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Folic acid says NO to vascular diseases.

OBJECTIVES: The possible link between folic acid or folate and tetrahydrobiopterin (H(4)B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated. METHODS: The literature pertaining to the actions of folic acid/folate, H(4)B, vitamin C, PUFAs, and NO was reviewed. RESULTS: Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H(4)B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H(4)B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of omega-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H(4)B and stabilization of H(4)B. Insulin stimulates H(4)B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-alpha and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels. CONCLUSIONS: The common mechanism by which folic acid, H(4)B, vitamin C, omega-3 fatty acids, and L-arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H(4)B, L-arginine, and omega-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.

Antioxidants↗

[Folic acid fortification: prevention as well as promotion of cancer].

In many countries foods are fortified with folic acid to prevent neural-tube defects. Beneficial effects on cancer, cardiovascular diseases and dementia are also assumed. Fortification with folic acid is not allowed in The Netherlands, although exemption can be granted. As well as beneficial effects, harmful effects may also occur. In addition to masking vitamin-B12 deficiency, there is some evidence that folic acid may promote progression of established tumours in laboratory animals and humans. In addition, it has been hypothesized that fortification with folic acid may have further negative effects on cancer through genetic selection. Given the high prevalence of cancer, these potentially harmful effects should also be taken into account in the Dutch debate on the advantages and disadvantages of folic acid fortification.

Animals↗

Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease.

OBJECTIVES: The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD). BACKGROUND: Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress. METHODS: In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level > or =9 micromol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment. RESULTS: Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 +/- 3.6% to 5.2 +/- 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 +/- 2.4% to 4.0 +/- 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group. CONCLUSIONS: Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.

Aged↗

Characterization of excipient and tableting factors that influence folic acid dissolution, friability, and breaking strength of oil- and water-soluble multivitamin with minerals tablets.

The goal of this study is to characterize the formulation and processing factors that influence folic acid dissolution from oil- and water-soluble multivitamin with minerals tablet formulations for direct compression. The following parameters were studied: bulk filler solubility, soluble to insoluble bulk filler ratio, triturating agent (preblending carrier) solubility, disintegrant usage, compression pressure, and folic acid particle size. Folic acid particle size was determined by using light microscopy, and surface area was measured by using BET adsorption. The tablets were compressed on an instrumented Stokes B2 tablet press, and the friability, weight variation, and dissolution were measured according to USP methods, along with tablet breaking strength. In summary, we found the following factors to be critical to folic acid dissolution: bulk filler solubility (soluble fillers, such as maltose, increase folic acid dissolution); disintegrant amount (levels less than 0.4% (w/w) are ineffectual, whereas levels greater than 1.2% (w/w) did not further increase dissolution); and compression force (generally, maltose produce harder tablets). In addition, folic acid dissolution was less affected by changes in compaction pressure when a "super" disintegrant and maltose, as a bulk filler, were used. It was determined that the trituration agent did not play a significant role in folic acid dissolution. In the range of parameters studied, statistical analysis found no significant interactions between the parameters studied, which means they act independently in an additive manner. The results also show that no one factor is completely responsible for dissolution failure. Thus, it is the combination of formulation factors and processing conditions that collectively add up to produce dissolution failure; however, the use of a disintegrant and a soluble filler such as maltose can make a formulation more robust to the inevitable changes that can occur during commercial production.

Dietary Supplements↗

[Distribution of the serum concentration of vitamin C, folic acid and vitamin B12 in a representative sample of the adult population of Catalonia (Spain)].

BACKGROUND: The subclinical deficiency of certain micronutrients (vitamin C, folic acid, vitamin B12) has been associated with disorders as cardiovascular diseases, cancer, cataracts, immunodepression and fetal neural tube defects. The purpose of this study was to determine the serum concentration of vitamin C, folic acid and vitamin B12 in the Catalan population and to examine the prevalence of deficits of these micronutrients. SUBJECTS AND METHOD: We studied a subsample of individuals (n = 378) from a representative sample of people aged 18 to 75 years who had participated in the study of the Nutritional Status of the Catalan Population (1992-93). Serum concentrations of vitamin C, folic acid and vitamin B12 were determined. RESULTS: The serum concentration of vitamin C was lower in men than in women. 4.6 and 0.5% subjects were found to have marginal and severe deficits of vitamin C, respectively. 4 and 1.6% subjects had marginal and severe deficits of folic acid, respectively. Folic acid deficit involved up to 12.9% women aged 18-34 years and up to 9.1% men within the same age group. Subjects who had a severe deficit of folic acid consumed more than 20 g/day of alcohol. The serum concentration of vitamin B12 was greater in women than in men. 1.9% individuals had a marginal deficit of this vitamin. CONCLUSION: The sample of individuals studied were found to have a correct nutritional status with regard to vitamin C, folic acid and vitamin B12. This may explain the lower incidence of cancer and ischemic heart disease associated with the Mediterranean diet.

