neural tube defects ( ntds ) are common and devastating congenital malformations of the central nervous system . over 90% of the cases are comprised of anencephaly ( a total or partial absence of brain tissue , skull , and overlying skin ) and spina bifida ( herniation of the spinal cord , meninges , or both through a defect in the spinal column ) . both arise from incomplete closure of the neural tube early in gestation , before 28 days after conception , and often before a woman is aware that she might be pregnant . ntds are a worldwide problem , with approximately 300,000 affected newborns every year and 3,000 cases per year in the united states alone . a 2005 report from the centers for disease control ( cdc ) estimated that the   rates for spina bifida and anencephaly were 17.96 and 11.11 per 100,000 live births , respectively , in the united states . in 1992 , the fda recommended that every woman of childbearing age should consume 0.4  mg folic acid daily . this 0.4  mg dose was based on several case control and cohort studies as well as a 1992 hungarian randomized controlled trial ( rct ) that used 0.8  mg daily for primary prevention . in 1999 , berry et al . provided additional evidence for 0.4  mg supplementation when a study carried out in china showed significant primary prevention of ntds with that dose [ 6 , 7 ] . the protective effect of folic acid delivered during the periconceptual period is the best studied of the numerous potential environmental factors contributing to ntds . folate is a water - soluble b vitamin that acts as a cofactor in one - carbon transfer reactions and plays a central role in nucleic acid biosynthesis . emerging research shows that folic acid may play dual and opposite roles in relation to cancer promotion [ 911 ] . because folate deficiency has long been suspected to promote cancer through destabilization of the genome , possibly through increased homocysteine levels , decreased methylation of the genome , uracil misincorporation , and double - strand breaks of dna leading to chromosomal damage [ 12 , 13 ] , adequate levels of folate could be protective against carcinogenesis through stabilization of the genome . however , because of the critical role that folate plays in nucleic acid biosynthesis , it may also have a role in cancer promotion in susceptible individuals . in patients harboring preneoplastic and neoplastic lesions , exposure to extra folate ( through supplementation or fortification ) could potentially promote cellular proliferation and cancer growth [ 10 , 14 ] . this is particularly true for those individuals who already possess tissues which have undergone early changes characteristic of malignancy . for example , in a standard chemical carcinogen rodent model of colorectal cancer , extreme dosages of folic acid ( > 20-times the basal daily dietary requirement ) have been shown to increase the development and progression of colorectal cancer . on the other hand , two other rodent models have shown that modest levels of folic acid supplementation ( 410-times the basal daily dietary requirement ) suppressed the development and progression of colorectal cancer . both , animal studies and recent epidemiological studies have begun to challenge the widely accepted notion that folate status is inversely related to the risk of developing cancers . studies have shown conflicting or equivocal results for the role of folic acid in other cancers , including breast [ 15 , 16 ] , prostate , and neuroblastoma cancers . the inability to reach a consensus represents a pressing issue that deserves further and detailed study in view of the fortification programs that are underway throughout the world , potentially exposing billions of people to higher levels of folic acid . the biochemical pathway of folic acid that works to prevent ntds is currently unclear , and many questions about the processes underlying normal and abnormal neurulation remain unanswered and the subject of continued investigation . what is well established , however , is that maternal folic acid intake during the periconceptual period is effective in reducing the occurrence of ntds [ 1921 ] . one of the most impressive studies illustrating this point was undertaken in china in an area of high ntd prevalence . half the population ( geographically confined ) was given folic acid supplementation whereas the other half received normal prenatal care . unfortunately , putting prevention into practice has been more difficult than initially anticipated , and numerous controversies are present throughout the literature about some of the most important folic acid - related issues facing women and public health authorities worldwide . among the contentious issues are questions related to the optimal dose of supplemental folic acid ( for the prevention of ntds ) , the safety of folic acid among individuals of all ages , the risk benefit profiles of synthetic and naturally derived folic acid , the optimal level of fortification , and if this is even an effective strategy , and the root causes of ntds in different populations . for example , a study on racial and ethnic differences in ntd rates showed that hispanics had the highest rates of ntd - affected pregnancies , non - hispanic blacks and asians the lowest , and the rates of non - hispanic whites being intermediate between the two . the reason for such disparities is unclear , and the involved factors likely go far beyond inherent folic acid status in different racial / ethnic groups . the recommended daily allowance of folic acid has been difficult to assess and remains the subject of much debate . although many countries have similar recommendations , no international consensus is available