Neural tube defects, folate, and immune modulation

Birth Defects Res A Clin Mol Teratol. 2013 Sep;97(9):602-609. doi: 10.1002/bdra.23177.


Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored.

Keywords: C5a; complement; folate; neural tube defects; neurulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anticonvulsants / adverse effects
  • Autoantibodies / immunology
  • Chemokine CCL2 / immunology
  • Chemokine CCL2 / metabolism
  • Complement System Proteins / immunology
  • Complement System Proteins / metabolism
  • Female
  • Folate Receptors, GPI-Anchored / immunology
  • Folate Receptors, GPI-Anchored / metabolism*
  • Humans
  • Immunologic Factors / blood
  • Immunologic Factors / metabolism*
  • Neural Tube Defects / epidemiology*
  • Neural Tube Defects / etiology*
  • Neural Tube Defects / physiopathology*
  • Neural Tube Defects / prevention & control
  • Neurulation / immunology
  • Neurulation / physiology*
  • Pregnancy
  • Pregnancy in Diabetics / immunology*
  • Risk Factors
  • Tetrahydrofolates / blood
  • Tetrahydrofolates / metabolism*
  • Valproic Acid / adverse effects


  • Anticonvulsants
  • Autoantibodies
  • CCL2 protein, human
  • Chemokine CCL2
  • Folate Receptors, GPI-Anchored
  • Immunologic Factors
  • Tetrahydrofolates
  • Valproic Acid
  • Complement System Proteins
  • 5-methyltetrahydrofolate