Adolescent↗

Serum homocysteine, B12 and folic acid concentration in Thai overweight and obese subjects.

This study investigated levels of serum homocysteine, vitamin B12, folic acid, vitamin B6 and vitamin C, in 37 male and 112 female overweight and obese Thai volunteers (body mass index; BMI > or = 25.00), and 23 male and 90 female normal-weight Thai volunteers, who came for a physical check-up at the Out-patient Department, General Practice Section, Rajvithi Hospital, Bangkok from March to October of 2000. Data included anthropometric measurements and waist/hip ratios. All anthropometric variables, except height, were significantly higher for the overweight subjects than for the normal subjects. Statistically significantly higher levels of serum homocysteine were found in the overweight subjects. Serum homocysteine concentrations in overweight and obese males were significantly higher than in overweight and obese females. Serum folic acid and vitamin C in the overweight and obese were found to be statistically significantly lower than in the control subjects. No statistically significant difference in vitamin B12 was found in the overweight and obese subjects compared with the normal control subjects. The medians of serum folic acid and vitamin C concentrations for the overweight and obese males were significantly lower than those of the overweight and obese females. A negative correlation was found between serum folic acid and homocysteine concentrations in all overweight and obese subjects. A significant negative correlation between serum folic acid and vitamin B6 was observed in both male and female overweight and obese subjects. The results of the investigation suggest that homocysteine levels in overweight and obese subjects seem to be caused by insufficient dietary folic acid intake and probably not by B12 deficiency.

Adolescent↗

Folic acid alters methotrexate availability in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the effects of repeated doses of folic acid on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis. METHODS: We studied 20 patients (ages 30-78 years) who received MTX intramuscularly (10 mm/week). MTX was administered alone or after treatment with folic acid (5 mg tablet once daily) for 13 days. Plasma samples were collected 2 and 8 h after dose intake. MTX concentrations in plasma and ultrafiltrate samples were measured by fluorescence polarization immunoassay. A Bayesian approach was used to determine individual MTX pharmacokinetic variables to minimize the number of samples collected. RESULTS: Folic acid supplementation led to reduced plasma MTX levels 2 and 8 h after MTX administration and reduced area under the plasma MTX concentration versus time curve (AUC) (about 20%; p < 0.02). Total clearance of MTX and Vd were higher when patients were also receiving folic acid than when they were taking MTX alone (p < 0.02). The plasma protein binding of MTX remains unchanged. CONCLUSION: The lower plasma MTX concentrations in patients taking folic acid supplements could be interpreted as increased cellular uptake of MTX; the folic acid supplements would promote the sequestering of MTX intracellularly. The decrease of MTX concentrations leads to reduced AUC; it is also possible that there are reduced AUC combined with increased intracellular folate levels. These results reopen the question of whether folic acid should be used immediately in all patients when MTX is begun.

Adult↗

The in situ localization of folic acid.

A histochemical azo-coupling method for localizing folic acid in situ is described. Cat and rat liver, kidney, bone marrow and brain were found to be rich in folic acid; stomach, intestine, salivary glands, and blood contained less. Folic acid was localized in the cytoplasm of tissues having a very active metabolism, but in the nucleus of highly specialized cells such as neurons.

Animals↗

Low-dose folic acid supplementation does not influence plasma methionine concentrations in young non-pregnant women.