on dosage , and some countries do not have official recommendations . in 1992 , the united states food and drug administration ( fda ) recommended that every woman capable of becoming pregnant should consume 0.4  mg folic acid daily for the prevention of ntds . four years later this same governmental agency advised folic acid fortification of enriched grains , such as flour , bread , farina , cornmeal , rice , and pastas . similar programs were rapidly adopted in many other countries . despite these advances in fortification , approximately 150 countries , including those of the european union , further studies are needed to evaluate the safety of high - dose folic acid in certain populations . the fundamental difference between natural food folates and synthetic folic acid is considerable and largely unappreciated by the medical community and the patients that they treat . natural food folates are approximately 50% less bioavailable than is the synthetic folic acid used in supplements and fortification . this decreased bioavailability is a result of several factors : ( 1 ) the nature of the food matrix , with some folates remaining bound and unavailable within plant material ; ( 2 ) factors affecting the deconjugation of the polyglutamate form of folates into the monoglutamyl form , which is the form needed for absorption in the small intestine ; ( 3 ) losses incurred during harvesting , processing , and cooking of foods . good sources of folate that are often cited include legumes , orange juice , leafy green vegetables , broccoli , and whole grains . whereas synthetic folic acid is highly stable , for example , broccoli has different folate values depending on whether it is cooked , raw , or frozen . the usual western diet contains about 0.2  mg natural folate per day . under these circumstances , the 1992 cdc guideline recommending 0.4  mg per day of folic acid means that a woman would have to consume 1000  /day of natural food folates to obtain that level , taking into account the bioavailability difference . such a consumption level is unpractical and underscores the potential value of population wide supplementation programs . it is axiomatic that such problems would not be confined solely to women , and that men would find similar difficulties if they tried to rely on diet alone for their daily values . sufficient data now exists to suggest that a correlation may be present between the amount of folic acid intake and between the promotion of cancer . recent evidence indicates that folic acid may facilitate the preliminary stages of specific types of malignancy . two norwegian studies , namely , the norwegian vitamin trial and the western norway b vitamin intervention trial , found that daily supplementation with 0.8  mg of folic acid and 0.4  mg b12 for more than three years increased the risk of lung cancer by 21% .   the two studies measured cancer incidence , cancer mortality , and all - cause mortality in a total of 6837 patients with ischemic heart disease . the results were able to show that treatment with folic acid plus vitamin b12 was associated with increased cancer outcomes and all - cause mortality in patients with ischemic heart disease in norway , where there is no folic acid fortification of foods . such studies suggest that high dose folic acid supplementation may unexpectedly increase cancer risks . however , it is important to note that the dose used in these two trials is twice that recommended on an international basis for pregnancy - related intakes . systematic studies of the safety of high doses of folic acid are lacking , and the absence of data does not imply assurance of safety . at the same time , observational epidemiologic studies show an inverse relationship between folate intake and cardiovascular disease . several randomized clinical trials have shown that increases in folic acid supplementation led to dramatic decreases in homocysteine levels , which has long been linked to cardiovascular disease . more studies , especially those that focus on the role of folic acid in primary prevention of cv disease and studies that follow cohorts over long periods of time , are required to address some of these issues . many questions remain surrounding folic acid , fortification policies , supplementation , and its likely or projected impact on ntds , public health , and a host of other diseases . some of the most pressing issues involve recent questions about the role of folic acid in cancer promotion and prevention . because of ongoing as well as substantial efforts and collaboration of scientists , public health authorities , nonprofit groups , and governmental agencies , women in many areas of the world benefit from significant improvements in their folic acid status through the use of folic acid supplementation and fortification , alone or combined . such efforts are likely to continue , especially those with a focus on public health strategies that target population - specific barriers to supplement use . this review focused on the effect of folic acid intake and supplementation ( table 1 ) in women , but recent evidence also suggests that it may be of great importance in men , not only in terms of potential cancer and/or other associated risks , but also in terms of improving sperm quality in men who are partners to women who are unable to conceive . in particular , men who take supplements containing folic acid have improved sperm counts , motility , and decreased numbers of abnormal forms . the number of such individuals is substantial , and many live in countries with few or incomplete medical resources . in such circumstances , use of vitamin supplements may bring cost - effective opportunities for parenthood .