Folate intake in Europe: recommended, actual and desired intake

OBJECTIVES: To evaluate possible inconsistencies between recommended, actual and desired folate intake in European adult populations. DESIGN: Review of dietary recommendations, of food consumption surveys, and of intervention and observational studies relating folate intake to the risk of neural tube defects and plasma homocysteine levels. RESULTS: In Europe, mean dietary folate intake in adults is 291 micrograms/d (range 197-326) for men and 247 micrograms/d (range 168-320) for women. The recommended intakes vary between 200-300 micrograms/d (men) and 170-300 micrograms/d (women). However, women with a previous pregnancy affected by a neural tube defect (NTD), are recommended to take 4000 micrograms/d of supplemental folic acid when planning a subsequent pregnancy. For those without a history of NTD, the use of 400 micrograms/d of supplemental folic acid is the best option to prevent the occurrence of NTDs. A daily dose of 650 micrograms supplemental folic acid normalises elevated plasma homocysteine levels, which is a risk factor for cardiovascular diseases. A dietary folate intake of at least 350 micrograms/d is desired to prevent an increase in plasma homocysteine levels of the adult population in general. CONCLUSIONS: Mean dietary folate intake in Europe is in line with recommendations, but the desired dietary intake of > 350 micrograms/d is only reached by a small part of studied European populations. It is considered unethical to investigate whether supplements with a dose lower than 400 micrograms/d of folic acid are also protective against NTDs. However, research to establish the lowest effective dose of dietary folate/supplemental folic acid to optimise homocysteine levels and research on the bioavailability of folate is required. This will enable the choice of a strategy to achieve desired folate intakes in the general population. In the meantime, consumption of plant foods like vegetables, fruits, and cereals should be stimulated to reach the desired level of 350 micrograms of dietary folate per day.     

Factors affecting the use of folic acid supplements in pregnant women in Glasgow

BACKGROUND: Use of folic acid supplements preconception, and during the first trimester, is associated with a reduced incidence of first and subsequent neural tube defects. The Department of Health guidelines recommend the use of folic acid supplements by all women planning a pregnancy. AIM: To ascertain the proportion using folic acid supplements and the factors affecting their use. METHOD: Questionnaires were distributed postpartum to the 515 women who delivered normal babies in three maternity units in Glasgow over a four-week period. RESULTS: Forms were completed by 487 (95%) women. Only 57% took supplements at some point during their pregnancy, and only 21% took them before conception. Failure to take supplements was significantly associated with unplanned pregnancy, younger age, and previous pregnancies. Lack of awareness of the potential benefits associated with folic acid use was the commonest reason cited by women for not taking supplements. CONCLUSIONS: Increased health education through health care professionals and mass media campaigns can improve awareness and thereby increase the use of supplements in planned pregnancies. However, 42% of women in our study had unplanned pregnancies. Intake of folic acid supplements in this group can only be increased by improvements in dietary intake within the population as a whole, and by fortification of commonly ingested foods.     

Megaloblastic anemia in pregnancy

Megaloblastic anemia is one of the acquired nutritional anemias that may complicate pregnancy. It is most often secondary to folic acid deficiency because folate requirements are increased during gestation. When the diagnosis of megaloblastic anemia is confirmed, appropriate therapy will initiate a rapid reversal of the anemia process. Because of the association between neural tube defects and folate deficiency, it is recommended that women of reproductive age take folic acid supplementation.     

Evaluation of hemoglobin and hematocrit in pregnant women receiving folate and iron supplements

BACKGROUND AND AIMS: From week 8 there is a reduction in hemoglobin and hematocrit (owing to the increased plasma volume which exceeds the increased erythrocytic content) that continues to fall steadily until week 16-22, flattening out at a level of 10-11 g/100 ml for hemoglobin and 32-34% for hematocrit. Bone marrow produces red blood cells and hemoglobin in proportion to the increase in plasma volume, provided that there is an adequate iron supply (higher in pregnancy compared to the usual dietary intake). For this reason, the authors examined the systematic supplementation of pregnant women with ferrous gluconate and folic acid, another important element for numerous metabolic reactions which is also lacking in pregnancy owing to increased requirements. METHODS: The study showed that pregnant patients receiving folic acid and iron supplements from week 5 to 40 presented hematocrit readings and hemoglobin levels from week 12 that were constantly higher compared to the population not receiving supplements, with statistically significant and highly significant differences respectively. The few collateral effects observed in a limited group of patients allow the authors to define the tolerability of the proposed treatment as "excellent". They emphasise, however, the importance of constant supplementation with folic acid and iron throughout pregnancy to avoid sideropenic anemia, with considerable benefits in terms of the physical conditions of the pregnant woman, the supply of O2 to the villi, fetal wellbeing and the need to resort to possible blood transfusions in the event of major blood losses at birth.     

