.
  • In the United States, birth prevalence has been decreasing due to periconceptional supplementation with folic acid, food fortification, as well as prenatal diagnosis and termination of pregnancy.
  • Centers for Disease Control and Prevention (CDC) data from 2004 to 2006 showed 0.64 NTDs per 1,000 births (~2,660 cases per year), with 54% classified as SB, 32% anencephaly, and 13% encephalocele.


Most NTDs are due to the interaction of genetic, environmental, and dietary risk factors.

  • Variants of multiple genes probably confer some increased genetic susceptibility.
  • Maternal nutrition and dietary factors, including inadequate maternal folic acid intake
  • Maternal diabetes mellitus
  • Maternal obesity
  • Maternal use of valproic acid (10 times risk), carbamazepine, or alcohol during pregnancy
  • Maternal exposure to hyperthermia during early pregnancy (e.g., sauna, hot tub, fever)
  • Prior pregnancy with NTD


  • A specific genetic cause is not found for most NTDs.
  • Positive family history in ~5% NTD cases
  • After one child with an NTD, the recurrence rate is 2–5% for subsequent pregnancies.
  • A chromosomal or cytogenetic abnormality found only in ~10% of isolated NTDs; higher percentage in those with multiple congenital anomalies
  • NTDs are common in trisomy 13 and 18 and can be seen with duplications and deletions.
  • Found in single gene disorders or syndromes (e.g., Meckel, Waardenburg, 22q11 deletion syndromes)
  • A number of candidate risk factor genes have been studied; the most implicated are those in the folate one-carbon metabolic pathway.
    • A homozygous 677C > T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene in mother or child is associated with ~1.8 times increased risk.


  • Periconceptual folic acid supplementation has the potential to reduce NTDs by 50–70%.
  • Because many pregnancies are not identified until after neural tube closure occurs and because >50% of pregnancies are unplanned, the CDC recommends that all women of childbearing age receive a minimum of 0.4 mg (400 mcg) of folic acid daily.
  • Women at high risk (prior pregnancy with NTD, on valproic acid, etc.) should take high-dose folic acid (4 mg daily), starting 1 month before and through the first 3 months of pregnancy.
  • If taking valproic acid, consider switching to alternative medication during pregnancy.


  • MMC is virtually always associated with some malformation of the brain.
  • Most children with MMC have a Chiari II (Arnold-Chiari) malformation, small posterior fossa with elongation of the cerebellum, and herniation through the foramen magnum.
    • Chiari II malformation often causes obstructive hydrocephalus.
    • Historically, about 80% of children with MMC required a CSF shunt.
  • Callosal dysgenesis, cortical dysplasia, and subependymal heterotopias are also common.
  • MMC is commonly associated with nonverbal learning disabilities and executive dysfunction.
  • Open and closed SB impairments from spinal cord dysfunction:
    • Paraparesis and sensory loss usually correlating with the level of the lesion
    • Neurogenic bladder dysfunction
    • Neurogenic bowel dysfunction
  • Congenital foot deformities (club foot) and hip dysplasia are common with NTDs.

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