Folic acid: a public-health challenge

Despite worldwide public-health campaigns recommending periconceptional daily supplementation of synthetic folic acid to reduce the risk of neural tube defects, many women are not following these recommendations. At the same time, in most European countries no decline in defects has been recorded in recent years. Vulnerable groups are those with a low standard of education, young people, and women with unplanned pregnancies. Furthermore, in most countries without mandatory fortification, the general population is not consuming the recommended 0.4 mg of food folate per day. Voluntary fortification improves the situation, but does not reach all parts of the population. In the USA, Canada, and Chile, mandatory fortification of flour substantially improved folate and homocysteine status, and neural tube defects rates fell by between 31% and 78%. Nevertheless, many countries do not choose mandatory folic acid fortification, in part because expected additional health benefits are not yet scientifically proven in clinical trials, in part because of feared health risks, and because of the issue of freedom of choice. Thus, additional creative public-health approaches need to be developed to prevent neural tube defects and improve the folate status of the general population.     

Fortifying food with folic acid

Folic acid supplementation may help prevent the following three common and important disorders: neural tube defect pregnancies, ischemic heart disease and strokes, and possibly colon cancer. Several studies have irrefutably established that folic acid supplementation in proper doses reduces neural tube defect pregnancies. Fortified food would be the most reliable way to address this health issue. Several epidemiologic reports have established a close link between hyperhomocysteinemia and ischemic heart disease. This is supported by evidence obtained from genetic defects leading to elevated plasma levels of homocysteine. There is reasonable evidence to conclude that hyperhomocysteinemia is the actual cause of excessive cardiac diseases. Again, folic acid supplementation in proper doses could potentially reduce ischemic heart disease by 40% There is also some evidence to suggest that folic acid treatment reduces the incidence of colon cancer. The reduction in all three health problems is dependent upon the dose of folic acid administered. The levels needed are rarely supplied by the daily food intake, even under ideal conditions, although breakfast cereals address this problem at least in part. It is proposed that flour be fortified because it is a food product heavily used by most people, and that governmental agencies should oversee such programs because they are responsible for setting public health policies.     

Association of neural tube defects and folic acid food fortification in Canada

Many women do not receive folic acid supplements before conception. In response, most of Canada's cereal grain products were being fortified with folic acid by January, 1998, thereby providing an additional 0·1–0·2 mg per day of dietary folate to the Canadian population. We assessed the effect of supplementation on prevalence of open neural tube defects in the province of Ontario. Among 336 963 women who underwent maternal serum screening over 77 months, the prevalence of open neural tube defects declined from 1·13 per 1000 pregnancies before fortification to 0·58 per 1000 pregnancies thereafter (prevalence ratio 0·52, 95% Cl 0·40–0·67, p<0·0001). At a population level, folic acid food fortification is associated with a pronounced reduction in open neural tube defects.     

Homocysteine and folic acid: implications for pregnancy

The role of folic acid and homocysteine in pregnancy is becoming clearer. The efforts of many countries to prevent neural tube defects through public awareness of folic acid have been disappointing, but evidence is now emerging that the food fortification programs in the United States and Canada are effective in reducing the numbers of neural tube defects, and there may be additional benefits in terms of other congenital defects such as oral-facial clefts and congenital heart disease. Homocysteine has a significant association with vascular disease in later life, is elevated in preeclampsia, and has been associated with other pregnancy complications such as early pregnancy loss. The data from cohorts of women with a history of preeclampsia during pregnancy indicate that they are at increased risk for cardiovascular and cerebrovascular disease in later life. Elevated homocysteine concentrations may be a common link that accounts for these associations.     

Acid folic and pregnancy: A mandatory supplementation

Neural tube defects (NTD) occur in 0.5 to 2 per 1000 pregnancies with various handicaps for the affected child. It is now well established that folic acid deficiency (absolute or relative) is a predisposing factor to this type of malformation. Several randomized controlled trials showed that high-dose folic acid (4 mg) is an essential factor for prevention of neural tube defects recurrence and significantly prevents the first occurrence of neural tube defects with a lower dose (0.4 mg). Other etiologies can favor the occurrence of NTD such as MTHFR polymorphism, some antiepileptic therapies, obesity and pregestational mellitus diabetes. Necessity of a preconception folic acid supplementation or at least folate nutritional status evaluation should be known for all of us including patients and public.     