An elevated plasma total homocysteine (tHcy) concentration is a risk factor for cardiovascular disease and for having offspring with a neural-tube defect. Folate is a methyl donor in the remethylation of homocysteine into methionine. Although folic acid supplementation decreases tHcy concentrations, effects of folic acid supplementation on plasma methionine concentrations are unclear. There is also concern that folic acid supplementation negatively affects vitamin B12 status. We studied effects of low-dose folic acid supplementation on methionine and vitamin B12 concentrations in plasma. We also investigated whether baseline plasma methionine and tHcy concentrations correlated with the baseline folate and vitamin B12 status. For a period of 4 weeks, 144 young women received either 500 micrograms folic acid each day, or 500 micrograms folic acid and placebo tablets on alternate days, or a placebo tablet each day. Plasma methionine, tHcy and plasma vitamin B12 concentrations were measured at start and end of the intervention period. Folic acid supplementation had no effect on plasma methionine or plasma vitamin B12 concentrations although it significantly decreased tHcy concentrations. Plasma methionine concentrations showed no correlation with either tHcy concentrations (Spearman rs-0.01, P = 0.89), or any of the blood vitamin variables at baseline. Baseline tHcy concentrations showed a slight inverse correlation with baseline concentrations of plasma vitamin B12 (rs-0.25, P < 0.001), plasma folate (rs-0.24, P < 0.01) and erythrocyte folate (rs-0.19, P < 0.05). In conclusion, low-dose folic acid supplementation did not influence plasma methionine or plasma vitamin B12 concentrations. Furthermore, no correlation between plasma methionine concentrations and the blood folate and vitamin B12 status was shown.

Adolescent↗

Broadcasting behavior change: a comparison of the effectiveness of paid and unpaid media to increase folic acid awareness, knowledge, and consumption among Hispanic women of childbearing age.

Awareness about folic acid's effectiveness in reducing the risk of certain birth defects has increased among women in the United States; however, few Hispanic women are consuming enough folic acid daily. A 1998 survey conducted by the Gallup Organization for the National March of Dimes Birth Defects Foundation found that English-speaking Hispanic women had lower folic acid awareness (53% vs. 72%) and lower daily consumption (29% vs. 33%) than non-Hispanic White women. In 1999, the Centers for Disease Control and Prevention (CDC) conducted baseline surveys with Spanish-speaking Hispanic women in selected U.S. markets to measure folic acid awareness, knowledge, and consumption. A Spanish-language public service announcement (PSA) volunteer campaign and a paid Spanish-language media and community education campaign were conducted in 2000 and 2002, respectively. Comparisons of postcampaign surveys indicate that the paid media campaign was significantly more effective than the PSA campaign in increasing folic acid awareness, knowledge, and consumption among Spanish-speaking Hispanic women.

Adolescent↗

Low-Dose folic acid supplementation decreases plasma homocysteine concentrations: a randomised trial.

An elevated plasma total homocysteine concentration is a risk factor for cardiovascular disease and neural tube defects. A high daily intake of supplemental folic acid is known to decrease total homocysteine concentrations. We studied the effect of low-dose folic acid administration (250 or 500 microg/day for 4 weeks on plasma total homocysteine concentrations and folate status. We also investigated whether total homocysteine concentrations and blood folate concentrations returned to baseline after an 8-week washout period. In this placebo-controlled study, 144 healthy women aged 18-40 years received 500 microg folic acid per day, 500 microg folic acid every second day (250 microg/day), or a placebo tablet with their habitual diet (mean dietary folate intake 280 microg/day). Administration of 250 and 500 microg folic acid per day for four weeks significantly increased folate concentrations in plasma (p<0.001) and red blood cells (p<0.01). Total homocysteine concentrations decreased significantly (p<0.001) in women (n=50) who took 250 microg folic acid daily [mean (+/- SEM) deviation from baseline -11.4 +/-1.98%] and in women (n=45) who took 500 microg folic acid daily (-21.8 +/- 1.49%). Eight weeks after the end of the intervention period (week 12), plasma total homocysteine concentrations in the folic acid-supplemented groups had not returned to baseline (week 0). In conclusion, doses of folic acid as low as 250 microg daily, on an average, in addition to usual dietary intakes of folate, significantly decreased plasma total homocysteine concentrations in healthy, young women. An 8-week washout period was not sufficient for blood folate and plasma total homocysteine concentrations to return to baseline concentration

Adolescent↗

The role of folic acid in deficiency states and prevention of disease.

