Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate

BACKGROUND: Inadequate maternal vitamin intake during pregnancy has been suggested as a risk factor for cleft lip with or without cleft palate (CLP). The independent role of folate has not been clarified. METHODS: To investigate the association between maternal folate intake by supplement and food and the risk of CLP offspring, a case-control study was conducted in the Netherlands (1998-2000) among 174 mothers of a child with nonsyndromic CLP and 203 mothers of a child without congenital malformations. RESULTS: Daily use of a folic acid supplement by mothers starting from 4 weeks before until 8 weeks after conception gave a 47% CLP risk reduction compared to mothers who did not use these supplements [odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33, 0.85]. Ninety-three percent of the users took a supplement containing folic acid only. Dietary folate intake reduced CLP risk independently in a dose-response manner. The largest risk reductions were found on those mothers who had a diet of more than 200 microg folate per day in combination with a folic acid supplement (OR: 0.26, 95% CI: 0.09, 0.72). CONCLUSIONS: We demonstrated that periconceptional maternal folic acid supplement use was beneficial to reduce the risk for CLP. An additional effect of food folate was shown.     

Low maternal vitamin B-12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal

Questions have been raised about potentially negative effects of antenatal folic acid use in populations with a high prevalence of vitamin B-12 deficiency. Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and/or vitamin B-12 status. Pregnant women were cluster randomized to receive daily supplements containing vitamin A alone or with folic acid, folic acid+iron, folic acid+iron+zinc, or a multiple micronutrient. In a subsample (n = 1132), micronutrient status biomarkers were analyzed at baseline and late pregnancy. Children born to the women who participated in the trial were visited at 6-8 y of age. Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment (HOMA-IR). Children whose mothers were deficient in vitamin B-12 (<148 pmol/L, 27%) during early pregnancy had a 26.7% increase in HOMA-IR (P = 0.02), but there was no association with maternal folate status. Among children born to women who were vitamin B-12 deficient at baseline, the percent difference in HOMA-IR compared to the control group was 15.1% (95% CI: -35.9, 106.4), 4.9% (-41.6, 88.5), 3.3% (-38.4, 73.5), and 18.1% (-29.0, 96.7) in the folic acid, folic acid-iron, folic acid-iron-zinc, and multiple micronutrient supplementation groups, respectively, none of which were significant. Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance, but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring.     

High dietary folate supplementation affects gestational development and dietary protein utilization in rats.

There is new evidence that good folate status may play a critical role in the prevention of neural tube defects and in the maintenance of adequate homocysteine levels, an amino acid recently identified as a risk factor for cardiovascular disease. This has led to different folate recommendations, all of them much higher than the present dietary recommendations. Folic acid is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term, high folate intakes are unknown. Therefore, the present study was undertaken to determine the effects of long-term, high dietary folate supplementation on gestational and nutritional markers in pregnant and virgin rats. Four groups of Wistar rats were classified on the basis of physiological status (virgin or pregnant) and the experimental diets administered (folic acid supplemented, 40 mg/kg diet; or control diet, 2 mg folic acid/kg diet). Rats were fed their respective diets for 3 wk. Two critical periods were used for metabolic balance studies (experimental d 1-5 and 17-21), which involved the determination of fat and protein digestibilities as well as metabolic protein utilization (MPU) and net protein utilization (NPU). Gestational development (number of live fetuses) was adequate in both diet groups regardless of folate supplementation. However, body weight and vertex-coccyx length in fetuses from supplemented dams were less than (P < 0.0001) in fetuses of control dams. Fat and nitrogen digestibilities were not affected by supplementation, but MPU and NPU coefficients were significantly lower (P < 0.05) in the folic acid-supplemented groups, irrespective of physiological status, compared to control rats. These new findings of macro-micronutrient interactions caused by high folate supplementation are discussed on the basis that the vitamin may act as a xenobiotic more than as a nutrient.     