Folate and health--new knowledge and new recommendation

The dietary intake of folate in Norway is not optimal with regard to minimizing the risk of birth defects (especially neural-tube defects), and poSsibly also cardiovascular diseases and other diseases. The National Nutrition Council has therefore initiated a project to evaluate the status of folate in Norway and to recommend actions for necessary improvement. A protective effect of folic acid supplements on neural-tube defects has been found in observational studies and clinical trials. The effects of folate on cardiovascular diseases and cancer are less certain. The estimated average intake of folate from foods in Norway is lower than the recommended 300 micrograms per day for adult women and men, and remarkably lower than the 400 micrograms per day recommended for pregnant and lactating women. Thus, with the aim of minimizing the risk for neural-tube defects, the National Nutrition Council now recommends that all women who are planning pregnancy or who are likely to become pregnant have an intake of at least 400 micrograms folate per day. Because it may be difficult to achieve this through diet alone, and because an additional risk-lowering effect of folic acid supplementation has been shown, a folic acid supplement of 400 micrograms per day is recommended for this group. The supplement should be taken one month before conception and during the first two months of pregnancy. Fortification of foods with folate is not recommended because some groups may then exceed the recommended upper intake level.     

Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity

In previous studies conducted in female rats and in women, oral contraceptives (OC) were found to induce a platelet hyperactivity that was related to an oxidative stress. Because cases of megaloblastic anemia have been reported to occur in women taking OC, these treatments are suspected of depleting folate stores. In the study presented herein, which was conducted in rats, we sought to determine the influence of dietary folic acid deficiency (FD) on the thrombogenicity of OC. Animals were fed for 6 weeks with either a folic acid-deficient diet (250 micrograms/kg folic acid) or a control diet (750 micrograms/kg). One-half of the animals in each group were treated with OC (ethinyl estradiol plus lynestrenol). FD and OC individually potentiated platelet aggregation in response to thrombin and ADP and the release and metabolism of arachidonic acid, in particular, the biosynthesis of thromboxane. These platelet activities were further enhanced in animals given both the folic acid-deficient diet and the OC treatment. In addition, FD enhanced the pro-oxidant state in OC-treated rats characterized by (1) a fall in platelet and plasma n-3 fatty acids, (2) an increase in plasma lipid peroxidation products such as conjugated dienes, lipid peroxides, and thiobarbituric reactive substances, (3) a rise in ex vivo erythrocyte susceptibility to free radicals. Moreover, we found that OC treatment led to a reduction of plasma and erythrocyte folate concentrations associated with a moderate hyperhomocysteinemia. Under our experimental conditions, we did not find significant synergistic effects between OC and FD. We propose that, although the untoward effects associated with the OC treatment may not primarily be dependent on FD, the folic acid deficiency magnified OC-induced oxidative stress, which resulted in platelet hyperactivity by elevating the pro-oxidant homocysteine plasma concentration. Despite the limitations of this animal model, the data of the present study suggest that in addition to cigarette smoking, inadequate folic acid intake might predispose those taking OC to vascular thrombosis.     

Hemolysis and schizocytosis, malabsorption and the "folate trap": unusual semiological peculiarities associated with vitamin B12 deficiency

INTRODUCTION: Hemolysis and red cell fragmentation accompanying vitamin B12 deficiency may misdirect the diagnosis. Signs of malabsorption and abnormalities related to folic acid metabolism characterized by discrepancies between folic acid normal serum levels and erythrocytic folic acid levels may also exist. EXEGESIS: We report the occurrence of hemolysis and red cell fragmentation mimicking microangiopathic hemolytic anemia, malabsorption and folic acid deficiency in the course of vitamin B12 deficiency. Appropriate replacement therapy corrected all abnormalities. CONCLUSION: An association between hemolysis, malabsorption and folic acid deficiency should lead physicians to search for signs of vitamin B12 deficiency.     

