Effect of time of initiation and dose of prenatal iron and folic acid supplementation on iron and folate nutriture of Korean women during pregnancy. Colorectal Adenomas in a Randomized Folate Trial: The Role of Baseline Dietary and Circulating Folate Levels Kinetics of folate turnover in pregnant women (second trimester) and nonpregnant controls during folic acid supplementation: stable-isotopic labeling of plasma folate, urinary folate and folate catabolites shows subtle effects of pregnancy on turnover of folate pools. Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal. Folic acid supplementation in early pregnancy and asthma in children aged 6 years. Maternal dietary folate, folic acid and vitamin D intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring. Effect of folic acid supplementation on small-for-gestational-age infants born at term Low-Dose folic acid supplementation decreases plasma homocysteine concentrations: a randomised trial. Folate intakes and awareness of folate to prevent neural tube defects: a survey of women living in Vancouver, Canada. Dietary and serum folate: their influence on the outcome of pregnancy. Responses of Biomarkers of Folate and Riboflavin Status to Folate and Riboflavin Supplementation in Healthy and Colorectal Polyp Patients (The FAB2 Study) MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Dietary folate intake during pregnancy and birth weight in Japan Dietary strategies for lowering homocysteine concentrations. Promotion of folate for the prevention of neural tube defects: who benefits? Influence of folate status and polyphenol intake on thiamin status of Irish women. Altered Folate Availability Modifies the Molecular Environment of the Human Colorectum: Implications for Colorectal Carcinogenesis Effect of daily milk supplementation on serum and umbilical cord blood folic acid concentrations in pregnant Han and Mongolian women and birth characteristics in China. Population red blood cell folate concentrations for prevention of neural tube defects: bayesian model Reduction of Incidence of Prematurity by Folic Acid Supplementation in Pregnancy Effects of multivitamin and folic acid supplementation in malnourished children. "Folate before pregnancy": the impact on women and health professionals of a population-based health promotion campaign in South Australia. Effect of multiple-micronutrient supplementation on maternal nutrient status, infant birth weight and gestational age at birth in a low-income, multi-ethnic population.
BACKGROUND In Korea , it is customary to prescribe iron and folic acid supplements to pregnant women after the 20th wk of gestation ; however , little evidence exists to support this practice . OBJECTIVE The objective was to determine the effects of time of initiation and dose of prenatal iron and folic acid supplementation on the iron and folate nutriture of Korean women during pregnancy . DESIGN A total of 131 pregnant women were placed into 1 of 5 experimental groups , either the control group or 1 of 4 supplemented groups . The supplemented groups varied by time of initiation , which was either during the first trimester or at week 20 of gestation , and by dose of iron and folic acid supplements provided , which consisted of either 30 mg Fe plus 175 microg folic acid or 60 mg Fe plus 350 microg folic acid . All supplemented groups continued supplementation until delivery . RESULTS Improvements in iron and folate nutriture were highly dependent on when the supplement program was initiated , but both supplement doses were equally effective . In contrast , the influence of folic acid supplementation on maternal folate status was not as pronounced as was the influence of iron supplementation on iron status . CONCLUSION In pregnant Korean women , initiating iron and folic acid supplementation earlier during pregnancy may prevent the deterioration of iron and folate nutriture more than does increasing supplement doses in later stages of pregnancy The Aspirin/Folate Polyp Prevention Study is a r and omized , placebo-controlled trial of aspirin use and folic acid supplementation and incidence of colorectal adenomas in individuals with a history of these lesions . The trial showed that folic acid supplementation does not prevent the occurrence of new adenomas and may increase risk . We extend these results by investigating whether the effect of folic acid treatment differed by baseline dietary and circulating folate levels . Diet and supplement use were ascertained at baseline through a food-frequency question naire ; a blood sample was used to determine plasma and RBC folate levels . Individuals were followed for 3 years ( first follow-up ) and subsequently for an additional 3 to 5 years ( second follow up ) . We used generalized linear regression to estimate risk ratios and 95 % confidence limits as measures of association . There was little evidence that baseline dietary and total folate intake , and