High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle

There is new evidence that a good folate status may play a critical role in the prevention of neural-tube defects and in lowering elevated homocysteine concentrations. This adequate folate status may be achieved through folic acid dietary supplementation. Folate is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term high-dose folic acid supplementation are unknown, especially those related to the methionine cycle, where folate participates as a substrate. With the aim of evaluating such possible effects, four groups of Wistar rats were classified on the basis of physiological status (virgin v. pregnant) and the experimental diet administered (folic-acid-supplemented, 40 mg/kg diet v. control, 2 mg folic acid/kg diet). Animals were fed on the diets for 3 weeks. Results showed that gestation outcome was adequate in both groups regardless of the dietary supplementation. However, there were reductions (P < 0.001) in body weight and vertex-coccyx length in fetuses from supplemented dams v. control animals. Folic acid administration also induced a higher (P < 0.01) S-adenosylmethionine: S-adenosylhomocysteine value due to increased S-adenosylmethionine synthesis (P < 0.01). However, hepatic DNA methylation and serum methionine concentrations remained unchanged. Serum homocysteine levels were reduced in supplemented dams (P < 0.05). Finally, pregnancy caused lower serum folate, vitamin B6 and vitamin B12 levels (P < 0.05). Folic acid administration prevented the effect of pregnancy and raised folate levels in dams, but did not change levels of vitamins B12 and B6. These new findings are discussed on the basis of potential benefits and risks of dietary folic acid supplementation.     

Oral facial clefts and gene polymorphisms in metabolism of folate/one‐carbon and vitamin A: a pathway‐wide association study

An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case‐parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one‐carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi‐Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway‐wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with P‐values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role. Genet. Epidemiol. 2009. © 2008 Wiley Liss, Inc.     

Folate-deficiency induced cell-specific changes in the distribution of lymphocytes and granulocytes in rats

Objective

Folate (vitamin B₉) plays key roles in cell growth and proliferation through regulating the synthesis and stabilization of DNA and RNA, and its deficiency leads to lymphocytopenia and granulocytopenia. However, precisely how folate deficiency affects the distribution of a variety of white blood cell subsets, including the minor population of basophils, and the cell specificity of the effects remain unclear. Therefore, we examined the effects of a folate-deficient diet on the circulating number of lymphocyte subsets [T-lymphocytes, B-lymphocytes, and natural killer (NK) cells] and granulocyte subsets (neutrophils, eosinophils, and basophils) in rats.

Methods

Rats were divided into two groups, with one receiving the folate-deficient diet (FAD group) and the other a control diet (CON group). All rats were pair-fed for 8 weeks.

Results

Plasma folate level was dramatically lower in the FAD group than in the CON group, and the level of homocysteine in the plasma, a predictor of folate deficiency was significantly higher in the FAD group than in the CON group. The number of T-lymphocytes, B-lymphocytes, and NK cells was significantly lower in the FAD group than in the CON group by 0.73-, 0.49-, and 0.70-fold, respectively, indicating that B-lymphocytes are more sensitive to folate deficiency than the other lymphocyte subsets. As expected, the number of neutrophils and eosinophils was significantly lower in the FAD group than in the CON group. However, the number of basophils, the least common type of granulocyte, showed transiently an increasing tendency in the FAD group as compared with the CON group.

Conclusion

These results suggest that folate deficiency induces lymphocytopenia and granulocytopenia in a cell-specific manner.     

Physiologic changes in homocysteine metabolism in pregnancy: a longitudinal study in Spain

Objective

The aim was to investigate whether pregnancy-induced changes in total homocysteine (tHcy) are associated with folate and vitamin B12 nutritional status, genetic C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) enzyme, and gestation outcome at a time when folic acid supplementation started to be recommended in the Spanish health system.

Methods

In total 154 pregnant women were recruited from among gynecologic patients of the Alcorcón Public Hospital Outpatient Clinic (Madrid, Spain). Blood tests were performed at weeks 15, 24, and 32 of pregnancy. Total Hcy, folate, and vitamin B12 serum fasting concentrations were measured using an IMx system. Genotype analyses were done by polymerase chain reaction/restriction fragment/length polymorphism analysis.

