Adherence and Costs of Micronutrient Supplementation in Pregnancy in a Double-Blind, Randomized, Controlled Trial in Rural Western China The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Folate supplements during pregnancy. Plasma folate level and high-dose folate supplementation predict sulfadoxine-pyrimethamine treatment failure in pregnant women in Western kenya who have uncomplicated malaria. Investigation of folic acid requirements in pregnancy. The effect of docosahexaenoic acid and folic acid supplementation on placental apoptosis and proliferation. Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial. Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking iron and folic Acid supplements. Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal. 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. Folate catabolism in pregnant and nonpregnant women with controlled folate intakes. Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal. [Deficiency of folates in pregnancy: effect of supplementary folic acid]. Biochemical assessment of nutritional status in pre- and post-natal Turkish women and outcome of pregnancy. PERICONCEPTIONAL MULTIVITAMIN USE IN RELATION TO THE RISK OF CONGENITAL URINARY TRACT ANOMALIES Prevention of congenital abnormalities by periconceptional multivitamin supplementation. Effects of topical and systemic folic acid supplementation on gingivitis in pregnancy. Effects of prenatal micronutrient supplementation on complications of labor and delivery and puerperal morbidity in rural Nepal. Comparison study on the effect of prenatal administration of high dose and low dose folic acid. A Randomized Controlled Trial of Folate Supplementation When Treating Malaria in Pregnancy with Sulfadoxine-Pyrimethamine Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow-up in a randomized, controlled community trial. The relationship between maternal dietary intake and infant birthweight. Study of the Haematological Effect of Profylactic Folic Acid Medicamentation in Pregnancy No effect of maternal micronutrient supplementation on early childhood growth in rural western China: 30 month follow-up evaluation of a double blind, cluster randomized controlled trial Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia Antenatal supplementation with folic acid + iron + zinc improves linear growth and reduces peripheral adiposity in school-age children in rural Nepal. Megaloblastic anaemia of pregnancy: a clinical and laboratory study with particular reference to the total and labile serum folate levels Effect of N-3 polyunsaturated fatty acid supplementation in pregnancy: the Nuheal trial. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. [Folic acid and pregnancy, a real problem?]. [Calcium folate in pregnancy. Therapeutic efficacy]. Effects of prenatal fish-oil and 5-methyltetrahydrofolate supplementation on cognitive development of children at 6.5 y of age. An Investigation of Folic Acid Requirements in Pregnancy. II Reduction of Incidence of Prematurity by Folic Acid Supplementation in Pregnancy Effect of supplementation with folic acid throughout pregnancy on plasma homocysteine concentration. Influence of fish oil or folate supplementation on the time course of plasma redox markers during pregnancy. The effect of maternal micronutrient supplementation on early neonatal morbidity in rural Nepal: a randomised, controlled, community trial Effects of extended systemic and topical folate supplementation on gingivitis of pregnancy. A prophylactic trial of iron and folic acid supplements in pregnant Burmese women. Folate Status Throughout Pregnancy and in Postpartum Period Anaemia of pregnancy in northern India. Nature and therapeutic follow-up. Low maternal vitamin B-12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal. OS040. Effect of folic acid supplementation in pregnancy on preeclampsia- Folic acid clinical trial (FACT).
Background Efforts to determine the impact of prenatal multivitamin supplementation on birth outcome have been carried out in several developing countries . A review of factors that would impact the effectiveness of prenatal supplementation under normal field conditions is currently lacking and will be required for exp and ed supplementation programs . An efficacy trial of a multiple micronutrient supplement for pregnant women was conducted in rural western China , and additional information on side effects , rates of adherence , program inputs , and cost was also gathered . Objectives To examine reports of side effects and rates of adherence to prenatal multiple micronutrient supplementation in comparison with supplementation with folic acid and with iron – folic acid , and to describe inputs and costs associated with prenatal supplementation in China . Methods A cluster-r and omized , double-blind , controlled trial was conducted in two rural counties in northwest China . All pregnant women in villages were r and omly assigned to take daily supplements of folic acid , iron – folic acid , or a recommended daily allowance of 15 vitamins and minerals from enrollment until delivery . Information was collected from the women on side effects and adherence . Program inputs and costs of supplementation were tracked . Descriptive statistics were used for the analysis . The biological effectiveness of prenatal multiple micronutrient supplements is reported elsewhere . Results Less than 4 % of women withdrew from the study because of side effects . Adherence to supplementation was high : the supplements were consumed on more than 90 % of the days on which they were available for consumption . The mean number of supplements consumed was high at 165 capsules , and about 40 % consumed the recommended 180 supplements during pregnancy . Conclusions High adherence to a prenatal supplement schedule can be achieved when mothers have frequent contact with trained health workers and a reliable supply of supplements Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid .  Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb .  Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF .  Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria In a controlled , prospect i ve trial , the effects of giving ferrous sulphate 50 mg daily to 76 pregnant women was compared with giving ferrous sulphate 50 mg daily plus folic acid 0.5 mg daily to 82 women in 12 general practice s in South-east Engl and .No differences in obstetric complications were found between the two groups , although the evidence of some of the listed complications may be too rare for detection in a sample of patients of this size UNLABELLED Sulfadoxine-pyrimethamine ( SP ) inhibits folate metabolism by the malaria parasite . We investigated the association between folate levels and SP failure in pregnant women . Data from a trial to assess the effect that folate supplementation has on SP failure in 467 pregnant women were analyzed . Plasma folate levels were determined at enrollment and at day 7 . High baseline folate levels , high parasite densities , and age < 20 years were risk factors for SP failure . High-dose ( 5 mg daily ) folate supplementation or high folate levels at day 7 were independent risk factors . Therefore , pregnant women receiving SP should receive low-/moderate-dose folate supplementation . TRIAL REGISTRATION http://www . clinical trials.gov identifier : NCT00130065 Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 The hypothesis was tested that the additional dietary uptake of n-3 fatty acids , in particular of DHA and 5-methyltetrahydrofolate ( 5-MTHF ) , during the second half of pregnancy would influence proliferation and apoptosis in the full-term human placenta . The diets of pregnant women from Spain ( n 55 ) were supplemented with modified fish oil and /or 5-MTHF or placebo , and assigned in a r and om , double-blind manner to one of the four groups . Immunohistochemistry and immunoblotting were used to detect placental proliferation and apoptosis with monoclonal antibodies for key proteins that reflected the extent of both processes : proliferation cell nuclear antigen ( PCNA ) , p53 , cytokeratin 18 neoepitope . The PCNA level in the fish oil/5-MTHF-treated group was higher by 66 % ( P < 0.05 ) than that of the placebo group , whereas the levels of p53 and cytokeratin 18 neoepitope were unaffected by treatment . PCNA expression was altered only in the trophoblast compartment ( placebo 11.1 ( se 0.5 ) % v. combination 21.5 ( se 1.2 ) % ; P < 0.05 ) , whereas the proportion of nuclei stained in endothelial and other stromal cells was similar in the placebo and combined treatment groups . No correlation was found between fish oil or 5-MTHF supplementation and the levels of the proteins . The present data suggest that supplementation with fish oil and /or 5-MTHF had no effect on the parameters reflecting placental proliferation and apoptosis . A defined combination of DHA and 5-MTHF may , however , affect placental proliferation Iron deficiency is one of the main causes of anemia during pregnancy , although other micronutrient deficiencies may play a role . We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on  maternal hematologic indicators  in a double-masked r and omized controlled community trial . Communities , called sectors , were r and omly assigned to supplementation with folic acid ( 400 microg ) , folic acid plus iron ( 60 mg ) , folic acid plus iron and zinc ( 30 mg ) and folic acid plus iron , zinc and 11 other micronutrients , each at the approximate recommended daily allowance for pregnancy all given with vitamin A as retinol acetate ( 1000 microg retinol equivalent ) , or vitamin A alone as the control group .  Hemoglobin ( Hb ) and indicators of iron status were assessed at baseline and at 32 wk of gestation . At 6-wk postpartum , Hb assessment was repeated using a finger stick . Severely anemic women ( Hb < 70 g/L ) were treated according to WHO recommendations . Folic acid alone had no effect on maternal anemia or iron status . Hb concentrations were 14 g/L , [ 95 % confidence limits ( CL ) , 8.3 - 19.2 ] , 10.0 g/L ( CL , 5.2 - 14.8 ) and 9.4 g/L ( CL , 4.7 - 14.1 ) higher in the groups receiving folic acid plus iron , folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients , respectively , relative to the control . Anemia in the third trimester was reduced by 54 % with folic acid plus iron , by 48 % with folic acid plus iron and zinc and by 36 % with folic acid plus iron , zinc and multiple micronutrients supplementation , relative to the control ( P < 0.05 ) . Thus , the combinations of folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients provided no additional benefit in improving maternal hematologic status during pregnancy compared with folic acid plus iron . The level of compliance and baseline Hb concentrations modified the effect of iron BACKGROUND Pregnant women usually meet their increased energy needs but do not always meet their increased micronutrient requirements . The supply of both folic acid and docosahexaenoic acid ( DHA ) has been related to positive pregnancy and infant outcomes . OBJECTIVE We aim ed to assess whether fish-oil ( FO ) supplementation with or without folate from gestation week 22 to birth improves maternal and fetal n-3 long-chain polyunsaturated fatty acid ( n-3 LC-PUFA ) status . DESIGN We conducted a multicenter ( Germany , Hungary , and Spain ) , r and omized , double-blind , 2 x 2 factorial , placebo-controlled trial . From gestation week 22 until delivery , 311 pregnant women received daily a preparation with FO [ 0.5 g DHA and 0.15 g eicosapentaenoic acid ( EPA ) ] , 400 microg methyltetrahydrofolic acid ( MTHF ) , FO with MTHF , or placebo . Outcome measures included maternal and cord plasma DHA and EPA contents at gestation weeks 20 and 30 and at delivery , indicators of pregnancy outcome , and fetal development . RESULTS FO significantly ( P<0.001 ) increased maternal DHA and EPA ( % by wt ) , as shown by 3-factor repeated- measures ANOVA ( ie , MTHF , FO , and time ) with adjustment for maternal baseline DHA and EPA . In addition , FO significantly ( P<0.001 ) increased cord blood DHA ( % by wt ; 2-factor ANOVA ) . MTHF was significantly ( P=0.046 ) associated with increased maternal DHA ( % by wt ) . There was no FO x MTHF interaction for the time course of DHA or EPA ( P=0.927 and 0.893 ) . Pregnancy outcomes and fetal development did not differ significantly among the intervention groups . CONCLUSIONS FO supplementation from gestation week 22 until delivery improves fetal n-3 LC-PUFA status and attenuates depletion of maternal stores . MTHF may further enhance maternal n-3 LC-PUFA proportions In rural China , many pregnant women in their third trimester suffer from anemia ( 48 % ) and iron deficiency ( ID ; 42 % ) , often with coexisting deficiencies of retinol and riboflavin . We investigated the effect of retinol and riboflavin supplementation in addition to iron plus folic acid on anemia and subjective well-being in pregnant women . The study was a 2-mo , double-blind , r and omized trial . Subjects ( n = 366 ) with anemia [ hemoglobin ( Hb ) < /= 105 g/L ] were r and omly assigned to 4 groups , all receiving 60 mg/d iron and 400 mug/d folic acid . The iron+folic acid ( IF ) group ( n = 93 ) served as reference , the iron+folic acid+retinol group ( IFA ) ( n = 91 ) was treated with 2000 mug retinol , the iron+folic acid+riboflavin group ( IFB ) ( n = 91 ) with 1.0 mg riboflavin , and the iron+folic acid+retinol+riboflavin group ( IFAB ) ( n = 91 ) with retinol and riboflavin . After the 2-mo intervention , the Hb concentration increased in all 4 groups ( P < 0.001 ) . The increase in the IFAB group was 5.4 + /- 1.1 g/L greater than in the IF group ( P < 0.001 ) . The reduced prevalence of anemia ( Hb < 110g/L ) and ID anemia were significantly greater in the groups supplemented with retinol and /or riboflavin than in the IF group . Moreover , gastrointestinal symptoms were less prevalent in the IFA group than in the IF group ( P < 0.05 ) and improved well-being was more prevalent in the groups receiving additional retinol and /or riboflavin than in the IF group ( P < 0.05 ) . Thus , a combination of iron , folic acid , retinol , and riboflavin was more effective than iron plus folic acid alone . Multimicronutrient supplementation may be worthwhile for pregnant women in rural China BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on  fetal loss and infant mortality .  DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality .  Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation 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 Measurement of the urinary folate catabolites , para-aminobenzoylglutamate ( pABG ) and the more predominant acetylated form , acetamidobenzoylglutamate ( apABG ) , has been used to assess folate requirements in both pregnant and nonpregnant women . Folate catabolite excretion has been reported to be significantly higher in pregnant women ( second trimester ) compared with nonpregnant controls . The primary goals of this study were to determine if pregnant women in a controlled metabolic study excreted higher quantities of urinary folate catabolites than nonpregnant controls and if catabolite excretion was influenced by folate intake . We evaluated the effect of gestation and folate intake on the urinary excretion of apABG and pABG in pregnant women ( n = 12 ; wk 14 - 26 gestation ) and nonpregnant controls ( n = 12 ) assigned to consume folate levels approximating the current ( 400 microg/d ) and previous ( 800 microg/d ) RDA . Subjects were fed a controlled diet containing 120 microg folate/d and either 330 or 730 microg synthetic folic acid/d . In contrast to previously reported data , no differences in mean folate catabolite excretion were detected between pregnant and nonpregnant subjects . Catabolite excretion ( pABG + apABG ) decreased significantly relative to initial values in pregnant women consuming 450 microg folate/d ( -40 + /- 20 % ; mean + /- SD ) and final mean excretion was significantly lower in the pregnant women consuming 450 microg folate/d ( 86 + /- 32 nmol/d ) compared with 850 microg folate/d ( 148 + /- 20 nmol/d ) . Data from this study indicate that second trimester pregnant women do not excrete more folate catabolites than nonpregnant controls and that consumption of 450 vs. 850 microg folate/d results in a significant reduction in the quantity of folate catabolites excreted 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 Higher folate needs are present during pregnancy , which may lead to tissular deficiency in the mother and to depleted newborn folate reserves . The aim of this work was to assess the prevalence of folate deficiency and to establish the rates of serum and red cell folate in two groups of mothers and newborn infants , one receiving only iron and the other iron and folate during pregnancy .  