plasma and RBC folate modified the association between folic acid treatment and risk of any adenomas or advanced lesions . However , there was a protective association of the highest tertile of dietary and total intake as well as circulating folate with risk of any adenomas among those in the placebo group but no association among individuals in the folic acid group . Our findings support the idea that although moderate doses of folate may be protective compared with deficiency , at some point of sufficiency , supplementation provides no additional benefit . ( Cancer Epidemiol Biomarkers Prev 2008;17(10):2625–31 To investigate the effects of pregnancy on folate metabolism , we conducted an 84-d study in second-trimester ( gestational wk 14 - 25 ) pregnant women ( n = 6 ) and nonpregnant controls ( n = 6 ) with stable-isotopic tracer methods . All subjects were fed a diet containing approximately 272 nmol/d ( 120 microg/d ) folate from food , along with supplemental folic acid that contained 15 % [ 3',5'-(2)H(2 ) ] folic acid ( [(2)H(2)]folic acid ) during d 1 - -41 and that was unlabeled during d 42 - -84 to yield a constant total folate intake of 1.02 or 1.93 micromol/d ( 450 or 850 microg/d ) . Isotopic enrichment of plasma folate , urinary folate and the urinary folate catabolites para-aminobenzoylglutamate ( pABG ) and para-acetamidobenzoylglutamate ( ApABG ) was determined at intervals throughout the study . The labeling of pABG and ApABG reflected that of tissue folate pools from which the catabolites originate . After the intake of labeled folic acid was terminated on d 41 , labeling of urinary folate exhibited a biphasic exponential decline with distinct fast and slow components . In contrast , during d 42 - -84 , the enrichment of urinary pABG and ApABG exhibited primarily monophasic exponential decline , and plasma folate underwent little decline of labeling during this period . Pregnant women and controls did not differ in estimates of body folate pool size and most aspects of the excretion of labeled urinary folate and catabolites , rates of decline of excretion , and areas under the curves for folate and catabolite excretion . Pregnant women , however , tended to have a slower rate of decline of pABG than ApABG and higher enrichment at d 42 of ApABG and pABG . These data support and extend our previous findings indicating that pregnancy ( gestational wk 14 - -26 ) causes subtle changes in folate metabolism but does not elicit substantial increases in the rate or extent of folate turnover at these moderately high folate intakes BACKGROUND Previously we showed that women in rural Nepal experience multiple micronutrient deficiencies in early pregnancy . OBJECTIVE This study examined the effects of daily antenatal micronutrient supplementation on changes in the biochemical status of several micronutrients during pregnancy . DESIGN In Nepal , we conducted a r and omized controlled trial in which 4 combinations of micronutrients ( folic acid , folic acid + iron , folic acid + iron + zinc , and a multiple micronutrient supplement containing folic acid , iron , zinc , and 11 other nutrients ) plus vitamin A , or vitamin A alone as a control , were given daily during pregnancy . In a sub sample of subjects ( n = 740 ) , blood was collected both before supplementation and at approximately 32 wk of gestation . RESULTS In the control group , serum concentrations of zinc , riboflavin , and vitamins B-12 and B-6 decreased , whereas those of copper and alpha-tocopherol increased , from the first to the third trimester . Concentrations of serum folate , 25-hydroxyvitamin D , and undercarboxylated prothrombin remained unchanged . Supplementation with folic acid alone or folic acid + iron decreased folate deficiency . However , the addition of zinc failed to increase serum folate , which suggests a negative inhibition ; multiple micronutrient supplementation increased serum folate .  Folic acid + iron + zinc failed to improve zinc status but reduced sub clinical infection .  Multiple micronutrient supplementation decreased the prevalence of serum riboflavin , vitamin B-6 , vitamin B-12 , folate , and vitamin D deficiencies but had no effect on infection . CONCLUSIONS In rural Nepal , antenatal supplementation with multiple micronutrients can ameliorate , to some extent , the burden of deficiency . The implication s of such biochemical improvements in the absence of functional and health benefits remain unclear OBJECTIVE The objective of the study was to assess whether folic acid intake during the first trimester of pregnancy is related to  asthma in the offspring by the age of 6 years . STUDY DESIGN This was a prospect i ve cohort study of 1499 women who were followed up from the first trimester of pregnancy . Their children were followed up until they were 6 years old . RESULTS Fifty-one percent of the women used folic acid in the month before conception and 88 % in the third