Results

Folate and vitamin B12 serum concentrations decreased significantly (P < 0.01) through pregnancy and reached the lowest values in the third trimester. Serum tHcy concentrations were significantly (P < 0.01) lower in the second trimester but increased in the third trimester. Frequencies of MTHFR C667T genotype were CC (35.7%), CT (57.2%), and TT (7.1%). Total Hcy concentration was not statistically influenced by maternal genotype. Plasma folate was the single negative predictor of maternal tHcy in the first trimester of pregnancy; 11.1% of gestations resulted in intrauterine growth restriction, 7.9% in gestational diabetes mellitus, and 4.8% in gestational hypertension. No significant differences in serum folate, vitamin B12, or tHcy concentrations were found in complicated pregnancies and these were unrelated to MTHFR genotype.

Conclusion

Although tHcy seems to be physiologically low in this Spanish population and unrelated to folate and B12 nutritional status, C677T MTHFR genotype, and some pregnancy complications, we support the statement that appropriate folate concentration may be important throughout pregnancy to prevent abnormalities associated with altered status (e.g., neural tube defects). According to our study, supplementation with folic acid seems to achieve this purpose because diet alone may be insufficient. In addition, a poor vitamin B12 status, as measured by plasma levels, may indicate that supplementation of both vitamins is needed.     

Effects of parental folate deficiency on the folate content,global DNA methylation,and expressions of FRα, IGF-2 and IGF-1R in the postnatal rat liver

We examined the effect of parental folate deficiency on the folate content, global DNA methylation, folate receptor-alpha (FRα), insulin-like-growth factor-2 (IGF-2) and -1 receptor (IGF-1R) in the liver and plasma homocysteine in the postnatal rat. Male and female rats were randomly fed a folic acid-deficient (paternal folate-deficient, PD and maternal folate-deficient, MD), or folic acid-supplemented diet (paternal folate-supplemented, PS and maternal-folate-supplemented, MS) for four weeks. They were mated and grouped accordingly: PSxMS, PSxMD, PDxMS, and PDxMD. Pups were killed on day 21 of lactation. The hepatic folate content was markedly reduced in the PDxMD and PSxMD and PDxMS as compared with the PSxMS group. The hepatic global DNA methylation was decreased in the PDxMS and PSxMD groups as much as in the PDxMD group, and all the three groups were significantly lower as compared to the PSxMS group. There were no significant differences in the hepatic FRα, IGF-2 and IGF-1R expressions among the groups. Positive correlations were found between the hepatic folate content and global DNA methylation and protein expressions of FRα, IGF-2 and IGF-1R, whereas an inverse correlation was found between hepatic folate content and plasma homocysteine level in the 3-week-old rat pup. The results of this study show that both paternal and maternal folate deficiency at mating can influence the folate content and global DNA methylation in the postnatal rat liver.     

Maternal nutrient intakes and risk of orofacial clefts

BACKGROUND: Information about nutritional factors as potential risks of orofacial clefts is limited. METHODS: In this population-based case-control study, we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. We included data on deliveries from 1997 through 2000 in the National Birth Defects Prevention Study. Orofacial cleft cases were infants or fetuses born with cleft palate (CP) or with cleft lip with or without cleft palate (CLP). Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. Interviews were completed for 704 CLP cases, 404 CP cases, and 2594 controls. RESULTS: The odds ratio (OR) for CLP associated with use of vitamin supplements containing folic acid was 0.88 (95% confidence interval = 0.73-1.07) and for CP was 1.09 (0.84-1.40). Adjusting for maternal race/ethnicity, age, and education produced an OR of 1.01 (0.82-1.24) for CLP and 1.02 (0.77-1.34) for CP. We found some evidence for decreased CLP risks (>or=30% reduction in risk) with increasing intakes of total protein, choline, and methionine. Decreased CP risk was associated with increased intake of cysteine. Intakes of only 2 micronutrients, iron and riboflavin, were found to reduce CLP risk when adjusted for other nutrients. CONCLUSION: Our observations contribute to the limited body of evidence suggesting a woman's periconceptional diet may influence clefting risks in her offspring. Our finding of no reduction in clefting risk with periconceptional use of supplements containing folic acid is inconsistent with many previous observations but not all.     