Quantitative responses of serum folate to increasing intakes of folic acid in healthy women

OBJECTIVES: Health authorities are advising people to increase folate intake and more foods are being fortified with folic acid. Estimation of dietary folate is difficult because nutrient data bases lack this nutrient in many countries and bioavailability is variable. To see if serum folate can be used to reflect effective folate intake, we have measured serum folate after healthy women had taken different doses of pure folic acid supplements in the nutritional range. METHODS: A total of 20 volunteer subjects took part in one or more of three experiments, six of them took part in all three. In each experiment subjects took two different doses of folic acid, each for three weeks. Experiment (1) 100 micrograms then 1000 micrograms/d; experiment (2) 500 micrograms then 1500 micrograms/d; experiment (3) 1000 then 2000 micrograms/d. Serum folate was measured after overnight fast with a homogenous enzyme binding assay kit. In experiment (3) red cell folates were also measured. RESULTS: It took three weeks' of the same supplement for serum folate to reach its full higher value. Mean serum folates of small groups of subjects were significantly higher with each higher dose of supplement. The biggest increase was for the first 100 micrograms that is in the range of intake from unfortified foods. The curve of serum folate against folic acid supplement intake shows that serum folate of groups of people, properly standardized, can provide a practical method for assessing adequacy or change of people's folate intake. Red cell folates were less responsive.     

Treatment of distal femoral fractures in the elderly. Results with the retrograde intramedullary supracondylar nail

The incidence of neural tube defects including myelomeningocele, which is one of the most common causes of infant and childhood disability, can be substantially reduced by folic acid supplementation to the diet of women before and during the early stages of pregnancy. All females of childbearing age should be taking folic acid supplements of 0.4 mg/day (400 micrograms/day) and consuming a diet rich in folate. Because many pregnancies are unplanned, supplementation should not await plans for pregnancy. Because pediatric nurse practitioners are in frequent contact with both adolescent patients and patients whose mothers are of childbearing age, and because pediatric nurse practitioners have an interest in preventing neural tube defects in future pediatric patients, they are in a good position to provide the necessary anticipatory guidance regarding the critical need for adequate folic acid intake by females of childbearing age. This article discusses and includes guidelines for providing this anticipatory guidance.     

Minimum effective dose of folic acid for food fortification to prevent neural-tube defects

BACKGROUND: Although a daily supplement of 400 micrograms folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 micrograms. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration. METHODS: We screened 323 women. 172 with red-cell folate between 150 micrograms/L and 400 micrograms/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 micrograms, 200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study. FINDINGS: There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100 micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503) in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571 micrograms/L (481-654) in the 400 micrograms/day group. INTERPRETATION: A fortification programme that delivered 400 micrograms folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 micrograms daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 micrograms daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.     

Product activation of human erythrocyte AMP deaminase

Maternal magnesium requirements increase during pregnancy because of the synthesis of new tissue--both fetal and maternal. Magnesium takes part in almost 300 enzymatic reactions in the human body and regulates membrane permeability and protein bio-synthesis by promoting initiation and dissociation factors. The absorption velocity of magnesium differs from one tissue to another in animal experiments. It is highest in the liver, kidney, heart and is low in skeletal muscle, the brain and erythrocytes. It obeys and follows the Michaelis-Menten Kinetic law. 15 mmol of magnesium is consumed daily depending on the types of food takenin. The main sources of magnesium are vegetables and meats. Many Nigerian women are not able to afford enough of these. The amount of magnesium reabsorbed depends on the magnesium intake and not on magnesium needed which is about 10-40% of the intake. In this study, we examined the short-term effect of magnesium asphat HCL (614.18 mgMG), magnesium diasporal (magnesium citrate 610 mg + magnesium laevalitat 30 mg = 100 mg magnesium = 8.2 mval), ferrous gluconate (300 mg) plus folic acid and chemiron, a new combination hematinic agent (ferrous fumarate 300 mg, folic acid 5 mg, vitamin B12 10 mg, vitamin C 25 mg, magnesium sulfate 0.3 mg and zinc sulfate 0.3 mg) on plasma magnesium concentration during early pregnancy in Nigerian women. Significant increases of plasma magnesium concentrations were found in these groups (magnesium asphat HCL, 0.83 +/- 0.12 to 0.96 +/- 0.14 mmol/l, magnesium diasporal 0.843 +/- 0.14 to 0.891 +/- 0.14 mmol/l and chemiron 0.848 +/- to 0.866 +/- 0.16 mmol/l after five days. The ferrous gluconate and folic acid treated group showed no significant changes. This study shows that a chemiron supplement leads to increased magnesium plasma levels whereas ferrous gluconate and folic acid do not. These results suggest that the low level of magnesium is a normal physiological adjustment of pregnancy and that iron supplementation does not influence this unless magnesium salt is given.     

