Looking at two examples from the older litera- ture, one can already see the likely problem that was to emerge with respect to folate status world- wide in the subsequent decades. Two studies in the 1980s showed a marked contrast in preva- lence. In Benin in rural central Africa, it was reported that of 586 adults, over 42% had overt anemia, and that over 20% of this was due to folate deficiency (8). This was contrasted with a study from southern Algeria by the same group, where only 7% of 254 young adult women were found to be anemic, with none of the anemia caused by folate deficiency (9). Thus, in contrast to vitamin B12deficiency where specific intestinal
(perncious anemia and gastric atrophy) or regional (veganism) factors contributed in a rea- sonable identifiable way to reduced status, severe folate deficiency worldwide may be very local- ized, apart from circumstances like pregnancy where there is a specific increased requirement which is frequently not met. The overall pattern that one sees with folate status is that even in developed countries such as the USA the diet as it has currently evolved has been inadequate for optimum folate status. This is perhaps best illus- trated by the paper by Jacques et. al. (10), which
found that in the USA prior to fortification of flour with folic acid in 1998, over 22% of the pop- ulation had impaired folate status, which fell to 1.7% post fortification. A pattern of general under-provision of folate right through to overt deficiency is seen in developing countries. This could be expected to depend upon the source and amounts of food available, mindful that folate is found in vegetable based diets, but as mentioned above, not really abundant in any particular food. In addition, amounts consumed will be subject to methods of preparation, in that natural folate is labile and easily destroyed during cooking (11). Folate also deteriorates during storage, a good example being the large difference in status found between northern and southern China due to lack of availability of fresh food during the long win- ter in the former (12). Taking a number of status studies by way of examples one sees, for exam- ple, a study of 278 randomly selected adults in Zimbabwe found 30% had low folate levels (13). By contrast, in 250 elderly women in New Zealand, only 3 and 5% have low serum and red cell folate (14). In a study of 567 school children in Thailand, hemoglobinopathies, vitamin A sta- tus and age were the major predictors of hemoglo- bin status. Only about 1% had biochemical evi- dence of reduced folate status, either by RCF or plasma folate (15).
In Sri Lanka in 945 schoolchildren, nearly half of females and over half of males had ane- mia. Iron deficiency was the cause of the anemia in 30% of the males and 48% of the females. However, impaired folate status were reported to be present in over half of either group (16).
Recent large studies continue to show reduced status as an issue. For example in a mixed group of 5,658 samples in Venezuela taken during 2001–2005, some 30% were considered to be folate deficient (17). However, as discussed below, Venezuela has now opted for mandatory fortification with folic acid, so this once serious problem has now probably largely disappeared.
Pregnancy has long been known to put extra pressure on folate status. While initially this was thought to be due simply to transfer of maternal folate to the fetus, it is now clear that the rapid cell proliferation associated with pregnancy greatly increases the rate of folate breakdown (catabolism) and thus increases in requirement (7). The topic of folate and pregnancy has recently been extensively reviewed by Tamura and Picciano (18). Histori- cally, the pattern that has emerged in developed countries was that some decades ago, the latter stages of pregnancy were often associated with overt deficiency. This was less and less observed as the food supply improved (19). The picture emerged in developed countries that if a woman entered pregnancy with sufficiently adequate stores they would be adequate to meet the extra burden required, and there would be no emergence of defi- ciency and certainly no anemia. This has resulted in different practices in developed countries, where some obstetricians recommend folic acid supple- ments in late pregnancy and others do not. Of course, this all depends on the mother entering the pregnancy with adequate stores, and this expecta- tion clearly would not be met in many developing countries.
There is thus a long established role of inade- quate folate status in the megaloblastic anemia of pregnant women (3). However such anemia was associated with poor maternal stores entering pregnancy, and was only seen late in pregnancy. More recently, a completely different role for folate/folic acid has been described. It is now established that women taking extra folic acid, before during and after conception (periconcep- tionally), can reduce the prevalence of spina bifida and other neural tube defects (NTDs) by certainly over a half and possibly as much as three-quarters.