The Chilean flour folic acid fortification program reduces serum homocysteine levels and masks vitamin B-12 deficiency in elderly people

Hyperhomocysteinemia is considered a risk factor for cardiovascular disease and is prevalent in the elderly. Supplementation with folic acid, vitamin B-6 and B-12 lowers homocysteine levels. In January 2000, the Chilean government initiated a flour folic acid fortification program to decrease the occurrence of neural tube defects. The aim of this study was to evaluate the effect of this program on serum homocysteine and folate levels in elderly subjects after 6 mo. A total of 108 elderly people were studied. We measured serum folate, homocysteine and vitamin B-12 levels before the fortification started and 6 mo later. At baseline, folate deficiency (<6.8 nmol/L) was present in 1.8%, vitamin B-12 deficiency (<165 pmol/L) in 27.6% and hyperhomocysteinemia (>14 micromol/L) in 31% of the sample. Six months later, serum folate levels increased from 16.2 +/- 6.2 to 32.7 +/- 7.1 nmol/L (P < 0.001), homocysteine levels decreased from 12.95 +/- 3.7 to 11.43 +/- 3.6 micromol/L (P < 0.001) and vitamin B-12 levels were unchanged. Flour fortification with folic acid had a moderate lowering effect on homocysteine levels. Given that vitamin B-12 deficiency was more common than folate deficiency, it may be more appropriate to add vitamin B-12 to food, at least in foods for this age group.     

Folate bioavailability and health

The vitamin folate has been largely responsible for a fundamental shift in our perception of the role of vitamins in maintaining health. Ten years ago, two independent clinical trials showed that supplementing a woman's diet with folic acid before and during early pregnancy reduced the prevalence of neural tube defects (NTDs) by more than 70%. A remarkable aspect was that folic acid supplementation was not correcting a clinical deficiency in most of these women. It was later shown that the risk of having an NTD-affected birth was negatively associated with maternal red cell folate status, and the level of risk varied throughout the normal range, suggesting an interaction of genetic factors with folate nutritional status. It now appears that an insufficient folate status might contribute to risk of developing a variety of medical conditions throughout an individual's lifetime, from certain congenital malformations and poor pregnancy outcomes to cardiovascular disease, some malignancies, and neurological dysfunction of the elderly. Thus, an alternative view of folate nutrition has emerged. This view goes beyond the idea of a dietary requirement to prevent signs and symptoms of clinical deficiency towards one of achieving an optimal status to reduce risk of certain chronic diseases, and includes the concept that an individual's genetic make-up may substantially affect the vitamin status that they can achieve without supplements or fortification.     

Bread cofortified with folic acid and vitamin B-12 improves the folate and vitamin B-12 status of healthy older people: a randomized controlled trial

BACKGROUND: Mandatory fortification of flour with folic acid has reduced the number of neural tube defects in North America. Concerns that high intakes of folic acid might mask vitamin B-12 deficiency in older persons have delayed the introduction of fortification in many European countries. Cofortification of flour with folic acid and vitamin B-12 could simultaneously improve folate and vitamin B-12 status. OBJECTIVE: The objective was to estimate the effect of the consumption of bread fortified with modest amounts of folic acid and vitamin B-12 on folate and vitamin B-12 status in healthy older persons living in the Netherlands, where folic acid fortification is not taking place. DESIGN: Men and women aged 50-75 y were randomly assigned in this 12-wk double-blind, placebo-controlled trial to consume bread fortified with 138 mug folic acid and 9.6 mug vitamin B-12 daily (n = 72) or unfortified bread (n = 70). RESULTS: The consumption of fortified bread increased serum folate concentrations by 45% (mean: 6.3 nmol/L; 95% CI: 4.5, 8.1 nmol/L) and serum vitamin B-12 concentrations by 49% (mean: 102 pmol/L; 95% CI: 82, 122 pmol/L) relative to the placebo group. Fortified bread increased erythrocyte folate concentrations by 22% and holotranscobalamin concentrations by 35%; it decreased homocysteine concentrations by 13% and methylmalonic acid concentrations by 10%. Consumption of fortified bread decreased the proportion of individuals with marginal serum vitamin B-12 concentrations (<133 pmol/L) from 8% at enrollment to 0% after 12 wk. CONCLUSION: Bread fortified with modest amounts of folic acid and vitamin B-12 will improve folate and vitamin B-12 status and a considerable proportion of vitamin B-12 deficiency in older people. This trial was registered at clinicaltrials.gov as NCT00353353.     