Health-Related Behavior and Beliefs of Pregnant Smokers.

To determine the association of smoking with other health-compromising behavior and beliefs during pregnancy, a cross-sectional survey of 1,203 women in the United Kingdom assessed smoking status, stage of change, fetal health locus of control, alcohol consumption, folic acid intake, and use of vitamin and iron supplements. Twenty percent were current smokers, and 33% were alcohol users. Pregnant smokers (especially those in the precontemplative stage) were less likely to increase folic acid intake, less likely to take vitamin and iron supplements, and less likely to feel personally responsible for the health of the fetus. Infants of smokers may be placed at an intrauterine disadvantage, not only in terms of smoking, but also in terms of nutrition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blood folic acid and vitamin B12 in relation to neural tube defects

OBJECTIVE: To determine the relation between blood folic acid and serum vitamin B12 in neural tube defect pregnancies using data from the MRC Vitamin Study and a literature review of all studies. DESIGN: Stored blood samples collected as part of a randomised trial of vitamin supplementation in the prevention of neural tube defects were retrieved from affected pregnancies (cases) and unaffected pregnancies (controls). Four controls were matched with each case by centre, maternal age and duration of storage of the blood sample. The samples had been collected from women at entry to the trial, immediately before the women became pregnant, and at around 12 weeks of pregnancy. Our results were combined with those already published from other studies to obtain an overall assessment of blood folic acid and vitamin B12 in relation to neural tube defects. SETTING: Blood samples were collected as part of the MRC Vitamin Study. The collaborating centres were in the United Kingdom, Hungary, Israel, Australia, Canada and Russia. PARTICIPANTS: Twenty-seven women with neural tube defect pregnancies and 108 matched controls with unaffected pregnancies. RESULTS: Serum and red cell folic acid and serum vitamin B12 levels were lower in the cases than in controls at each of the three occasions when blood samples were collected, but no comparison was significant (P > 0.05). A systematic review of all studies from the literature showed that on average, during the 1st trimester of pregnancy, serum folic acid was 0.6 ng/ml lower in neural tube defect pregnancies (P < 0.01), red cell folic acid was 77 ng/ml lower (P < 0.001) and serum vitamin B12 was 38 ng/l lower (P < 0.001). A logistic regression showed no association between serum B12 and neural tube defects after allowing for serum folic acid. CONCLUSION: our results are consistent with other evidence that folic acid and vitamin B12 levels are lower in women with neural tube defect pregnancies and consistent with evidence from randomised trials which showed that folic acid is protective.     

Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages

To determine the effects of daily supplementation of 0.5 mg folic acid on homocysteine and folate concentrations, we investigated 49 women with a history of unexplained recurrent miscarriages. A methionine loading test (including the vitamin concentrations of concern) was used preceding and after 2 mo of folic acid intake. Subsequently, these effects were studied after stratification for C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism. Folic acid supplementation (for 2 mo) reduced the median fasting and delta (after-load minus fasting) total plasma homocysteine (tHcy) concentrations 27% (P < 0.001) and 14% (P < 0.05), respectively. Median serum and red cell folate concentrations increased 275 and 70%, respectively (P < 0.01). The homocysteine-lowering effect was most marked in women with the highest tHcy concentrations at baseline. All MTHFR-genotypes (homozygous T/T, n = 8; heterozygous T/C, n = 23; wild type C/C, n = 18) had a different response to the supplementation. After 2 mo, homozygous women showed the greatest decline in median fasting (-41%; P < 0.01) tHcy concentrations, but the lowest absolute increase in serum folate concentration (+26 nmol/L; P < 0.05). In conclusion, 2 mo of daily supplementation of 0. 5 mg folic acid in women with a history of unexplained recurrent miscarriages caused, in general, substantially reduced tHcy concentrations. This effect was most distinct in women with the highest tHcy concentrations at baseline and in women homozygous for the 677 C-->T mutation of the MTHFR-gene.     

Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Improvement with folic acid

OBJECTIVE: To provide a comprehensive review of periconceptional folic acid supplementation and factors affecting folate supplementation trials. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, spina bifida, and anencephaly. STUDY SELECTION: Relevant animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included: type of study, folate dosing, dietary folate intake, serum and red blood cell folate concentrations, type of defect(s) studied, vitamin usage, parental risk factors, factors affecting trial results. DATA SYNTHESIS: Nine key factors have been identified that affect outcomes of folic acid supplementation trials. Daily doses of 0.8 mg decreased the occurrence and doses of 4 mg decreased the recurrence of neural tube defects in randomized clinical trials. Since lower folic acid doses were effective in nonrandomized trials, research is needed to determine the lowest effective dosage. Other benefits involving pregnancy outcome are suggested. CONCLUSIONS: Women of childbearing age should take a daily folic acid supplement to reduce the risk of pregnancies resulting in infants with a neural tube defect and other potential adverse pregnancy outcomes. Further health benefits from folic acid supplementation are reviewed in Part III of this series.     

The PEGASUS project--a prospective cohort study for the investigation of drug use in pregnancy. PEGASUS Study Group

Since the thalidomide disaster, it is well accepted that drugs can have adverse effects on the developing human being. Although numerous studies show that medication during pregnancy is wide-spread, there still is a serious lack of comprehensive and valid data concerning the risks of drug use during pregnancy. One objective of the PEGASUS project, a population-based cohort study focusing on Munich, is to prospectively record information on drug exposure during pregnancy, to evaluate these data with regard to teratogenic properties, and to contribute to the quality assurance of medical treatment in pregnancy. The results of PEGASUS confirm that drug utilization during pregnancy is rather common--84% of the women use at least one preparation. The most frequent groups are minerals (mainly magnesium), iodide, and iron preparations. Although randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects, only very few women in the PEGASUS project recorded folic acid intake during the critical period and in sufficient dosage. Moreover, only 42% of the pregnant women apply iodide prophylaxis in the recommended dosage.     

Bowel problems after enterocystoplasty

BACKGROUND: The Medical Research Council vitamin trial highlighted the importance of folic acid in the prevention of neural tube defects. Since 1993, the Irish Department of Health has recommended periconceptional folic acid supplements. The objective of this study was to document the knowledge and behaviour of women in child-bearing years to periconceptional folic acid. METHODS: A cross-sectional community-based survey was conducted in Dublin using an interviewer administered questionnaire. RESULTS: A total of 335 women took part in the study, a response rate of 84 per cent. Approximately two-thirds (213/ 335, 63.6 per cent) had heard of folic acid. Knowledge was significantly associated with higher social class and higher education (p < 0.05). Few (18/335, 5.4 per cent), had been advised to take folic acid before pregnancy. Only 9/335 (2.7 per cent) of the women in the study were currently taking folic acid supplements. Three-quarters (75.9 per cent) of the group would be willing to take periconceptional folic acid supplements if they believed it would reduce the risk of malformations. The majority (77.4 per cent) would prefer to take folic acid in tablet form rather than have it added to food. CONCLUSIONS: This study shows that few women in child-bearing years in Dublin have been advised on folic acid, and very few are taking supplements. However, if advised appropriately the majority would be willing to take periconceptional folic acid in tablet form.     

Drug and environmental factors associated with adverse pregnancy outcomes. Part III: Folic acid: pharmacology, therapeutic recommendations, and economics

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine-homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 micrograms of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 micrograms/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.     

Open or closed? A world of difference: a history of homocysteine research

This article presents the research of the Nijmegen homocysteine team on birth defects and vascular disease. Hyperhomocysteinemia was found in women who gave birth to offspring with neural tube defects (NTDs) and other birth defects and in women with vascular disease. Elevated homocysteine levels in the blood plasma can be explained by lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) genes, or both. Genetic mutations were found on the first chromosome (677 C T and 1298 A-C) and can explain up to 50% of the protective effect of folic acid against NTDs. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects, and vascular problems such as placental abruption, infarcts, and fetal growth retardation. One of the most exciting medical findings of recent years is that folic acid can prevent NTDs. This might also hold true for other birth defects and vascular disease.