Folic acid, a water-soluble vitamin, has been used since the 1940s to treat some cases of macrocytic anemia without neurologic disease. Folate deficiency is best diagnosed with red blood cell folate levels along with macrocytosis and/or megaloblastic anemia. In addition to reversing overt deficiency, the vitamin may reduce the incidence of neural tube defects by 45% in women who receive 400 micrograms per day. It is recommended that all women of childbearing age take 400 micrograms of folate per day. Elevations in homocysteine levels, a metabolite intimately associated with folate, are also being found with increasing regularity in those with cardiovascular diseases. Homocysteine levels are reduced by folic acid administration. Therefore, there is some biologic plausibility, but not currently direct proof, for the assumption that folate supplements may prevent heart disease, stroke, and peripheral arterial disease. Controlled trials should take place before widespread food supplementation with folate is carried out on a large scale because of the possibility of outbreaks of permanent B12-related neurologic damage in those with undiagnosed pernicious anemia. However, if a patient has a premature cardiovascular event and has minimal risk factors, ordering a test to determine homocysteine level may be advisable, and if elevated, treating with folic acid supplement as long as B12 deficiency does not coexist.

Anemia, Macrocytic↗

Use of the affinity/HPLC method for quantitative estimation of folic acid in enriched cereal-grain products.

In 1998, the United States introduced mandatory fortification of enriched cereal-grain products with folic acid to reduce the incidence of neural tube defects. As a consequence, substantial amounts of folic acid, the synthetic form of folate, were added to the American diet, and the ability to assess folic acid intake took on greater importance. The purpose of the current study was to separate and quantify folic acid and 5-methyltetrahydrofolate, the most prominent naturally occurring folate in fortified foods, with a reliable and robust method. Folates were heat-extracted from food samples. A trienzyme treatment (alpha-amylase, rat plasma conjugase, and protease) was applied to the extracts followed by purification by affinity chromatography. Folic acid and 5-methyltetrahydrofolate were separated and quantified by reversed-phase HPLC with fluorescence and UV detection. A gradient elution with phosphate buffer and acetonitrile was used to separate the different forms of folates. The method gave a linear response in a range of 0.1-3 mumol/L and 0.0125-0.25 mumol/L for folic acid and 5-methyltetrahydrofolate, respectively. These ranges were similar to the expected levels in the samples. The CV of the peak areas of folic acid and 5-methyltetrahydrofolate for 5 commercial wheat flour samples extracted and run separately on the same day was 2.0 and 5.7% and, run over 5 consecutive days, was 7.2 and 7.3%, respectively. Total folate values in 45 samples of fortified food measured by HPLC and by the traditional microbiological assay demonstrated a high correlation (r(2) = 0.986).

Chromatography, Affinity↗

Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada.

OBJECTIVE: Canada introduced a mandatory folic acid food fortification program in November 1998. We investigated whether the rate of folate and vitamin B12 insufficiency among adults has changed since this mandatory fortification program was implemented. METHODS: We conducted a retrospective cross-sectional study using a large Ontario laboratory database. We included all individuals who underwent evaluation of their serum folate, red cell folate and serum vitamin B12 between April 1, 1997 to July 31, 1998 (Period A), August 1, 1998 to January 30, 1999 (Period B) and February 1, 1999 to March 31, 2000 (Period C). RESULTS: A total of 8,884 consecutive samples were analyzed during the period of study. Mean age was 57.4 years (SD 21.1), and 63.2% were female. The prevalence of serum folate insufficiency (below 3.4 nmol/L) fell from 0.52% in Period A to 0.22% in Period C [prevalence ratio (RR) 0.41, 95% confidence interval (CI) 0.18-0.93)]. The prevalence of red cell folate insufficiency (below 215 nmol/L) declined from 1.78% during Period A to 0.41% in Period C (RR 0.23, 95% CI 0.14-0.40). No significant difference was observed between periods in the prevalence of B12 insufficiency below 120 pmol/L (3.93% versus 3.11%, respectively; RR 0.79, 95% CI 0.62-1.01). CONCLUSIONS: There has been a significant decline in the prevalence of folate, but not vitamin B12 insufficiency, following Canadian folic acid food fortification. These changes may have important implications for the prevention and detection of folate and vitamin B12 insufficiency, including identifying the benefits of folic acid food fortification and the need to further consider fortification or supplementation with vitamin B12.

