Vitamin B12 insufficiency and the risk of fetal neural tube defects

QJM. 2003 Apr;96(4):289-95. doi: 10.1093/qjmed/hcg043.


Background: Although maternal folate insufficiency is a risk factor for fetal neural tube defects (NTDs), there is controversy about whether vitamin B12 (B12) insufficiency is also associated with an increased risk of NTDs.

Aim: To investigate whether low maternal B12 is associated with an increased risk of fetal NTDs.

Design: Systematic review.

Methods: A systematic search of Medline between 1980 and October 2002, with an examination of the citations of all retrieved studies. Studies were included that: (i) used a cohort or case-control design; (ii) included case mothers with a prior or current NTD-affected pregnancy; (iii) assessed a group of unaffected 'controls'; and (iv) measured the vitamin B12 status of all participants.

Results: Overall, 17 case-control studies were included, mean sample size 33 cases and 93 controls. In 5/6, mean amniotic fluid B12 concentration was significantly lower in case mothers than in controls. Of 11 that measured maternal serum or plasma B12, three observed a significantly lower mean concentration in case mothers vs. controls, while five others found a non-significant lower trend in the case group. One study observed a significantly higher mean concentration of maternal serum methylmalonic acid among the maternal cases, while another found a non-significant lower mean concentration of plasma holo-transcobalamin. Five studies estimated the risk of NTDs in relation to low B12 or B12-related metabolic markers: it was significantly increased in three studies, with a non-significant trend in the fourth.

Discussion: There seems to be a moderate association between low maternal B12 status and the risk of fetal NTDs. However, several design limitations, and the inclusion of few study participants, may have under-represented this. A large observational study, using reliable and valid indicators of B12 status in early pregnancy, could best assess the association between B12 insufficiency and the risk of fetal NTDs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Case-Control Studies
  • Female
  • Humans
  • Neural Tube Defects / etiology*
  • Pregnancy
  • Risk Factors
  • Vitamin B 12 Deficiency / complications*