Neural‐tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid

Abstract

While folate supplementation reduces the risk of recurrent neural-tube defects (NTD), both folate and cobalamin deficiencies may be independent risk-factors for neural-tube defects. Folate-dependence and impaired remethylation of homocysteine are implicated as mechanisms for NTD. There are few references reported for folate, cobalamin, homocysteine and methionine in the fetal compartment. This case-controlled pilot study of amniotic fluid (AF) samples derived from 16 NTD pregnancies and 64 age-matched controls quantities total homocysteine (tHcy), total cysteine (tCys), folate, cobalamin (B12), and methionine. Only decreased AF B12 concentrations were found (150 pg/ml versus 540 pg/ml, P < 0.02). Since cobalamin, folate and homocysteine participate in the remethylation of homocysteine, via methyl transfer from 5-methyltetrahydrofolate to B12, to methionine, we compared ratios of these methionine synthase (EC 2.1.1.13)-related intermediates. The ratio of B12/folate for NTD versus controls was 48 (34-90) versus 126 (123-182), P < 0.001. The ratio of methionine/(folate x tHcy) was 1.4 (1.2-2.2) versus 2.7 (2.4-3.3), P < 0.001. We conclude that AF from pregnancies with NTD have lower B12 concentrations, and that ratios of product to substrate(s) of homocysteine remethylation suggest impaired methionine synthase in the fetal compartment through the early second trimester.

Serum vitamin B12 and homocysteine levels in pregnant women with neural tube defect

“…Steegers-Theunissen et al [17] and Mills et al [18] found that homocysteine levels were higher in NTD pregnancies compared to control pregnancies matched for vitamin B12 levels. Steen et al [19] and Steegers et al [20] observed decreased vitamin B12 levels in the amniotic fluid of mothers with a NTD child. These findings point to a possible role for vitamin B12 in the aetiology of NTD.…”

Perinatal folate supply: relevance in health outcome parameters

“…However, plasma Hcy cannot be considered a highly specific biomarker of folate status. Other determinants of circulating Hcy are vitamin B 6 ‐, choline‐ and vitamin B 12 deficiencies due to deregulation of their metabolism or low dietary availability, or the combination of these two factors (Locksmith & Duff 1998; Steen et al . 1998; Obeid & Herrmann 2005; Castro et al .…”

“…Women with low folate supply in combination with low blood vitamin B 12 levels had a drastically increased risk of NTDs (Padmanabhan 2006). Low B 12 concentrations seem to be associated not only with NTDs (Steen et al . 1998; Ray & Laskin 1999; Ray & Blom 2003) but with CHDs as well (Verkleij‐Hagoort et al .…”

Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications

“…In agreement with this view, a recent population-based case-control study showed an increased risk of early spontaneous abortion among pregnant women with low plasma folate levels [32]. Vitamin B 12 deficiency during pregnancy results in elevated homocysteine concentration in the embryo and increases the incidence of NTD [26,31,33,34]. In addition, hereditary deficiency of transcobalamin results in profound neurological abnormalities and mental retardation [35].…”