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Published in: Homocysteine Metabolism: From Basic Science to Clinical Medicine, ed. Ian Graham, Helga Refsum, Irwin H. Rosenberg, Per Magne Ueland, & Jill M. Shuman (Boston: Kluwer Academic Publishers, 1997).


This article is a U.S. government work, and is not subject to copyright in the United States.


Evidence continues to confirm that periconceptional ingestion of folic acid can prevent neural tube defects, although the basis of this prevention has been unclear. To further elucidate the mechanism by which this occurs, blood samples were collected from more than 50,000 pregnant women and the samples analyzed for red cell folate, plasma folate, plasma vitamin B12, and plasma homocysteine levels. Based on the results, it appears that the beneficial effect of folic acid is in overcoming a metabolic block in a folatedependent enzyme or transport process. It is likely that methionine synthase may be directly or indirectly involved.

The neural plate closes to form the spinal cord and the cranium between days 24 and 28 postconception. Incomplete closure of the former causes spina bifida; of the latter, anencephaly. The two conditions are called neural tube defects (NTD) [l}. Earlier evidence that folic acid taken periconceptionally by women could prevent NTDs (2-4} has recently been confirmed by two randomized trials using peri conceptional ingestion of folic acid supplements (5,6}.

There are three possible ways by which folic acid might exert this protective effect: (1) it might treat folate deficiency; (2) it might overcome malabsorption; or, (3) it might overcome a metabolic block. The future public health response to this important development would depend to a considerable extent on which one of these three mechanisms is actually involved. If simple folate deficiency is involved, protection might be achieved at levels of folic acid far lower than the 400 lJ,g per day used in the trials. By contrast, if folic acid overcomes malabsorption or an impairment or block in some folate-dependent enzyme or process, the relatively high levels of folic acid used in the trials may be essential to achieve protection.

We set out to test which of the three was the operative alternative by collecting blood samples from women early in pregnancy, when their folate status would most accurately reflect that pertaining to the time of closure of the neural tube (days 24-28 postconception). When it was subsequently ascertained which women had an NTD-affected pregnancy, blood samples were retrieved and their plasma and red cell folates (RCFs) were compared with controls matched for length of storage. We further investigated evidence that a metabolic block in folate metabolism actually existed in these women.

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