Adult↗

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

OBJECTIVES: To assess the effects of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) and haematologic side effects of low-dose of Methotrexate (MTX) in patients with Rheumatoid Arthritis (RA) and to determine whether or not folate supplementation alters MTX efficacy. SEARCH STRATEGY: We searched the Cochrane Controlled Clinical Trial's Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register and Medline up to and including June 1999, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). We also handsearched the following: (i) bibliographic references; (ii) current contents of the last 6 months; (iii) abstracts of the rheumatology meetings; and (iv) all issues of four journals; Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatology. All languages were included. Principal investigators were also contacted in order to look for unpublished literature. SELECTION CRITERIA: We selected all double-blind, randomized, placebo-controlled, clinical trials (RCTs), in which adult RA patients were treated with a low dose of MTX (<20 mg / week) concurrently with folate supplementation. DATA COLLECTION AND ANALYSIS: Two observers extracted the data and assessed the quality of the trials. (BS, Z0) The overall treatment effect across trials was calculated using a fixed effect model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Results are presented with 95% Confidence Inervals (95% CI). Subgroup analyses were conducted evaluating different doses and sensitivity analysis looking at the quality of the trials. Publication bias was assessed with an inverted funnel plot technique. Heterogeneity of the trials was measured using a standard chi square test. Costs per month in different countries were compared. MAIN RESULTS: Of the 12 trials retrieved, 7 met the inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but non-statistically significant reduction of 43% was found [OR = 0. 57 (95% CI 0.28 to 1.15)]. No major differences were observed between low and high doses of folic or folinic acid. Haematologic side effects could not be analyzed, since details of each haematologic side effect by patients were not provided. No consistent differences in disease activity parameters were observed when comparing placebo and folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all. REVIEWER'S CONCLUSIONS: The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.

Antirheumatic Agents↗

Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution.

OBJECTIVE: To determine whether prescription prenatal vitamins meet United States Pharmacopeial Convention (USP) standards for folic acid dissolution. METHODS: Dissolution was measured using USP Apparatus II and test conditions specified in the 23rd revision of the United States Pharmacopeia (USP 23). Folic acid was assayed by a chromatographic method modified from that specified in the official monographs, for oil- and water-soluble vitamins with minerals tablets, in USP 23. RESULTS: Only three out of nine multivitamin products met USP specifications for folic acid release. Most missed by a wide margin; folic acid dissolution from two products was less than 25%. CONCLUSIONS: Because a wide variety of brand-name and generic prescription prenatal multivitamin products were tested, these results are likely to be representative of the multivitamin products on the market. Given the significance of folic acid to public health, the authors believe that this subject should be studied further and that prompt action should be taken to ensure that folic-acid-containing products are of the highest quality possible.

Chemistry, Pharmaceutical↗

Characterization of the folic acid C9-N10-cleaving enzyme of Dictyostelium minutum V3.

Folic acid is a chemoattractant for the slime mold Dictyostelium minutum V3. The activity of extracellular folic acid is regulated by a folic acid C9-N10 splitting enzyme (FAS). The products were identified as pterin-6-aldehyde and p-amino-benzoylglutamic acid. The enzyme was stabilized by EDTA. For the extracellular enzyme, the Km was 10(-7) M, and the optimal pH was 4.0. During starvation, FAS activity was mainly secreted into the medium; after 3 h, a plateau was reached. The membrane-bound activity was constant, but only 12% of the extracellular activity at 3 h. Intracellular activity also increased up to 3 h to a level of 23% of the extracellular FAS. The substrate recognition of FAS was found to be based on 4-O or N3 or both, N5 or N8 or both, N10, and the p-aminobenzoic acid moiety, whereas 2-NH2, N1, and the glutamic acid moiety were not recognized. Other slime mold species were found to secrete FAS with 20-fold or more reduced activity than D. minutum V3.

Aminohydrolases↗

[Folic acid and pregnancy, a real problem?].

The efficacy of prophylactic treatment with ferrous sulfate (80 mg Fe++) and the combination of ferrous sulfate with folic acid (80 mg Fe++ and 350 microgram folic acid) were studied in a double blind trial in the 20th, and again in the 30th and 36th week of pregnancy (29 patients). At the beginning of the treatment (20th week) 29% of the patients showed a pathologically reduced serum folic acid level. Combined therapy has a favorable effect on the folic acid levels in the serum and red blood cells; this was confirmed statistically. At the end of pregnancy, 69% of the patients of the control group (ferrous sulfate) showed a pathologically reduced serum level and 23% a subnormal level in erythrocytes. These results unquestionably justify the prophylactic prescription of folic acid during pregnancy.

Erythrocytes↗