Professor John Scott,folate and neural tube defects

John Scott (1940–2013) was born in Dublin where he was to spend the rest of his career, both as an undergraduate and subsequently Professor of Biochemistry and Nutrition at Trinity College. His research with the talented group of scientists and clinicians that he led has had a substantial impact on our understanding of folate metabolism, mechanisms of its catabolism and deficiency. His research established the leading theory of folate involvement with vitamin B12 in the pathogenesis of vitamin B12 neuropathy. He helped to establish the normal daily intake of folate and the increased requirements needed either in food or as a supplement before and during pregnancy to prevent neural tube defects. He also suggested a dietary supplement of vitamin B12 before and during pregnancy to reduce the risk of neural tube defects. It would be an appropriate epitaph if fortification of food with folic acid became mandatory in the UK and Ireland, as it is in over 70 other countries.     

Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid-fortified cereal grain flour

The prevalence of deficient plasma folate status and elevated total plasma levels of homocysteine (tHcy), have been dramatically reduced after fortification of all enriched cereal grain flour products with folic acid at 140 microg/100 g flour. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid-based vitamin B supplementation among stable coronary artery disease (CAD) patients. Using a 2x2 factorial design, 131 stable CAD patients (mean age 60.1 years; 29.8% women) were randomly assigned to receive a combination of folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d, or placebo, with or without vitamin B6 50 mg/d, for 12 weeks of treatment. ANCOVA adjusted for baseline fasting tHcy levels revealed only very modest (ie, approximately 1.0 micromol/L), albeit statistically significant (P<0.05), reductions in mean fasting tHcy levels afforded by the folic acid-containing treatments. Additional analyses indicated that none of the treatments provided a statistically significant reduction in the 2-hour post-methionine increase in tHcy levels, relative to placebo treatment. CAD patients exposed to cereal grain flour products fortified with folic acid who receive high-dose, folic acid-containing vitamin B regimens, experience only very modest reductions in their mean fasting plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.     

Folic acid consumption throughout pregnancy: differentiation between trimesters

Intervention trials have demonstrated conclusively that oral ingestion of extra folic acid can prevent the majority of cases of spina bifida and other neural tube defects (NTDs). Data from these studies offer conclusive evidence that the intake of 400 μg/day folic acid provides this benefit. The big problem has remained that the neural plate closes to form the neural tube between day 21 and day 28 postconception, at which point most women do not even realize that they are pregnant. This, coupled with the fact that over half of all pregnancies are unplanned, has resulted in many studies showing that less than one-fifth of pregnancies have followed the recommendation for prevention. However, where compliance has been good or where folic acid has been added mandatorily, there has been the expected reduction in NTDs. Clarity regarding what is recommended for early pregnancy does not carry through to the second or third trimester of pregnancy where practices vary widely not only from country to country but even from clinician to clinician within particular countries.     

Periconceptional folic acid-containing multivitamin supplementation for the prevention of neural tube defects and cardiovascular malformations

The prevention of neural tube defects with periconceptional folic acid or folic acid-containing multivitamin supplementation is accepted by the scientific community; here the possible prevention of cardiovascular malformations is discussed. The aim of this presentation is to show the main findings of trials and studies that resulted in the prevention of neural tube defects and particularly cardiovascular malformations by folic acid-containing multivitamins or folic acid supplementation in order to stimulate the incorporation of folic acid-containing multivitamins or folic acid in the prevention of cardiovascular malformations.     

