Effect of supplementation with folic acid throughout pregnancy on plasma homocysteine concentration. Effect of folic acid supplementation on small-for-gestational-age infants born at term Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. Effect of time of initiation and dose of prenatal iron and folic acid supplementation on iron and folate nutriture of Korean women during pregnancy. Fortification of flour with folic acid 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. Neither Preconceptional Weekly Multiple Micronutrient nor Iron-Folic Acid Supplements Affect Birth Size and Gestational Age Compared with a Folic Acid Supplement Alone in Rural Vietnamese Women: A Randomized Controlled Trial. Effects of once-a-week or daily folic acid supplementation on red blood cell folate concentrations in women Micronutrient supplementation and pregnancy outcomes: double-blind randomized controlled trial in China. Promotion of folate for the prevention of neural tube defects: who benefits? Periconceptional multivitamin folic acid use, dietary folate, total folate and risk of neural tube defects in South Carolina. OS040. Effect of folic acid supplementation in pregnancy on preeclampsia- Folic acid clinical trial (FACT). A randomised trial of low dose folic acid to prevent neural tube defects. The Irish Vitamin Study Group. "Folate before pregnancy": the impact on women and health professionals of a population-based health promotion campaign in South Australia. Reduction of Incidence of Prematurity by Folic Acid Supplementation in Pregnancy 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. Knowledge and Clinical Practice Regarding Folic Acid Among Obstetrician‐Gynecologists
It is well established that folic acid supplementation in early pregnancy significantly reduces the incidence of neural tube defects ( NTDs ) [ 1 ] . Consistent with national guidelines [ 2 ] , it is current practice in the UK to advise pregnant women to take folic acid supplementation until 12 weeks gestation . A recent report , however , suggests that supplementation with folic acid throughout pregnancy may effect a reduction in adverse pregnancy outcomes [ 3 ] , although this is not yet confirmed . If folic acid supplementation throughout pregnancy led to a reduction in such outcomes , it would be a safe , simple , and inexpensive therapeutic intervention 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 A r and omized controlled double-blind trial was undertaken in south Wales to prevent the recurrence of  neural-tube defects in women who had had one child with a neural-tube defect . Sixty women were allocated before conception to take 4 mg of folic acid a day before and during early pregnancy and 44 complied with these instructions . Fifty-one women were allocated to placebo treatment . There were no recurrences among the compliant mothers but two among the non-compliers and four among the women in the placebo group . Thus there were no recurrences among those who received supplementation and six among those who did not ; this difference is significant ( p = 0.04 ) . It is concluded that folic acid supplementation might be a cheap , safe , and effective method of primary prevention of neural-tube defects but that this must be confirmed in a large , multicentre trial 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 Thirty three years ago Hibbard and Smithells linked folate deficiency in pregnancy with neural tube defects.1 Smithells then led a series of observational and intervention studies which showed that improving folic acid status early in the pregnancy of mothers who had previously had a child with neural tube defects reduced the recurrence in that pregnancy.2 A r and omised trial by Britain 's Medical Research Council confirmed that finding3 and a Hungarian trial showed a reduction in the first occurrence too . 4 To reach almost all women in the very early stages of pregnancy , when few would be sure they were pregnant , folic acid fortification of a staple food has been advocated , and a Department of Health committee has now recommended universal fortification of flour in the United Kingdom . Though the benefits are clear , the possible harms of such a policy are not . We need to be cautious in implementing a universal policy . After the initial British and Hungarian studies several others gave mostly similar results . 