month of pregnancy . The adjusted odds ratio for asthma per 100 μm increase in the average daily intake of folic acid was 0.98 ( 95 % confidence interval , 0.93 - 1.04 ) . For categories of daily folate intake , there was no evidence of associations with childhood asthma or evidence of any dose response relation for any time period ( all P(trend ) > .05 ) . CONCLUSION Our results do not support any association of folic acid supplementation in pregnancy and asthma risk in offspring by age 6 years Maternal nutrient intake during pregnancy and lactation potentially influences the development of allergic diseases . Cows ' milk allergy ( CMA ) is often the first manifestation of atopic diseases , but the impact of early nutritional influences on CMA has not been explored . The associations between maternal intakes of folate , folic acid and vitamin D during pregnancy and lactation were addressed in a prospect i ve , population -based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study . Mothers of 4921 children during pregnancy and 2940 children during lactation provided information on maternal dietary intake during the 8th month of pregnancy and the 3rd month of lactation using a detailed , vali date d FFQ . Information on diagnosed CMA in the offspring was obtained from a medical registry as well as queried from the parents . The Finnish food composition data base was used to calculate nutrient intake . Logistic regression was applied for statistical analyses .  Folate intake and folic acid and vitamin D supplement  use were associated with an increased risk of CMA in the offspring , whereas vitamin D intake from foods during pregnancy was associated with a decreased risk of CMA . Thus , maternal nutrient intake during pregnancy and lactation may affect the development of CMA in offspring . Supplementation with folic acid may not be beneficial in terms of CMA development , especially in children of allergic mothers . The association between dietary supplement use and CMA risk can at least partly be explained by increased health-seeking behaviour among more educated mothers who also use more dietary supplements The effect of 250 μg folic acid (FA)/day or placebo given to 21 small-for-gestational-age infants born at term was studied during the first 3 months of life . The design of the study was double blind with r and om allocation . No r and omization was performed in respect of breast-feeding or formula-feeding with a folate content of 60–70 μg/l . No significant differences were observed in haemoglobin concentration , haematocrit , weight and length between FA-supplemented and non-supplemented infants . A negative correlation was demonstrated between gestational age and erythrocyte folate ( E-folate ) concentration at 1 week . E-folate content was higher when no supplement was given in breast-fed than in formula-fed infants 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 OBJECTIVE To estimate folate intake and knowledge in women of childbearing age , in relation to risk of neural tube defects . SUBJECTS/ SETTING One hundred forty-eight women ( aged 18 to 45 years ) in the Vancouver area of British Columbia , Canada . DESIGN Using an interviewer-administered survey , we examined women for folate knowledge and the relation of folate knowledge to intake in a r and om sample . Contribution of folate from food , fortified grain products , and supplements was assessed by vali date d semiquantitative food frequency question naire . STATISTICAL ANALYSIS PERFORMED Descriptive statistics , t tests , Chi;(2 ) , Pearson correlation analysis . RESULTS Mean daily folate intake from food , fortified foods , and supplementation was 812+/-710 Dietary Folate Equivalents (DFE)/day . Fortification of bread and grain products contributed 104+/-68 microg synthetic folic acid (SFA)/day ( equal to 174+/-114 DFE ) , and supplements contributed 205+/-388 microg SFA/day . Although 86 % of women met the Estimated Average Requirement ( 320 DFE/day ) for folate , only 26 % met the recommendation ( 400 microg SFA/day ) for women capable of becoming pregnant . Most ( 95 % ) of the women had heard of folate , but only 25 % knew that it could prevent birth defects . One-fourth of the women had good or very good knowledge of folate-rich foods . However , folate knowledge was not related to its intake . The most common sources of folate information were magazines/newspapers , doctors , and television/radio . Lack of awareness of the importance of folate was the most common reason given for choosing not to use folic acid supplements before pregnancy . However , 78 % of the women indicated that , with knowledge of the benefits of folate , they would use supplemental folic acid daily to reduce the risk of birth defects . APPLICATIONS/ CONCLUSIONS Educational strategies are required to increase folate awareness among women and to promote the benefits of periconceptional folic acid supplementation . Targeting physicians to educate women on the importance of folate could be a potentially successful route . We examined the influence of folate intake from diet and supplements b y 28 wk of gestation and third trimester circulating concentrations of serum folate on the outcome of pregnancy in women from Camden , NJ . Mean daily folate intake by week 28 included both dietary and supplemental folate obtained prospect ively in 832 women . Circulating concentrations of serum folate as well as serum vitamin B-12 were assayed at 28 wk of gestation ( + /- 2 wk ) by radioimmunoassay . The outcomes of interest included preterm delivery ( < 37 wk ) and  infants with low birth weight ( < 2500 g ) . Mean folate intake was significantly correlated with circulating concentrations of serum folate ( r=0.17 , P<0.001 ) . Women with a low mean daily folate intake ( < /-240 microgram/d ) had an approximately twofold greater risk of preterm delivery and infant low birth weight after maternal characteristics , energy intake , and other correlated nutrients were controlled for . Lower concentrations of serum folate at week 28 were also associated with a greater risk of preterm delivery and low birth weight Epidemiologic data suggest that increasing folate intake may protect against  colorectal cancer .  Riboflavin may interact with folate to modulate the effect . A double-blind r and omized placebo-controlled intervention study ( the FAB2 Study ) was carried out in healthy controls and patients with colorectal polyps ( adenomatous and hyperplastic ) to examine effects of folic acid and riboflavin supplements on biomarkers of nutrient status and on putative biomarkers of colorectal cancer risk ( DNA methylation and DNA damage ; to be reported elsewhere ) . Ninety-eight healthy controls and 106 patients with colorectal polyps were stratified for the thermolabile variant of methylene tetrahydrofolate reductase , MTHFR C677 T , and were r and omized to receive 400 μg of folic acid , 1,200 μg of folic acid , or 400 μg of folic acid plus 5 mg of riboflavin or placebo for 6 to 8 weeks . Blood sample s and colon biopsy sample s were collected for the measurement of biomarkers of folate and riboflavin status . Supplementation with folic acid elicited a significant increase in mucosal 5-methyl tetrahydrofolate , and a marked increase in RBC and plasma , with a dose-response . Measures of riboflavin status improved in response to riboflavin supplementation . Riboflavin supplement enhanced the response to low-dose folate in people carrying at least one T allele and having polyps . The magnitude of the response in mucosal folate was positively related to the increase in plasma 5-methyl tetrahydrofolate but was not different between the healthy group and polyp patients . Colorectal mucosal folate concentration responds to folic acid supplementation to an extent comparable to that seen in plasma , but with a suggestion of an upper limit . ( Cancer Epidemiol Biomarkers Prev 2007;16(10):2128–35 BACKGROUND The methylenetetrahydrofolate reductase ( MTHFR ) genotype is associated with modification of disease and risk of neural tube defects . Plasma and red blood cell ( RBC ) folate and plasma homocysteine concentrations change in response to daily intakes of folic acid supplements , but no large-scale or population -based r and omized trials have examined whether the MTHFR genotype modifies the observed response . OBJECTIVE We sought to determine whether the MTHFR 677C→T genotype modifies the response to folic acid supplementation during and 3 mo after discontinuation of supplementation . DESIGN Northern Chinese women of childbearing age were enrolled in a 6-mo supplementation trial of different folic acid doses : 100 , 400 , and 4000 μg/d and 4000 μg/wk  . Plasma and RBC folate and plasma homocysteine concentrations were measured at baseline ; after 1 , 3 , and 6 mo of supplementation ; and 3 mo after discontinuation of supplementation . MTHFR genotyping was performed to identify a C→T mutation at position 677 ( n = 932 ) . RESULTS Plasma and RBC folate and homocysteine concentrations were associated with MTHFR genotype throughout the supplementation trial , regardless of folic acid dose . MTHFR TT was associated with lower folate concentrations , and the trend of TT < CC was maintained at even the highest doses . Folic acid doses of 100 μg/d or 4000 μg/wk did not reduce high homocysteine concentrations in those with the MTHFR TT genotype . CONCLUSION MTHFR genotype was an independent predictor of plasma and RBC folate and plasma homocysteine concentrations and did not have a significant interaction with folic acid dose during supplementation . This trial was registered at clinical trials.gov as NCT00207558 Background Inadequate folate status has been associated with many negative reproductive outcomes , such as neural tube defects ( NTD ) , low birth weight and placental abruption . Aim of the study The objectives of this study were to evaluate the levels of dietary folate intake  during pregnancy in Japanese women and the subsequent birth weight of their babies . Methods A longitudinal prospect i ve study was conducted with 197 women with a singleton pregnancy in 2005 .  