Risk of Folate Deficiency

Definition of populations at risk for folate deficiency

Nutritional deficiency of folate is common in people consuming a limited diet. This can be exacerbated by malabsorption conditions, including coeliac disease and tropical sprue. Pregnant women are at risk of folate deficiency because pregnancy significantly increases the folate requirement, especially during periods of rapid foetal growth (i.e., in the second and third trimester. During lactation losses of folate in milk also increase the folate requirement.

During pregnancy there is an increased risk of foetal neural tube defects (NTDs), with risk increasing 10-fold as folate status goes from adequate to poor. Between days 21 and 27 post-conception, the neural plate closes to form what will eventually be the spinal cord and cranium. Spina bifida, anencephaly, and other similar conditions are collectively called NTDs. They result from improper closure of the spinal cord and cranium, respectively, and are the most common congenital abnormalities.

Delineation of dietary sources

Although folate is found in a wide variety of foods, it is present in a relatively low density except in liver. Diets that contain adequate amounts of fresh green vegetables (i.e., in excess of three servings per day) will be good folate sources. Folate losses during harvesting, storage, distribution, and cooking can be considerable. Likewise, folate derived from animal products is subject to loss during cooking. Some staples, such as white rice and unfortified corn, are low in folate. In view of the increased requirement for folate during pregnancy and lactation and by select population groups and in view of its low bio-availability, it may be necessary to consider fortification of foods or selected supplementation of women of child-bearing years.

Evidence on which to base a recommended intake

The 1988 Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO) Expert Consultation report indicated that there were three states of folate nutrition: folate adequacy, impending folate deficiency, and overt folate deficiency. This represented the thinking at the time with respect to folate status – that a status necessary to prevent clinical deficiency was clearly present with folate adequacy and that further improvement in folate status would have no benefit. It would thus be appropriate to increase intake in those with impending folate deficiency or more importantly in those with overt folate deficiency but that nothing was to be gained by increasing the status of those who had adequate status. 

In the 1988 FAO/WHO report it was suggested that adequate folate status is reflected in a red cell folate level of greater than 150 μg/L. Of less relevance was a liver folate level of greater than 7.5 μg/g, because such values are only available in rare circumstances. A normal N-formino-L-glutamate test was also cited as evidence of sufficiency, but this test has largely been discredited and abandoned as not having any useful function. In more recent literature red cell folate continues to be used as an important index of folate status. Plasma folate is also used but is subject to greater fluctuation. Indicators of haematologic status such as raised mean corpuscular volume, hypersegmentation of neutrophils, and, eventually, the first stages of anaemia remain important indicators of reduced folate status.

The biomarker plasma homo-cysteine is a very sensitive indicator of folate status and must be added to the indicators of folate adequacy. This applies not only to the deficient range of red blood cell folate but includes normal and even above-normal levels of red cell folate. There is also very strong evidence that plasma homo-cysteine is an independent risk factor for cardiovascular disease. Any elevation in homo-cysteine, even at levels where overt folate deficiency is not an issue, may be undesirable because it is a risk factor for chronic disease. 

Thus, newer thinking would require consideration of a folate intake that would reduce plasma homo-cysteine to a minimum level of less than 7.0 μmol/l. Formerly acceptable levels of red cell folate may therefore be associated with an increased rise of cardiovascular disease and stroke. The possible benefit of lowering plasma homocysteine through increased folate intake can be proven only by an intervention trial with folic acid supplementation in large populations. Using plasma homo-cysteine as a biomarker for folate adequacy can only be done on an individual basis after the possibility of a genetic mutation or an inadequate supply of vitamin B6 or vitamin B12 has been eliminated.

There is now conclusive evidence that most NTDs can be prevented by the ingestion of folic acid near the time of conception. Lower red cell folate, including what was previously considered an adequate or normal range, is associated with an increased risk of spina bifida and other NTDs. Red cell folate levels greater than 150 μg/L, which are completely adequate to prevent anaemia, are associated with increase risk of NTDs. Low folate status, including red cell levels in the normal range, increases the risk of colorectal cancer.

In 1998, the US National Academy of Sciences exhaustively reviewed the evidence of folate intake, status, and health for all age groups and also reviewed the literature on the extra requirements during pregnancy and lactation. This review led to calculations of an estimated average requirement (EAR) and a subsequent estimation of the recommended dietary allowances (RDAs) to be the EAR plus 2 standard deviations. This definition of the RDA agrees with the definition of the FAO/WHO recommended nutrient intake (RNI), and members of this FAO/WHO expert group agreed that the values published by the US National Academy of Sciences were the best estimates of folate requirements based on the current literature. 

References:

McPartlin, J., Halligan, A., Scott, J.M., Darling, M. & Weir, D.G. 1993 Accelerated folate breakdown in pregnancy. Lancet, 341:148-149.

Wald, N.J., Watt, H.C., Law, M.R., Weir, D.G., McPartlin, J. & Scott, J.M. 1998. Homo-cysteine and ischaemic heart disease: results of a prospective study with implications on prevention. Arch. Internal Med., 158: 862-867.

Chanarin, I. 1979. The Megaloblastic Anaemias 2nd Edition Blackwell Scientific Publications Oxford.

Daly, L.E., Kirke, P.M., Molloy, A., Weir, D.G. & Scott, J.M. 1995. Folate levels and neural tube defects. Implications for prevention. JAMA, 274: 1698-1702.

Scott, J.M., Kirke, P., Molloy, A.M., Daly, L. & Weir, D. 1994. The role of folate in the prevention of neural tube defects Proc. Nutr. Soc., 53: 631-636.

FAO/WHO. FAO/WHO Expert Consultation. 1988. Requirements of Vitamin A, Iron,

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Sauberlich, H. 1995. Folate status in the US Population groups. Folate in Health and Disease. Lynn Bailey editor p. 171-194 Marcel Dekker, New York.

Lindenbaum, J., Savage, D.G., Stabler S.P. & Allen, R.H. 1990. Diagnosis of cobalamin deficiency : II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homo-cysteine concentrations. Am. J. Haematol., 34: 99-107.

Boushey, C.J. Beresford S.A., Omenn, G.S. & Motulsky A.G. 1995. A quantitative assessment of plasma homo-cysteine as a risk factor for vascular disease. JAMA, 274: 1049-1057.

Selhub, J., Jacques, P.F., Wilson, P.W.F., Rush, D. & Rosenberg, I.H. 1993. Vitamin status and intake as primary determinants of homo-cysteinemia in an elderly population. JAMA, 270: 2693-2698.

Perry, I.J., Refsum, H., Morrise, R.W., Ebrahim, S.B., Ueland, P.M. & Shaper, A.C. 1995. Prospective study of serum total homo-cysteine concentrations and risk of stroke in a middle aged British men. Lancet, 346: 1395-1398.

Kirke, P.M., Molloy, A.M., Daly, L.E., Burke, H., Weir, D.G. & Scott, J.M. 1993. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q. J. Med., 86: 703-708.

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Kim, Y.I., Fowaz, K., Knox, T., Lee, Y., Norton, R., Arora, S. Paiva, L. & Mason, J.B. 1998. Colonic mucosal concentrations of folate correlate well with blood measurements of folate in persons with colorectal polyps. Am. J. Clin. Nutr., 68: 866-872.

National Academy of Sciences. 1998. Dietary Reference Intakes: Folate, other B Vitamins and Choline. Wasington, D.C., National Academy Press.