Concomitant supplemental vitamin A enhances the response to weekly supplemental iron and folic acid in anemic teenagers in urban Bangladesh.

BACKGROUND: Iron deficiency is the most common micronutrient deficiency and affects >2 billion persons worldwide, leading to anemia in >40% of women of reproductive age in the developing world. OBJECTIVE: The objective was to determine whether weekly supplementation with iron and folate would reduce the frequency of anemia in teenage women in urban Bangladesh before they became pregnant. DESIGN: Participants with a hemoglobin concentration of 80-120 g/L were entered into a randomized, double-blind, placebo-controlled trial and received supplements of placebo, vitamin A, iron + folic acid, or iron + folic acid + vitamin A weekly for 12 wk. The supplements contained 2.42 mg vitamin A (retinol) as retinyl palmitate, 120 mg elemental Fe as ferrous sulfate, and 3.5 mg folic acid. RESULTS: Hemoglobin concentrations increased significantly more after supplementation with iron + folic acid or iron + folic acid + vitamin A than after either the placebo or vitamin A alone. There was a significantly greater increase in hemoglobin after iron + folic acid + vitamin A than after iron + folic acid, but the additional effect disappeared after adjustment for baseline hemoglobin, serum vitamin A, and ferritin and the number of supplements taken. Those with the lowest baseline hemoglobin had the greatest increase in hemoglobin. Compared with the placebo, iron + folic acid + vitamin A reduced anemia by 92%, iron deficiency by 90%, and vitamin A deficiency by 76%. CONCLUSION: There may be significant health benefits from a program that enhances the nutritional status of iron, folate, and vitamin A in poor urban young women before they become pregnant.     

The influence of dietary folate supplementation on the incidence of teratogenesis in zinc-deficient rats

Two studies were conducted to investigate the possibility that pteroylmonoglutamic acid supplementation would alleviate teratogenesis in zinc-deficient rats. Pregnant rats of the Wistar strain were fed on Zn-deficient (less than 0.5 mg Zn/kg) or Zn-supplemented (75 or 95 mg Zn/kg) diets from mating until day 18.5 of gestation. The basal level of pteroylmonoglutamic acid added to all diets (0.56 mg/kg) was supplemented with 30-200 mg/kg in selected diets. Dietary Zn deprivation resulted in fetal resorption, fetal growth retardation and reduced concentrations of Zn in fetuses and maternal plasma and tibia. Low maternal body-weight at conception emerged as an important determinant of risk of resorption in Zn-deficient rats. Dietary Zn deficiency resulted in reduced maternal plasma folate concentrations and these values were inversely correlated with litter size or weight in Zn-deficient rats. Pteroylmonoglutamic acid supplementation increased maternal plasma folate concentrations, but did not reduce the high incidence of teratogenesis which occurred in Zn-deficient rats. Supplementation of Zn-deficient rats with pteroylmonoglutamic acid significantly increased the incidence of clubbed foot and tended to increase the incidence of brain or meningeal abnormalities, or both, and cleft palate, but did not reduce maternal or fetal Zn status. Pteroylmonoglutamic acid supplementation also increased the weights of Zn-supplemented control fetuses.     

Associations of maternal folic acid supplementation and folate concentrations during pregnancy with foetal and child head growth: the Generation R Study

Purpose

Folic acid supplementation during pregnancy has been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is unclear whether low folate status has effects on the developing brain. We evaluated the associations of maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal and postnatal head circumference in the offspring.

Methods

Within a population-based prospective cohort, we measured maternal plasma folate concentrations at approximately 13 weeks of gestation (90 % range 10.5–17.2) and assessed folic acid supplementation by questionnaire (2001–2005). Up to 11 repeated measures of head circumference were obtained during foetal life (20 and 30 weeks of gestation) and childhood (between birth and age 6 years) in 5866 children (2002–2012).

Results

In unadjusted models, foetal head growth was 0.006 SD (95 % CI 0.003; 0.009, P < 0.001) faster per week per 1-SD higher maternal folate concentration. After adjustment for confounders, this association was attenuated to 0.004 SD per week (95 % CI 0.000; 0.007, P = 0.02; estimated absolute difference at birth of 2.7 mm). The association was independent of overall foetal growth. No associations were found between maternal folate concentrations and child postnatal head growth. Preconceptional start of folic acid supplementation was associated with larger prenatal head size, but not with prenatal or postnatal head growth.