Dietary folate was investigated 3 times : in the first trimester at 12 weeks , in the second trimester at 20 weeks and in third trimester at 32 weeks using a diet history question naire ( DHQ ) . Non fasting blood sample s were collected from the women for measurement of homocysteine , hemoglobin , ferritin , unbound iron-binding capacity ( UIBC ) and total iron-binding capacity ( TIBC ) . Results Energy intake increased as pregnancy advanced , but not significantly . The daily intake of folate  increased from 248.5 ± 113.1 µg/d in the first trimester to 275.4 ± 100.2 µg/d in the third trimester ( P = 0.04 ) . This was well below the recommended level of 440 µg/d and only 10 % of mothers were above the levels . In the third trimester , plasma homocysteine concentration was significantly higher in the low folate group of less than 250 µg/d ( P = 0.02 ) , but not the first and second trimesters . Dietary folate intake and plasma homocysteine concentrations were not likely to be predictors of birth weight in our subjects . Conclusions Our study shows that Japanese women ’s energy and folate intakes do not meet their energy needs during pregnancy and are at an extremely low recommended dietary allowance level throughout pregnancy BACKGROUND Elevated plasma total homocysteine ( tHcy ) concentrations are associated with increased risk of vascular disease , and there is a strong inverse association between dietary and blood folate and blood tHcy concentrations . Increased folate consumption may lower the risk of tHcy-mediated cardiovascular disease . OBJECTIVES The objective was to determine the most appropriate means of increasing dietary folate to reduce plasma tHcy . DESIGN Sixty-five free-living subjects aged 36 - 71 y with tHcy concentrations > /=9 micromol/L participated in a r and omized , controlled trial to compare 3 approaches for increasing dietary folate to approximately 600 microg/d : folic acid supplementation , consumption of folic acid-fortified breakfast cereals , and increased consumption of folate-rich foods . RESULTS An intake of 437 microg folic acid/d from supplements result ed in a 27-nmol/L increase in serum folate and a 21 % reduction in tHcy , relative to the change in a control group . In subjects who consumed folic acid-fortified breakfast cereal , folate intake increased by an average of 298 microg , serum folate increased by 21 nmol/L , and tHcy concentrations decreased by 24 % . Increased intakes of folate-rich foods result ed in a 418-microg increase in dietary folate , a 7-nmol/L increase in serum folate , and a 9 % reduction in tHcy concentrations . The decrease in tHcy was negatively correlated ( r = -0.66 ) with the increase in serum folate . CONCLUSIONS Daily consumption of folic acid-fortified breakfast cereals and the use of folic acid supplements appear to be the most effective means of reducing tHcy concentrations . The reduction in tHcy was significantly negatively correlated with the increase in serum folate , which may be a useful marker for measuring dietary change Since the publication of r and omised trials showing firm evidence of prevention of neural tube defects with periconceptional folic acid , there have been population health promotion programmes to encourage women to take folic acid supplements , and the introduction of voluntary fortification of some foods with folic acid in Australia . In order to evaluate these two strategies , we collected data by self-administered question naire from a r and om sample of recently pregnant women in Western Australia between September 1997 and March 2000 .  Response to health promotion was measured in three ways : ( 1 ) knowledge of the association between periconceptional folate and prevention of spina bifida ( the ' correct message ' ) ; ( 2 ) use of periconceptional vitamin supplements of folic acid daily in the periconceptional period ; and ( 3 ) daily folate intake from fortified foods in the 6 months before pregnancy . We examined the relationship of maternal demographic and behavioural characteristics with these three measures . Overall , 62.3 % of women were aware of the correct message before pregnancy , 28.5 % reported taking 200 microg or more of folic acid from supplements daily in the periconceptional period and 56.6 % of women obtained 100 microg or more of folic acid from fortified foods . Women who first became aware of the correct message during pregnancy or who were unaware of the correct message before or during pregnancy were more likely than women aware before pregnancy to be younger , having their first pregnancy , be single or in a de facto relationship , have no tertiary education , and be a public patient . Similar associations were seen for women taking either no folic acid or < 200 microg of folic acid in supplements daily in the periconceptional period . There were no significant associations between these demographic variables and amount of folate obtained from fortified foods . Women who were unaware of the correct message and did not take folic acid supplements were more likely to have smoked , not to have engaged in exercise , and not to have planned their pregnancy , whereas there was no association with these behavioural characteristics and intake of folate from fortified foods . These results indicate that health promotion strategies have not reached all segments of the target population equally , but there is no such disparity with folate-fortified foods , and they suggest that m and atory fortification of a staple food is likely to reach all women regardless of demographic and behavioural characteristics , and hence provide improved opportunity for prevention of neural tube defects in Australia The relationship of folate status and polyphenol intake to thiamin status was studied in 80 r and omly selected elderly and young Irish women , with key variables affecting thiamin nutrition controlled for .  Folate , thiamin , and polyphenol intakes  were measured during a 4-wk baseline ( elderly and young ) and 6-wk double-blind ( elderly ) supplementation period . Only elderly subjects were r and omly assigned to placebo , folic acid ( 400 micrograms ) , thiamin ( 10 mg ) , or folic-acid-plus-thiamin groups .  Thiamin status ( TPP effect ) was not affected by folate status ( plasma and erythrocyte folate ) during the baseline period or with folic acid supplementation alone . Polyphenol intake was not correlated with thiamin status . Only thiamin intake and thiamin supplementation significantly affected thiamin status . Because the majority of subjects ( 102 of 160 ) were initially thiamin deficient , enrichment of Irish grain products with thiamin is recommended Low folate status increases colorectal cancer risk . Paradoxically , overly abundant folate supplementation , which is not uncommon in the United States , may increase risk . The mechanisms of these effects are unknown . We conducted two translational studies to define molecular pathways in the human colon altered either by folate supplementation or by dietary folate depletion ( followed by repletion ) . In the first study , 10 healthy , at-risk volunteers ( with documented stable/normal folate intake ) received supplemental folic acid ( 1 mg/d ) for 8 weeks . In the second study , 10 similar subjects were admitted to a hospital as in patients for 12 weeks to study folate depletion induced by a low folate diet . A repletion regimen of folic acid ( 1 mg/d ) was provided for the last 4 of these weeks . Both studies included an 8-week run-in period to ensure stabilized folate levels prior to intervention . We obtained 12 rectosigmoid biopsies ( from 4 quadrants of normal-appearing mucosa 10–15 cm from the anal verge ) at baseline and at measured intervals in both studies for assessing the primary endpoints : genome-wide gene expression , genomic DNA methylation , promoter methylation ( depletion/repletion study only ) , and p53 DNA str and breaks . Serum and rectosigmoid folate concentrations accurately tracked all changes in folate delivery ( P < 0.05 ) . In the first study , gene array analysis revealed that supplementation upregulated multiple inflammation- and immune-related pathways in addition to altering several 1-carbon – related enzymes ( P < 0.001 ) . In the second study , folate depletion downregulated genes involved in immune response , inflammation , the cell cycle , and mitochondrial/energy pathways ; repletion reversed most of these changes . However , changes in gene expression after repletion in the second study ( involving immune response and inflammation ) did not reach the levels seen after supplementation in the first study . Neither genomic nor promoter-specific DNA methylation changed during the course of the depletion/repletion protocol , and genomic methylation did not change with supplementation in the first study . p53 DNA str and breaks increased with depletion after 12 weeks . In sum , depletion downregulates , whereas repletion or supplementation upregulates pathways related to inflammation and immune response . These findings provide novel support to the concept that excessive folate supplementation might promote colorectal carcinogenesis by enhancing proinflammatory and immune response pathways . These results indicate that modest changes in folate delivery create substantial changes in the molecular milieu of the human colon . Cancer Prev Res ; 4(4 ) ; 530–43 . © 2011 AACR Many studies have demonstrated the efficacy of folic acid ( FA ) supplementation in prevention of neural tube defects ( NTDs ) , although the extent of NTDs varies among individuals of different races and ethnic