It is now clear that the prevention of NTDs by women taking extra folic acid prior to the crucial period of the closure of the neural tube between days 21 and 27 only happens in less than a quarter
of pregnancies, despite intensive public aware- ness campaigns in many developed countries. This is largely due to the fact that in all communi- ties where it has been examined, over half of pregnancies are unplanned. Even in the planned pregnancies the message is difficult to get across, and there is also the issue of compliance, even where women understand the benefit. This has led many developed countries to turn to the manda- tory fortification of a staple such as flour with folic acid, with an impressive reduction of NTD prevalence, for example in Canada, where per- haps as much as half are prevented. It seems appropriate, as discussed elsewhere, that such for- tification might be extended to developing coun- tries. The dilemma with such a public health policy is that one has to balance the amount of the nutrient, in this instance, folic acid, so as to produce an optimal benefit but still not expose those who benefit or, of even greater concern, the general population, to risks associated with high intakes of the vitamin. With respect to folic acid, the most commonly discussed adverse effect is the masking of vitamin B12 deficiency. Such
masking is very dose-dependent, and it is consid- ered that it does not happen at intakes of less than 1,000 mg (or 1.0 mg) of folic acid per day. This
concern is the basis for setting the Upper Tolera- ble Intake Level (UL) for folic acid at that amount. There is, however, a different concern, namely that the addition of folic acid might accel- erate the growth of existing tumors. This is most often cited with respect to colorectal cancer (CRC), but it could also be true of other cancers. Most studies would consider that improving folate status and increased intake of folic acid are associated with a reduction in the occurrence of CRC. The concern, however, relates not to caus- ing a new cancer to emerge, but to its subsequent more rapid growth and progression. This would have a particular and obvious disadvantage with CRC, where all such cancers, before they become adenomas requiring surgery and chemotherapy, go through a stage where they exist as a polyp. If such polyps are suspected to be present, as they
117 Nutritional anemia: B-vitamins
Table 9.1: Forty-two countries have mandatory folic acid food fortification programs (see dark shaded areas in Figure 9.2).
119 Nutritional anemia: B-vitamins
Table 9.1 (continued): Forty-two countries have mandatory folic acid food fortification programs (see dark
frequently are as a result of bleeding or irregular bowel habits, they can be identified and removed at colonoscopy without further difficulty. It is estimated from various strands of evidence that such polyps may be there for perhaps a decade prior to their conversion to an adenoma, but a conservative estimate is that in most instances they are present for in excess of three years. Clearly if this conversion to full cancer took place more rapidly, as is suggested could be brought about by folic acid, particularly high levels of folic acid, this diagnostic window of opportunity is decreased. The evidence that such acceleration of CRC and other cancers does occur is generally seen in the first instance by the fact that one of the most effective drugs in treating and retarding the tumor growth is the anti-folate methotrexate. In addition, the front line drug in treating CRC, 5- fluorouracil, acts by inhibiting the folate depend- ent enzyme thymidylate synthase. In addition,
some animal tumor implants have their growth rate accelerated by folic acid. Further concerns relate to an intervention trial that found that folic acid ingestion over a three year period compared to placebo, while it did not cause an increase in the number of patients recurring with polyps, did show more polyps in those that did have such a recurrence. Finally, there was an apparent in- crease in the prevalence of CRC in North America that appears to have occured simultaneously or shortly after fortification was introduced in 1998. The arguments for and against the involvement of folic acid in CRC has been discussed at length by the Scientific Advisory Committee in the UK. They, in conjunction with a special committee on cancer, concluded that the evidence that folic acid advances the growth of existing tumors to be unproved and have recommended unreservedly that fortification with folic acid proceed in the UK.
Table 9.1 (continued): Forty-two countries have mandatory folic acid food fortification programs (see dark