Folate recommendations for pregnancy, lactation, and infancy

An adequate intake of folate during pregnancy, lactation, and infancy is essential for maternal and child health and normal growth. Higher folate requirements during pregnancy and lactation are difficult to meet by increased intake of folate-rich food products only. Supplementation with folic acid is recommended not only to meet the higher requirements but also to prevent adverse pregnancy outcomes such as neural tube defects (NTDs). In countries that have implemented food fortification with folic acid, the folate intake has raised but does not yet meet the recommended amount for NTD risk reduction. Women's awareness of the need to supplement with folic acid prior to conception shall be raised in all countries. It is under debate whether a high folic acid intake might have metabolic and functional effects in utero and for the infant. Research is needed to investigate potential alternative folate forms for food fortification programs and to test their efficacy in risk reduction of adverse pregnancy outcomes. Breast-fed infants most likely receive sufficient folate. While the folate level of human milk is simulated in infant formula, data are lacking on the bioavailability and effect of folic acid in infants and on whether a tolerable upper intake level should be defined.     

Folic acid and other potential measures in the prevention of neural tube defects

Neural tube defects (NTD) are common congenital malformations leading to severe disability or even death. The causes of NTD are multifactorial, including genetic predisposition, nutritional and environmental risk factors, and other maternal conditions. Some countries have introduced mandatory or at least voluntary folic acid fortification as an effective measure to reduce NTD, whereas others support periconceptional supplementation of women of childbearing age. Countries with mandatory fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTD. This was also true for supplementation trials. However, the magnitude of the decline depends on the initial NTD rate. This review clearly shows that not all cases of NTD can be prevented by increasing the folate intake. Other relevant causes of NTD, which are largely disregarded, have also to be taken into account in research and consultation to reduce the risk and economic burden of NTD.     

Focus on folic acid benefits

Folic acid, or vitamin B9, derives its name from the Latin word folium, which was used to indicate large-leafed plants rich in folic acid. Naturally occurring in spinach leaves, this complex acid was first synthesized in 1945. Since then, mounting scientific evidence has demonstrated its beneficial effects on the human body. An essential nutrient for well-being and health, folic acid intake during pregnancy is especially important for preventing neural tube defects. This focus highlights the importance of correct intake levels of folic acid, particularly in subjects at risk of vitamin B(9) deficiency.     

Folate supplementation,MTHFR gene polymorphism and neural tube defects: a community based case control study in North India

The present study analyses the potential role of MTHFR gene polymorphism, folate supplementation and dietary pattern among the mothers of NTD neonates and controls in heterogeneous populations of North India, with the special focus on their ethnic labels. Results indicated significant increased risk for neural tube defects with respect to low folic acid supplementation and vegetarian diet in univariate and multivariate analyses. There was no significant difference in the genotypic or allelic distribution of MTHFR C677T polymorphism, however, high frequency of CT genotype, as observed, among controls suggests heterozygous advantage probably due to supplementary folate. Among the two communities, Muslim NTD mothers had higher TT genotype showing increased risk for neural tube defects (adjusted OR: 12.9; 95% CI: 1.21–136.8) and lower folic acid supplementation (adjusted OR: 3.5; 95% CI: 1.18–10.22). Whereas, marginal increased risk for NTDs with vegetarian diet was observed among Hindus. Cultural and ethnic variation in the risk factors for neural tube defects is highlighted in the study.     

Homocysteine and methylmalonic acid as indicators of folate and vitamin B12 deficiency in pregnancy

Deficiency of folate during pregnancy is associated with megaloblastic anaemia. Lower levels of folate and vitamin B12 have been reported in mothers whose offspring had neural tube defects compared to unaffected controls. Increased methylmalonic acid levels are a sensitive indicator of mild vitamin B12 deficiency and elevated homocysteine levels denote vitamin B12 or folate deficiency. We have investigated the relationship between serum concentration of total homocysteine, methylmalonic acid, vitamin B12 and folate in pregnancy. A significant inverse correlation was found between homocysteine and red cell folate and, to a lesser extent, serum folate. In addition, a significant inverse correlation was found between methylmalonic acid and vitamin B12. No significant relationship was found between homocysteine and vitamin B12. The relationship between red cell folate and serum folate and homocysteine may be useful for detecting borderline folate deficiency in pregnancy and indicate pregnancies at risk of neural tube defect. These sensitive assays are useful tools for the further investigation of folate vitamin B12 and metabolism in normal and abnormal pregnancy.     