origin . China is a multi-ethnic country with no st and ard practice for FA-fortified food . Milk is consumed by women , but little is known about the effects of milk on folate concentration in maternal blood and neonatal umbilical cord blood in Han and Mongolian women after stopping taking the supplement for a month and five month , respectively . The objective of this study was to determine whether only daily consumption of liquid milk can increase the blood folate concentration in pregnant women and whether there are differences in blood folate concentrations between Han and Mongolian women after cessation of FA supplementation . Of the 4052 women enrolled in the parallel group design study . Three thous and five hundred and twenty-six women had confirmed pregnancies and were r and omized to receive liquid milk or not until delivery . Women who consumed the liquid milk had significantly increased serum folate concentrations at 16 and 32 weeks of gestation as well as cord blood at birth compared to control groups in both ethnic groups . Infants born to women drinking milk also had better the term birth weight and height , which may be related to the increased concentration of folate . In conclusion , daily consumption of milk can increase the serum folate concentration in pregnant Han and Mongolian women in China ( differences in the efficacy of FA and milk supplementation ) and may enhance birth outcomes Objective To determine an optimal population red blood cell ( RBC ) folate concentration for the prevention of neural tube birth defects . Design Bayesian model . Setting Data from two population based studies in China . Participants 247 831 participants in a prospect i ve community intervention project in China ( 1993 - 95 ) to prevent neural tube defects with 400 μg/day folic acid supplementation  and 1194 participants in a population based r and omized trial ( 2003 - 05 ) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age . Intervention Folic acid supplementation ( 400 μg/day ) . Main outcome measures Estimated RBC folate concentration at time of neural tube closure ( day 28 of gestation ) and risk of neural tube defects . Results Risk of neural tube defects was high at the lowest estimated RBC folate concentrations ( for example , 25.4 ( 95 % uncertainty interval 20.8 to 31.2 ) neural tube defects per 10 000 births at 500 nmol/L ) and decreased as estimated RBC folate concentration increased . Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L ( for example , 6 neural tube defects per 10 000 births at 1180 ( 1050 to 1340 ) nmol/L ) . The modeled dose-response relation was consistent with the existing literature . In addition , neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid . Conclusions A threshold for “ optimal ” population RBC folate concentration for the prevention of neural tube defects could be defined ( for example , approximately 1000 nmol/L ) . Population based RBC folate concentrations , as a biomarker for risk of neural tube defects , can be used to facilitate evaluation of prevention programs as well as to identify sub population s at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency Folic acid administered to pregnant Bantu , whose diet is low in folate , was associated with a significant reduction in the incidence of prematurity . No such effect could be demonstrated in White patients subsisting on an average Western diet . This suggests that folate deficiency may contribute to the “ pregnancy wastage ” in population s whose dietary folate intake is low , and is a further indication for folic acid supplementation during pregnancy in these groups OBJECTIVE To study the effect of multivitamin and folic acid supplementation on serum folate level and weight gain . MATERIAL AND METHOD A prospect i ve r and omized controlled study was conducted in malnourished children at the Nutrition Clinic , Queen Sirikit National Institute of Child Health from February to June 2000 . History taking , weight-height measurement , and blood testing for complete blood count ( CBC ) and serum folate level were done . Patients were r and omly by assigned into 2 groups . The study group was supplemented daily with multivitamins ( MVD ) along with a folic acid tablet while the control group was supplemented daily with MVD only , for 6 weeks . RESULTS Twenty-nine malnourished children were enrolled in the present study . They were r and omly by assigned into 2 groups , 14 children in the study group and 15 children in the control group . There were 11 boys ( 38 % ) and 18 girls ( 62 % ) . Mean age was 36.3 months .  