5 6 As a result a campaign led by the Health Education Authority in the UK aim ed to improve folate status from before conception to 12 weeks of pregnancy by increasing folic acid intake from foods and supplements . A third of 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 Maternal nutritional status before and during early pregnancy plays a critical role in fetal growth and development . The benefits of periconception folic acid ( FA ) supplementation in the prevention of neural tube defects is well recognized , but the evidence for preconception micronutrient interventions for improving pregnancy outcomes is limited . OBJECTIVE This study aim ed to evaluate whether preconception supplementation with weekly iron and folic acid ( IFA ) or multiple micronutrients ( MMs ) improves birth outcomes compared with FA alone . METHODS We recruited 5011 women of reproductive age in a double-blind , r and omized controlled trial in Vietnam and provided weekly supplements containing either 2800 μg FA , 60 mg Fe and 2800 μg FA ( IFA ) , or the same amount of FA and iron plus other MMs until they conceived ( n = 1813 ) . All pregnant women received daily IFA through delivery , and were followed up for birth outcomes , including birth weight , gestational age , preterm delivery and small for gestational age ( SGA ) . Group comparisons were done with the use of ANOVA or chi-square tests for both intention-to-treat ( n = 1599 ) and per- protocol analyses ( women consumed supplements ≥26 wk before conception ; n = 824 ) . Effect modification by baseline underweight or anemia status was tested with the use of generalized linear models . RESULTS The mean age of the women was 26 y , 30 % were underweight , and < 10 % were nulliparous . The groups were similar for most baseline characteristics . The mean ± SD duration of the preconception intervention was 33 ± 25 wk and compliance was high ( > 90 % ) . Infants born to the 3 groups of women did not differ ( P ≥ 0.05 ) on mean ± SD birth weight ( 3076.8 ± 444.5 g ) or gestational age ( 39.2 ± 2.0 wk ) , or prevalence of SGA ( 12 % ) , low birth weight ( 5 % ) and preterm delivery ( 10 % ) . There were no significant differences in women who consumed supplements ≥26 wk before conception or by baseline underweight or anemia . CONCLUSION Weekly supplementation with MMs or IFA before conception did not affect birth outcomes compared with FA in rural Vietnamese women . The trial was registered at clinical trials.gov as NCT01665378 Objective : Our aim was to determine if a once-a-week folic acid supplement increases women 's red blood cell folate to concentrations ( > 905 nmol/l ) that are associated with a low risk of bearing a child with a neural tube defect . Design : R and omized control trial . Setting : General community . Subjects : In total , 114 nonpregnant women ( 18–40 y ) volunteers , with red blood cell folate concentrations between 295 and 905 nmol/l at screening . Interventions : Women were r and omized to receive a once-a-week 2800 μg folic acid supplement , a daily 400 μg folic acid supplement or a daily placebo for 12 weeks . Results : The mean ( 95 % CI ) red blood cell folate concentrations increased during the 12-week intervention from 608 ( 553–668 ) to 900 ( 828–978 ) in the weekly folic acid group ( P<0.05 ) and from 615 ( 560–677 ) to 1053 ( 957–1158 ) nmol/l in the daily group ( P<0.05 ) during the trial . At week 12 , 49 % of women ingesting the weekly folic acid supplement had red blood cell folate concentrations greater than 905 nmol/l compared to 74 % of women ingesting the daily supplement . Conclusions : A once-a-week 2800 μg folic acid supplement can increase women 's red blood cell folate to concentrations associated with a reduced risk of bearing a child with a neural tube defect , but is less effective than a 400 μg daily supplement . Use of a weekly folic acid supplement over at least 12 weeks before conception by women of child-bearing age may prevent neural tube defects . Funding : The Otago Medical Research Foundation ( Laurenson Award ) . Healtheries ( New Zeal and ) provided the supplements BACKGROUND Beyond perinatal folic acid supplementation , the need for additional prenatal prophylaxis of iron with or without other micronutrients remains unclear . We aim to investigate the maternal and infant health effects of iron plus folic acid and multiple micronutrient supplements vs folic acid alone when provided to pregnant women with no or mild anemia . METHODS In this r and omized double-blind controlled trial , 18,775 nulliparous pregnant women with mild or no anemia were enrolled from 5 counties of northern China from May 2006 through April 2009 . Women were r and omly assigned to daily folic acid ( 400 μg ) ( control ) , folic acid-iron ( 30 mg ) , or folic