Critical micronutrients in pregnancy, lactation, and infancy: considerations on vitamin D, folic acid, and iron, and priorities for future research

The Early Nutrition Academy and the European Commission-funded EURRECA Network of Excellence jointly sponsored a scientific workshop on critical micronutrients in pregnancy, lactation, and infancy. Current knowledge and unresolved questions on the supply of vitamin D, folic acid, and iron for pregnant women, lactating women, and infants, and their health effects were discussed. The question was addressed of whether, and under which circumstances, supplementation with these micronutrients in addition to usual dietary intakes is advisable. The workshop participants concluded that public health strategies for improving supplementation with these micronutrients in pregnancy, lactation, and infancy are required. Further research priorities should focus on adequately powered human intervention trials to obtain a stronger evidence base for the amounts of vitamin D, folic acid, and iron that have optimal effects on health. The conclusions of the workshop should help to inform the scientific community as well as public health policy strategies.     

Vitamin D Deficiency in the Middle East and its Health Consequences for Children and Adults

Despite its abundant sunshine the Middle East, a region spanning latitudes from 12°N to 42°N allowing vitamin D synthesis year round, registers some of the lowest levels of vitamin D and the highest rates of hypovitaminosis D worldwide. This major public health problem affects individuals across all life stages including pregnant women, neonates, infants, children and adolescents, adults, and the elderly. Furthermore, while rickets is almost eradicated from developed countries, it is still reported in several countries in the Middle East. These observations can be explained by limited sun exposure due to cultural practices, dark skin color, and very hot climate in several countries in the gulf area, along with prolonged breast feeding without vitamin D supplementation, decreased calcium content of diets and outdoor activity, obesity, and lack of government regulation for vitamin D fortification of food, in several if not in all countries. The lack of population based studies renders estimates for the prevalence and incidence of rickets in the Middle East difficult, but several series from the region illustrate its dire consequences on growth and development. Furthermore, it is reported that 20–80% of apparently healthy individuals from several countries in this region have suboptimal vitamin D levels, depending on the cut-off used for defining hypovitaminosis D, the country, season, age group, and gender studied. Suboptimal levels have been associated with compromised skeletal health across age groups, and with poor muscular function and increased fall risk and osteoporotic fractures in the elderly. Studies detailing associations between low vitamin D levels and musculoskeletal health in the Middle East, and the impact of various treatment regimens are reviewed. Current recommendations for vitamin D derived from data in western subjects may not be sufficient for subjects from the Middle East, therefore suggestions for vitamin D replacement doses based on evidence available to-date are provided. Hypovitaminosis D is a major public health problem across all life stages in the Middle East with deleterious immediate and latent manifestations. Long term strategies to address this often silent disease should include public education, national health policies for screening and prevention through food fortification, and treatment through vitamin D supplementation.     

Power Shortage: clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour.

Large randomized, controlled trials of total homocysteine-lowering therapy for the potential reduction of cardiovascular disease outcomes are ongoing in the United States and Canada. These trials are the Vitamin Intervention for Stroke Prevention (VISP) trial, the Women's Antioxidant Cardiovascular Disease Study (WACS), and the Heart Outcomes Prevention Evaluation (HOPE-2). However, the dramatic effect of policies mandating fortification of cereal grain flour products with folic acid may reduce the statistical power of these trials. All three trials assume that the active treatment groups will achieve the same mean effects of total homocysteine-lowering therapy as those reported in the absence of folic acid-fortified cereal grain flour. This paper examines this assumption using data from studies of total homocysteine-lowering therapy in U.S. and Canadian patients with cardiovascular disease who were exposed to products made with folic acid-fortified cereal grain flour. These data showed that the VISP trial, HOPE-2, and WACS will probably achieve only approximately 20% to 25% of the projected treatment effects of mean total homocysteine-lowering therapy (1.0 to 1.5 micromol/L vs. 4.0 to 6.0 micromol/L). As a result, all three trials will be substantially underpowered to test the specific hypotheses of total homocysteine-lowering therapy identified a priori. In contrast, renal transplant recipients have a persistent excess prevalence of hyperhomocysteinemia in the era of fortification but remain very responsive to supraphysiologic doses of folic acid-based supplementation (mean reduction in total homocysteine level, 5.0 to 6.0 micromol/L). Therefore, unlike other populations with normal renal function that are at high risk for cardiovascular disease but are profoundly affected by fortification efforts, renal transplant recipients continue to merit serious consideration for a controlled trial of the "homocysteine hypothesis."     

Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease.

Hyperhomocysteinemia is frequently found in patients with end-stage renal disease (ESRD). Plasma total homocysteine (tHcy) concentrations may be reduced by supplementation with folic acid or combinations of folic acid, vitamin B12, and vitamin B6. Supplementation studies with vitamin B12 alone in patients with ESRD have not yet been published. In this study, we investigated the effects of intravenous injection of cyanocobalamin (1 mg/wk for 4 weeks) in ESRD patients (N = 14) with low serum cobalamin concentrations (<180 pmol/L). All patients had elevated levels of plasma tHcy, methylmalonic acid (MMA), and cystathionine before supplementation. After supplementation, plasma tHcy and MMA decreased 35% and 48%, respectively; however, cystathionine levels were unchanged. The extent of the plasma tHcy reduction tended to be influenced by the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR). Serum cobalamin increased significantly upon supplementation, whereas serum folate levels were substantially reduced by 47%. In contrast, red blood cell (RBC) folate was unchanged. This study shows that vitamin B12 supplementation effectively decreases both MMA and plasma tHcy in ESRD patients with low B12 levels. Furthermore, it illustrates the close interrelation between vitamin B12 and folate metabolism.     

Prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients after fortification of cereal grain flour with folic acid.

Cereal grain flour products fortified with 140 microg folic acid per 100 g flour became widely available in southeast New England by July 1997. We hypothesized that improved folate status secondary to this fortification policy would have a much more limited impact on the prevalence of mild fasting hyperhomocysteinemia in renal transplant versus coronary artery disease patients. Between October 1997 and October 1998, fasting plasma total homocysteine (tHcy), folate and vitamin B12 levels were determined in a total of 86 renal transplant patients with stable allograft function, and 175 coronary artery disease patients whose serum creatinine was (1.4 mg/dl). All subjects lived in the Providence, RI, metropolitan area, and were either non-users of any supplements containing folic acid, vitamins B6 or B12, or had refrained from using such supplements for > or = 6 weeks. Geometric mean fasting tHcy levels were 88.0% higher (15.6 vs. 8.3 micromol/l; P < 0.001), and the prevalence of fasting tHcy levels > or = 12 microM (69.8% vs. 10.9%, P < 0.001) was markedly increased in the renal transplant patients, despite a much younger mean age and a relative preponderance of women. In the era of folic acid fortified flour, hyperhomocysteinemia is much more common in stable renal transplant versus coronary artery disease patients. As a result, renal transplant patients are a preferable high risk target population for controlled trials evaluating the tenable hypothesis that lowering total homocysteine levels will reduce cardiovascular disease outcomes.     

Homocysteine-lowering trials for prevention of heart disease and stroke

Dietary supplementation with B-vitamins that lower plasma total homocysteine concentrations are expected to lower the risk of cardiovascular disease. Folic acid and vitamin B (12) lower blood homocysteine concentrations by about 25-30% in populations without folic acid fortification, but by only 10-15% in populations with fortification. In observational studies, 25% lower homocysteine is associated with about 10% less coronary heart disease (CHD) and about 20% less stroke. This review examines the current status of 12 large-scale randomized trials of B-vitamin supplementation and risk of cardiovascular disease. Seven of these trials are being performed in populations without fortification (five involving participants with prior CHD, two with prior stroke) and five in populations with fortification (two with prior CHD, two with renal disease, and one with prior stroke). Many of these trials may not have included a sufficient number of people or lasted long enough to have adequate power to exclude false-negative results. Taken together, however, these trials involve 32,000 patients with prior vascular disease in unfortified populations and 20,000 (14,000 with vascular disease and 6000 with renal disease) patients in fortified populations. A metaanalysis of these trials should have adequate power to determine whether homocysteine-lowering vitamin supplements can reduce the risk of cardiovascular disease.