Folate Folic Acid and NTDs Mechanisms

Does folic acid prevent NTDs by correcting simple dietary deficiency, by overcoming a problem in gastrointestinal absorption, or by overcoming some type of metabolic block? Recent research has helped to clarify the role of folate/folic acid in the etiology and prevention of these malformations. Blood samples were collected from women at their first antenatal clinic in the Dublin maternity hospitals and 81 women in this cohort subsequently had infants affected by NTDs. Folate and B12 status were compared in these 81 cases and in a control sample of 247 unaffected pregnancies by measuring plasma and RCF and plasma vitamin B12. Although folate levels were significantly lower in the cases than in the controls, more than 91 and 86% of the cases had normal plasma and RCF levels, respectively. Thus, the vast majority of women who had an

Mechanism Folic Acid Nutrition
Figure 1 Intracellular pathways of folate and homocysteine metabolism and their relation to vitamin B12 function.

NTD birth were not folate deficient, as defined by conventional levels.

It has been suggested that women who have had children with NTDs may have a defect in gastrointestinal absorption of folate or folic acid, but there is no strong evidence to support this hypothesis. In a study designed to overcome the methodological problems of earlier investigations, folic acid absorption was similar in a group of nonpregnant women with a history of an NTD pregnancy and in control women with a normal pregnancy history. These findings suggest that the absorption of folic acid routinely consumed in supplements and fortified food products is not impaired in women with a history of an NTD pregnancy. However, autoanti-bodies against folate receptors have been reported in women who have had a pregnancy complicated by an NTD. These autoantibodies bind to the folate receptors and can block the cellular uptake of folate.

A woman's risk of having an NTD baby has been shown to be closely related to her early pregnancy levels of plasma folate and RCF, the relationship being stronger for RCF (Table 6). There is a strong dose-response effect. Those with RCF levels less than 150mgl 1 have more than eight times the risk of those with levels of more than 400 mgl 1 Although the most marked absolute reductions in risk occur by elevating the lower RCF levels, risk continues to decrease as RCF levels increase well beyond what would be considered normal levels, with little further protection apparently being gained at levels higher than 400 mgl-1. Most of the NTDs were born to women whose RCFs would have been considered to be in the normal range (i.e., >150mgl1). Thus, views on what constitutes desirable levels of RCF need to be reconsidered.

The lack of evidence of a simple dietary deficiency or of malabsorption and the marked dose-response relationship between maternal RCF level and risk of

Table 6 Distribution of cases and controls and risk of NTDs by red cell folate level

Red cell

No. of

No. of

Risk of NTD





per 1000








11 (13.1)

10 (3.8)




13 (15.5)

24 (9.0)




29 (34.5)

75 (28.2)




29 (23.8)

77 (29.0)




11 (13.1)

80 (30.0)




84 (100.0)

266 (100.0)



From Daly LE, Kirke PN, Molloy A, Weir DG and Scott JM (1995) Folate levels and neural tube defects—Implications for prevention. Journal of the American Medical Association 274: 1968-1702. Copyright © 1995, American Medical Association.

From Daly LE, Kirke PN, Molloy A, Weir DG and Scott JM (1995) Folate levels and neural tube defects—Implications for prevention. Journal of the American Medical Association 274: 1968-1702. Copyright © 1995, American Medical Association.

NTD point to a metabolic explanation for the aetiology of these conditions. Since it is estimated that folic acid can prevent up to 71% of NTDs, defects in folate-related enzymes or processes have been candidates for study. There are 16 folate-dependent enzymes in the internal metabolism of mammalian cells. The finding in the Dublin study of significantly higher plasma homocysteine levels in case mothers than in controls suggested that one or more enzymes involved in homocysteine metabolism may be abnormal. The main folate-related enzymes involved in homocysteine metabolism are illustrated in Figure 1. Homocysteine levels in the amniotic fluid of women carrying a fetus with an NTD have been reported as being higher compared with those of normal pregnancies. Evidence of deranged homo-cysteine metabolism also comes from metabolic studies conducted in Holland. In a study in which women who had given birth to an NTD baby were given a methionine-loading test, methionine intolerance and very high peak levels of homocysteine were found in a subgroup of the NTD women. Cystathio-nine synthase levels in skin fibroblasts taken from the methionine-intolerant women were normal. Plasma folate and vitamin B12 were found to be independent risk factors for NTDs in the Dublin study. Although the results of this study pointed to an abnormality in the methionine synthase enzyme, there is no strong evidence linking genetic variants of the enzyme to NTDs. However, it is possible that vitamin B12 status may influence NTD risk in ways other than directly affecting the activity of this enzyme.

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