Anemia and low serum folate level were found in 24 per cent and 21 per cent respectively . There was no significant difference in the data of both groups , except that anemia was more common in the study group ( p = 0.018 ) . After 6 weeks of supplementation , increases in weight and serum folate level were significantly higher in the study group , but there was no significant difference in weight increased between both groups . CONCLUSION Folate deficiency may be found in malnourished children . Efficacy of folic acid supplement is good . Folic acid needs to be supplemented in malnourished children OBJECTIVES To evaluate a South Australian campaign to promote and implement knowledge that taking adequate folate/folic acid in the periconceptional period can reduce the risk of having a baby with a neural tube defect . DESIGN AND SETTING The campaign , conducted in October 1994 - -August 1995 , targeted women of reproductive age and health professionals . Evaluation was by computer-assisted telephone interviews undertaken by r and om dialling throughout the State before and after the campaign , and by self-administered question naires to health professionals and women in the postnatal period . PARTICIPANTS Women of reproductive age and four groups of health professionals . MAIN OUTCOME MEASURES Knowledge about folate , folate-rich foods and the periconceptional period ; participation of health professionals in advising women about folate ; use of periconceptional folic acid supplements ; sales of folic acid tablets ; and prevalence of neural tube defects . RESULTS Significant increases in knowledge about folate followed the campaign . Health professionals and women in the postnatal period had higher initial levels of knowledge about folate , which also increased significantly . The proportions of women taking periconceptional folic acid supplements  , and of health professionals advising women planning a pregnancy about folate , also increased significantly , and folic acid tablet sales doubled . Total prevalence of neural tube defects declined between 1966 and 1999 from a baseline of 2.0 per 1,000 births to 1.1 per 1,000 births ( Poisson regression , P= 0.03 ; average decline of 1.0 % per year ) . CONCLUSIONS A short educational campaign with a limited budget ( $ 40,000 ) can promote folate successfully , but alternative strategies such as food fortification are likely to be needed to achieve adequate periconceptional folate intake for a very high proportion of women Poor nutrient intake during pregnancy can adversely affect both infant and maternal health . The aim was to investigate the efficacy of multiple-micronutrient supplementation during pregnancy in a socially deprived population in the developed world . We conducted a r and omised , double-blind , placebo-controlled trial of multiple-micronutrient supplementation including 20 mg Fe and 400 microg folic acid , from the first trimester of pregnancy in 402 mothers , in East London , UK .  Nutrient status was measured at recruitment , and at 26 and 34 weeks of gestation . Infants were weighed at birth . At recruitment the prevalence of anaemia was 13 % , vitamin D insufficiency 72 % , thiamin deficiency 12 % and folate deficiency 5 % , with no differences between groups . Only 39 % of women completed the study ; rates of non-compliance were similar in both groups . Intention-to-treat analysis showed that participants receiving treatment had higher mean Hb at 26 weeks of gestation ( 110 ( sd 10 ) v.108 ( sd 10 ) g/l ; P = 0.041 ) and 34 weeks of gestation ( 113 ( sd 12 ) v.109 ( sd 10 ) g/l ; P = 0.003 ) and packed cell volume concentrations at 26 weeks of gestation ( 0.330 ( sd 0.025 ) v. 0.323 ( sd 0.026 ) l/l ; P = 0.011 ) and 34 weeks of gestation ( 0.338 ( sd 0.029 ) v. 0.330 ( sd 0.028 ) l/l ; P = 0.014 ) compared with controls . Analysis of compliant women showed supplemented women had higher median concentrations of serum ferritin , erythrocyte folate and 25-hydroxyvitamin D later in gestation than controls . In the compliant subset ( n 149 ) , placebo mothers had more small-for-gestational age ( SGA ) infants ( eight SGA v. thirteen ; P = 0.042 ) than treatment mothers . Baseline micronutrient deficiencies were common ; the multiple-micronutrient supplement was well-tolerated and improved nutrient status .  Multiple-micronutrient supplements from early pregnancy may be beneficial and larger studies are required to assess impact on birth outcomes and infant development
In contrast , we did not find any beneficial effect of  folate supplementation on placental weight or on length of gestation .
There is a paucity of well-conducted RCTs investigating the effect of  folate supplementation on health outcomes in pregnancy .
The beneficial effect of folic acid supplementation before and shortly after conception is well recognized , whereas the effect of supplementation during the second and third trimesters is controversial and poorly documented .
Our aims were to systematic ally review r and omized controlled trials ( RCTs ) investigating the effect of folate supplementation on birth weight , placental weight and length of gestation and to assess the dose – response relationship between folate intake ( folic acid plus dietary folate ) and health outcomes .