Conclusions

Our results suggest an independent, modest association between maternal folate concentrations in early pregnancy and foetal head growth. More research is needed to identify whether specific brain regions are affected and whether effects of folate on foetal head growth influence children’s long-term functioning.

     

The effects of feeding rats diets deficient in folic acid and related methyl donors on the blood pressure and glucose tolerance of the offspring

In humans poor maternal folate status is associated with a decrease in infant birth weight. As low birth weight increases the risk of cardiovascular and metabolic disease in adults, an inadequate supply of folic acid in the mother's diet may increase the susceptibility of the offspring to disease. We have fed laboratory rats diets deficient in folic acid and the related methyl donors methionine and choline to examine the effects on growth, blood pressure and insulin action in the offspring. Poor folate status transiently increased fetal growth but did not produce a long-term change in body weight. There were, however, small changes in the hearts of the female offspring. When folate deficiency was combined with low intakes of methionine and choline, the kidneys of the male offspring were proportionately smaller, probably because of the limited availability of methionine. There was no effect on the blood pressure of either the male or female offspring. The pancreatic insulin content of fetuses from animals fed the folate-deficient diets were higher than those of the controls. Following an oral glucose challenge, there was a weak trend for glucose-stimulated insulin release to be increased in the offspring of dams fed the folate-deficient diet. The changes in insulin concentrations were, however, much smaller than the corresponding changes observed in the offspring of animals fed protein-deficient diets. These results suggest that folate deficiency during gestation causes modest changes to the insulin axis of the fetus.     

Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study

BACKGROUND: Food fortification with folic acid has been introduced in several countries for the prevention of neural tube defects. Fortification has lowered total homocysteine (tHcy) concentrations in the US population, a consequence that may have health benefits. However, folic acid fortification could mask vitamin B-12 deficiency. Synthetic L-5-methyltetrahydrofolate (L-MTHF) may be more appropriate than folic acid as a fortificant because it is unlikely to mask the hematologic indicators of vitamin B-12 deficiency. OBJECTIVE: The objective of the study was to compare the effectiveness of 100 micro g folic acid/d with that of equimolar L-MTHF in lowering tHcy in healthy volunteers. DESIGN: The study was designed as a 24-wk, randomized, placebo-controlled intervention. Free-living healthy volunteers (n = 167) were randomly assigned to receive a daily supplement containing folic acid (100 microg), L-MTHF (113 microg), or placebo. Blood collected at baseline and at 8, 16, and 24 wk was analyzed for tHcy, plasma folate, and red blood cell folate (RCF) concentrations. RESULTS: At 24 wk, after adjustment for baseline values, mean (95% CI) tHcy was 14.6% (9.3, 19.5%) and 9.3% (3.7, 14.6%) lower, mean plasma folate was 34% (14, 56%) and 52% (30, 78%) higher, and mean RCF was 23% (12, 35%) and 31% (19, 44%) higher in the L-MTHF and folic acid groups, respectively, than in the placebo group. L-MTHF was more effective than was folic acid in lowering tHcy (P < 0.05). At 24 wk, the increases in plasma folate and RCF concentrations did not differ significantly between the 2 supplemented groups. CONCLUSION: Low-dose L-MTHF is at least as effective as is folic acid in reducing tHcy concentrations in healthy persons.     

High frequency of maternal vitamin B12 deficiency as an important cause of infantile vitamin B12 deficiency in Sanliurfa province of Turkey