acid , iron , and 13 additional vitamins and minerals provided before 20 weeks gestation to delivery . Primary outcome was perinatal mortality . Secondary outcomes included neonatal and infant mortality , preterm delivery , birth weight , birth length , gestational duration , and maternal hemoglobin concentration and anemia . RESULTS A total of 92.7 % of women consumed 80 % to 100 % of supplements as instructed . On average , women consumed 177 supplements . Compared with daily prenatal folic acid , supplementation with iron-folic acid with or without other micronutrients did not affect the rate of perinatal mortality ( 8.8 , 8.7 , and 8.3 , respectively ) per 1000 births , and relative risks ( RRs ) were 1.00 ( 95 % CI , 0.68 - 1.46 ; P = .99 ) and 0.94 ( 95 % CI , 0.64 - 1.39 ; P = .76 ) , respectively . Risk of other adverse maternal and infant outcomes also did not differ , except that RRs for third-trimester maternal anemia were 0.72 ( 95 % CI , 0.63 - 0.83 ; P < .001 ) and 0.71 ( 95 % CI , 0.62 - 0.82 ; P < .001 ) , respectively . CONCLUSION Prenatal iron-folic acid and other micronutrient supplements provided to Chinese women with no or mild anemia  prevented later pregnancy anemia beyond any benefit conferred by folic acid alone but did not affect perinatal mortality or other infant outcomes . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00133744 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 PURPOSE To investigate whether dietary folate or multivitamin folic acid taken 3 months before conception and during the first 3 months of pregnancy reduces the risk of isolated occurrent neural tube defect (NTD)-affected pregnancies . METHODS This population -based case control study conducted between 1992 and 1997 included 179 women with NTD-affected pregnancies and 288 r and omly selected controls . Women completed a food frequency question naire and were interviewed about lifestyle behaviors , pregnancy histories and use of multivitamins . RESULTS Use of 0.4 mg or more of multivitamin folic acid at least 3 times per week during the periconceptional period showed no statistically significant reduction in NTD risk [ adjusted odds ratio ( AOR ) = 0.55 , 95 % confidence interval ( CI ) = 025 , 1.22 ] . After adjusting for covariates , protective effects for NTDs were observed at the highest quartiles of  dietary folate  and  total folate  ( daily dietary folate plus daily multivitamin folic acid ) ; the respective odds ratios were 0.40 ( 95 % CI = 0.19 , 0.84 ) and 0.35 ( 95 % CI = 0.17 , 0.72 ) . CONCLUSIONS This study illustrates some of the difficulties in determining effects of folic acid and dietary folate in a population where the consumption of foods rich in folate and the use of multivitamins are increasing and the rate of NTDs is declining . Studies are needed to monitor future changes in folate levels and their effect on health INTRODUCTION Observational studies suggest that folic acid supplementation during pregnancy can reduce the risk of preeclampsia ( PE ) . No r and omized controlled trial has been conducted to demonstrate the effect of folic acid supplementation on PE . OBJECTIVES FACT aims to determine efficacy on a new PE prevention strategy of high dose folic acid supplementation from early pregnancy ( 8(0/7 ) to 16(6/7)weeks of gestation ) until delivery in women with high risk of developing PE . METHODS DESIGN FACT is an international , multi-centre , double-blind , placebo controlled clinical trial of 3656 women . Eligible women will be r and omised in a 1:1 ratio to folic acid 4.0 mg or placebo .  POPULATION Pregnant women ( 8(0/7 ) and 16(6/7 ) weeks of gestation ) ⩾18 years of age , taking ⩽1.1 mg of folic acid supplementation  who fulfill at least one of the following identified risk factors for PE  .  Pre-existing hypertension  ( blood pressure ⩾90mmHg on two separate occasions or at least 4h apart prior to r and omization , or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to r and omization ) , pre-pregnancy diabetes ( Type I or Type II DM ) , twin pregnancy , history of PE in a previous pregnancy , BMI ⩾35kg/m(2 ) within 3 months prior this pregnancy or during the first trimester of this pregnancy . PRIMARY OUTCOME PE is defined as blood pressure ⩾d90mmHg on two occasions ⩾4 h apart and proteinuria developed in women greater than 20 weeks of gestation . Or HELLP ( Haemolysis , Elevated , Liver Enzymes , Low Platelets ) syndrome Or superimposed PE , defined as history of pre-existing hypertension ( diagnosed pre-pregnancy or before 20 weeks ' gestation ) with new proteinuria . Proteinuria is defined as : Analysis plan : Intent-to-Treat ( ITT ) population will be analyzed . Chi-square test will be used in the comparison of incidence of PE between the intervention and placebo groups for analysis of the primary outcome . RESULTS The Ottawa Hospital r and omized the first FACT subject in April 2011 . As of February 29th , 2012 , 62 subjects have been r and omized . There are currently 18 Canadian sites participating in FACT , of which 10 are actively recruiting and 8 are pending site activation . Internationally , Argentina , Australia and the United Kingdom are anticipating first recruits in the late spring of 2012 . Israel and Holl and are expected to begin enrolment as early as the fall of 2012 . CONCLUSION Recruitment is on target and expected to end August 2014 . Results from this large scale trial will provide a definitive answer to the important question whether folic acid supplementation can prevent PE A r and omised trial was initiated in Irel and in 1981 to determine if periconceptional supplementation with either folic acid alone or a multivitamin preparation alone could reduce the recurrence risk of neural tube defects ( NTDs ) in women with a previously affected pregnancy from 5.0 % to 1.0 % or less . The trial was concluded before the initial target number of study subjects was reached and without a clear treatment effect being observed . A total of 354 women were r and omised to receive one of three treatments : folic acid , multivitamins without folic acid , and folic acid plus multivitamins . At the end of the trial 257 women had had a first trial pregnancy outcome ( 261 infants/fetuses ) where the presence or absence of NTDs was ascertainable . There was one NTD recurrence in the 89 infants/fetuses of women in the multivitamin group and no recurrence in the 172 infants/fetuses of women in the folic acid groups , a non-significant difference . Otherwise eligible women who were pregnant when first contacted constituted a non-r and omised control group ; there were three recurrences among the 103 infants in this group . The difference in the recurrence rate between the folic acid groups and the non-r and omised controls was statistically significant but we have reservations about the validity of this comparison . Although our findings do not provide clear evidence of a protective effect of folic acid supplementation they are consistent with those of the Medical Research Council ( MRC ) trial which demonstrated the efficacy of folic acid in preventing recurrence of NTDs and they raise the possibility that folic acid may be protective at a much lower dosage than that used in the MRC trial 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 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 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 assess obstetrician-gynecologists ' knowledge of and clinical practice concerning folate . Methods We mailed surveys on nutrition during pregnancy to the 230 ACOG Fellows who are members of the Collaborative Ambulatory Research Network and to a r and om sample of 800 Fellows who are not members of the Network . Our results focus on questions concerning folate . Results We analyzed 488 surveys ( a 47.4 % response rate ) . Approximately two thirds of respondents screen their pregnant patients for folate  intake . Fewer ( 53 % ) screen their nonpregnant patients of childbearing age . Those who screened their patients for folate intake were more likely to counsel pregnant patients about diet . They also were more likely to believe that nutritional counseling would improve pregnancy outcomes ( 70.0 % versus 56.5 % ) and overall patient health ( 77.5 % versus 66.5 % ) . Most Fellows were aware that macrocytic anemia was a manifestation of folate deficiency ( 90.4 % ) and that folic acid supplementation during preconception and the early prenatal period helps protect against neural tube defects ( 96.5 % ) . They were aware that alcoholics ( 91.4 % ) , smokers ( 61.3 % ) , and lactating women ( 53.5 % ) are at increased risk of folate deficiency . They were less aware of other consequences of low folate intake , such as increased serum homocysteine ( 20.3 % ) . Respondents who screen their pregnant patients for folate intake correctly answered more of the knowledge questions about folate than physicians who do not screen . Conclusion Obstetrician-gynecologists are generally aware of the link between folate intake and neural tube defects , but are less aware of other aspects of folate metabolism
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 .