Folic acid is a water-soluble vitamin needed for DNA synthesis - folic acid is essential for cellular replication and differentiation. Vegetables, especially green leafy vegetables, cruciferous vegetables, legumes, citrus fruits, melons and organ meats are the principle sources of folic acid in the human diet. Fortified breakfast cereals, now widely consumed throughout Central and South America and in parts of the Middle East, make important contributions to folic acid intake in those regions. Dietary intakes will be low wherever effective access to folate-rich foods is limited, or where cooking practices lead to high loss. Folic acid is sensitive to certain storage conditions and to heat, oxidation, and ultraviolet light. It is estimated that 50% to 90% of folic acid in food is destroyed during cooking (Institute of Medicine, 1997, p. 18). Reducing agents such as vitamin C preserve folic acid.

Folic acid deficiency leads to megaloblastic anaemia, a condition where red blood cells are characteristically large and pale. Interest in folic acid has heightened recently because of conclusive findings showing that, in industrialized and Eastern European countries, additional folate consumption during the peri-conceptional period significantly reduces the risk of recurrence of neural tube defects such as anencephaly and spina bifida (MRC, 1991). Recent data also suggest that a poor folate status is related to high blood homocysteine levels, which in turn have been identified as a risk factor for cardiovascular disease (Selhub and Rosenberg, 1996).

Recommended intakes of folic acid for developing countries are expressed in mg/d (FAO/WHO, 1988). These are 170 mg/d for female adults, 370-470 mg/d for pregnant women, and 270 mg/d for breastfeeding women. This FAO/WHO report advises that folate requirements during pregnancy 'are very high' and strongly recommends daily supplements during both pregnancy and breastfeeding. Folate as well as vitamin B12 requirements are elevated by malaria and other haemolytic conditions (Fleming, 1996). The FAO/WHO recommendations will be brought up to date at an expert consultation planned for late 1998 (FAO, personal communication).

Extent of Folic Acid Deficiency

As an anaemia prevention and control strategy, for many years the WHO has recommended adding 250 mg of folic acid to iron-containing tablets provided to pregnant women in developing countries (DeMaeyer et al, 1989). As mentioned in the previous section, this level was recently increased to 400 mg (see page 38). Research conducted in many countries shows that haemoglobin levels during pregnancy improve more when folic acid is given together with iron than when iron alone is given (Baker and DeMaeyer, 1979).

There is a dearth of information on the epidemiology of folic acid deficiency in developing countries. Although data collected over two decades ago suggested that it may be prevalent, more recent studies suggest regional variations. A study conducted in rural Mexico did not identify folic acid deficiency (Black et al., 1994), but rather vitamin B12 deficiency (Allen et al., 1995) among children and pregnant and breastfeeding women. By contrast, studies in South Africa have found that folic acid deficiency is very common among pregnant women in their last trimester (Fleming, 1996). There are no internationally agreed criteria for the establishment of folic acid deficiency as a public health problem in developing countries.

The proportion of anaemia cases that can be attributed to folic acid deficiency in developing countries is generally unknown. FAO/WHO stated about ten years ago that folate deficiency is the second most common cause of nutritional anaemia (FAO/WHO, 1988, p 83). However there are virtually no current epidemiological data to back this up. Similarly there are no data on trends in folic acid status in developing countries. There are numerous nutritional (iron, folate and vitamin B12 deficiencies) and non-nutritional primary causes (e.g., parasites such as hookworm and malaria, and genetic disorders) of anaemia. In addition, both folic acid deficiency and B12 deficiency can cause megaloblastic anaemia. Work is needed to describe the current epidemiology of folic acid and vitamin B12 deficiency, and the independent role that these nutrients play in the development of anaemia in different regions of the world. One attempt to assess relative contributions of different causes of anaemia is presented on page 36 of this Report.

Folic Acid and Neural Tube Defects (NTDs)

Recent findings linking additional folic acid intake during the peri-conceptional period to significantly reduced risk of a recurrent NTD pregnancy led the US Center for Disease Control and Prevention to recommend 4000 mg/d of folic acid for women who had experienced a previous NTD pregnancy. This amount is to be administered under the supervision of a physician when a pregnancy is planned. Furthermore, the US Public Health Service recommends that all women of childbearing age consume 400 mg/d folic acid (CDC, 1992). This is in contrast to the existing recommended dietary allowance (RDA) for US women which was set at 180 mg/d in 1989.

In a controversial decision, the US Food and Drug Administration has approved the fortification of cereal grains with folic acid in an attempt to prevent 1000 cases of NTDs per year in the US. The FDA regulation requires that by January 1, 1998 all enriched cereal grain flours, breads, rice, noodles, macaroni and other grain products be fortified with folic acid at a concentration of 140 mg/100 g grain. These foods were selected because they are staple products for most of the US population. This will increase average consumption for women of reproductive age by about 100 mg/d (FDA, 1996). Authorities expressed concern to limit intakes at the upper end because of persons with B12 deficiency who may have a delay in diagnosis.

NTDs do not appear to be more prevalent in developing countries than in industrialized countries (Little and El-wood, 1992). Folic acid-sensitive NTDs are likely to be the result of a genetic defect in the metabolism of folic acid and/or other nutrients such as vitamin B12 (Czeizel, 1995). Women affected by folic acid-sensitive NTD pregnancies may experience mutations in genes coding for folate-dependent enzymes (Whitehead et al., 1995). Although the morbid effects of this genetic disorder are in part overcome by additional folic acid intake, folic acid deficiency does not appear to be the primary cause of NTDs. This may explain why blood folic acid concentrations of women with NTD-affected pregnancies are similar to those with unaffected pregnancies (Picciano, 1996).

The dosage used in the MRC clinical trial was intentionally high, around 4 mg/d. There is evidence that 400 mg of folic acid daily may be enough to prevent NTDs. This is why the US Public Health Service bases its recommendations for women of reproductive age without a previous history of NTDs on this much tower dosage. Folic acid intakes over 1 mg have the potential of masking vitamin B12 deficiency by correcting the anaemia but not preventing the onset of central nervous system disorders. Since the magnitude of B12 deficiency is virtually unknown on a world scale the potential risks posed by broad implementation of folic acid fortification programmes in the developing world are also unknown. In addition, there is some indication that additional folic acid intake may interfere with the action of some malaria medications (Perez-Escamilla, 1995).

Programmes

Folic acid has been offered along with iron in tablet form for many years in all regions, especially to women during pregnancy. These programmes have historically been justified on the basis of widespread iron deficiency anaemia. Consequently the impact on folic acid deficiency has been relatively neglected (Yip, 1996; Galloway and McGuire, 1996). There are very few documented programmes aimed at reducing folic acid deficiency. One pilot trial in South Africa demonstrated that corn-based meals can be successfully fortified with folic acid and have a positive impact on haemoglobin levels of pregnant women (Fleming, 1996).