Summary Background Vitamin B₁₂ deficiency in infancy may cause failure to thrive, severe neurological disorders and megaloblastic pancytopenia. It is well known that infants born with deficient vitamin B₁₂ storage have increased the risk of vitamin B₁₂ deficiency. Vitamin B₁₂ deficiency is more prevalent in infancy in Sanliurfa province (at the southeast region of Turkey). Aim of the study The aim of this study was to determine the frequencies of vitamin B₁₂, folic acid and iron deficiencies in pregnants and their babies at birth and to what extend the mothers’ deficiency becomes effective on babies’ deficiencies. Methods The study groups were constituted by 180 pregnant women and their single and term babies. Venous blood samples of pregnants were obtained 1–3 h before delivery and babies’ cord bloods were collected at birth. Vitamin B₁₂ and folic acid levels were measured with electro chemiluminiscence method; serum iron and iron binding capacities were measured by colorimetric method and complete blood counts were performed by automatic blood counter. Results Mean vitamin B₁₂ levels in maternal and cord blood serum were 130 ± 61.7 pg/ml and 207 ± 141 pg/ml; mean folic acid levels were 8.91 ± 6.46 ng/ml and 17.8 ± 11.8 ng/ml; mean serum iron levels were 56.9 ± 37.5 μg/dl and 147 ± 43.2 μg/dl; and mean transferrin saturations were 11.8 ± 8% and 65.6 ± 24%, respectively. There were vitamin B₁₂ deficiency (<160 pg/ml) in 72% of the mothers and 41% of the babies, and severe deficiency (<120 pg/ml) in 48% of the mothers and 23% of the babies. Folic acid deficiency was found in 12% of the mothers, but was not found in the babies. There were iron deficiency in 62% of the mothers and 1% of the babies. There were statistically significant correlation between maternal and cord blood serum vitamin B₁₂ levels (r = 0.395, P < 0.001) and folic acid levels (r = 0.227, P = 0.017), while there were no correlation between maternal and cord blood iron levels and transferrin saturations. Conclusion The study results showed that vitamin B₁₂ deficiency is prevalent in pregnants in this region and that 41% of infants have born with deficient vitamin B₁₂ storages. Therefore, prophylactic use of vitamin B₁₂ by pregnant women in Sanliurfa and other poor communities could have considerable benefits to prevent vitamin B₁₂ deficiency and its complications in infants.     

High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring

Recent studies suggest that in utero exposure of methyl donors influences programming of the fetal immune system in favor of development of allergic disease. The aim of this study was to assess whether the MTHFR C677T polymorphism, folic acid supplementation, and circulating folate and vitamin B-12 concentrations during pregnancy were associated with wheezing, shortness of breath, and atopic dermatitis in offspring. The study was a population-based birth cohort from fetal life until 48 mo (n = 8742). The use of folic acid supplementation during pregnancy was assessed by questionnaire. Plasma folate and serum vitamin B-12 concentrations and the MTHFR C677T polymorphism were available from blood collected in early pregnancy. Atopic dermatitis, wheezing, and shortness of breath in the offspring were assessed by parental-derived questionnaires at 12, 24, 36, and 48 mo. Maternal folate >16.2 nmol/L and vitamin B-12 >178 pmol/L were positively associated with the development of atopic dermatitis [adjusted OR: 1.18 (95% CI: 1.05-1.33) and adjusted OR: 1.30 (95% CI: 1.06-1.60) for the highest quartiles of folate and vitamin B-12 concentrations, respectively] but not with wheezing and shortness of breath. Maternal MTHFR C677T polymorphism and folic acid supplementation were not associated with wheezing, shortness of breath, and atopic dermatitis. No interactions were found by age, family history of atopy, folic acid supplementation, MTHFR C677T polymorphism, or maternal smoking (P-interaction > 0.10). High folate and vitamin B-12 levels during pregnancy are associated with increased prevalence of atopic dermatitis in the offspring. Potential risks of high folate and vitamin B-12 concentrations on allergic outcomes should be evaluated when discussing mandatory fortification programs.     

Effect of folate deficiency on microsomal drug metabolism and heme content in the intestinal mucosa of guinea pigs

The relationship between folate deficiency, heme content, and microsomal drug metabolism in the intestinal mucosa of the guinea pig was examined. Weanling male guinea pigs were pair‐fed a folate‐deficient diet, and intestinal mucosal folate levels were measured. A significant decrease (75%) in these levels was observed at 3 weeks after diet initiation. A significant decrease (78%) in intestinal mucosal drug metabolism (7‐ethoxycoumarin O‐deethylase activity) and a significant decrease (46%) in intestinal mucosal heme content were also observed at this time. These findings indicate that folic acid deficiency in the guinea pig results in a marked reduction in heme content and microsomal drug metabolism of the intestinal mucosa.