The rates of serum and red cell folate found at the end of pregnancy were significantly higher in the group which received folate ; however , the percentage of cases with tissular folate deficiency was low in both groups , with no significant difference ( 3.8 % and 1.3 % , respectively ) . These findings , along with the lack of effect of supplemental folate on erythropoiesis , pose some questions on the usefulness of supplemental folate during pregnancy in our country OBJECTIVE To determine by biochemical methods the nutritional status of pre- and post-natal Turkish women and its relationship with offspring anthropometry . DESIGN Longitudinal study . SETTING Health centres in Istanbul and Izmit , research department and university hospital laboratories . SUBJECTS R and omly selected group of women attending health centres at 13 - 17 weeks gestation ( n = 130 ) ; same sample of women at 28 - 32 weeks gestation ( n = 88 ) and 13 - 17 weeks post-partum ( n = 95 ) ; offspring at 13 - 17 weeks post-partum ( n = 90 ) . INTERVENTIONS Blood sample s taken from mothers at all three stages and analysed for ferritin , iron , zinc , calcium , alkaline phosphatase , total protein , albumin , vitamins B2 , B6 , B12 , A , E , beta-carotene and folate levels ;  question naire completed for recording medical and socio-demographic background . Anthropometric measurements taken from mothers and offspring . RESULTS High percentages of subjects were at risk for deficiencies of vitamin B12 ( 48.8 % ) and folate ( 59.7 % ) in early pregnancy ; ferritin ( 52.3 % ) , zinc ( 72.3 % ) , vitamin B2 ( 38.8 % ) , vitamin B12 ( 80.9 % ) , and folate ( 76.4 % ) during late pregnancy ; and ferritin ( 39.0 % ) , vitamins B2 ( 43.1 % ) , B6 ( 36.4 % ) , B12 ( 60.0 % ) , and folate ( 73.3 % ) at the post-partum stage . Bone loss was indicated in 55.0 % and 80.0 % of the subjects in late pregnancy and post-partum respectively . Haematocrit in later pregnancy correlated strongly with prenatal body fat ( P < 0.001 ) . Infant anthropometry at 13 - 17 weeks post-partum was significantly affected by pre-natal weight gain and a number of maternal blood nutrients in pregnancy and post-partum . CONCLUSIONS Nutrition education programmes and enrichment of the staple food with iron , zinc , calcium , and the B vitamins should be considered To study the relation of maternal periconceptional vitamin use  to the risk of  a congenital urinary tract anomaly ( CUTA )  , we conducted a case-control study using the Washington State Birth Defect Registry . We identified CUTA cases with no known chromosomal abnormality in seven counties in western Washington State occurring between January 1 , 1990 , and December 31 , 1991 . We r and omly selected a sample , as controls , of all infants delivered in five large hospitals in King County who did not have a birth defect and who were born in the same year as the cases . About 55 % of all infants in King County and a smaller proportion of infants in the other six counties are delivered in these five hospitals . We interviewed mothers of 118 cases and 369 controls to obtain information about their vitamin use during the pregnancy and during the year before the conception . After adjustment for maternal race , family income , county of maternal residence , and birth year , we found that women who used multivitamins during the first trimester had only 15 % the risk of bearing a child with a CUTA compared with women who did not take vitamins [ odds ratio ( OR ) = 0.15 ; 95 % confidence interval ( CI ) = 0.05–0.43 ] . The reduction was smaller for use restricted to the second or third trimesters ( OR = 0.31 ; 95 % CI = 0.09–1.02 ) . Among women who used vitamins during the first trimester , vitamin use before conception was not associated with any further reduction in the risk , nor did there appear to be an association with the amount or br and of vitamin used . Restricting the analysis to residents of King County did not change the results . Our results indicate that prenatal multivitamin use , particularly during the first trimester , may reduce the risk of a CUTA . Because all of the preparations taken by study participants contained many vitamins as well as folic acid , it was not possible to identify which one ( or several ) chemical(s ) may have been responsible for the reduced risk of a CUTA OBJECTIVE --To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities . DESIGN --R and omised controlled trial of supplementation with multivitamins and trace elements . SETTING --Hungarian family planning programme . SUBJECTS--4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life . INTERVENTIONS --A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception . MAIN OUTCOME MEASURES --Number of major and mild congenital abnormalities . RESULTS --The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference can not be explained totally by the significant reduction of neural tube defects . The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group ; relative risk 1.85 ( 95 % confidence interval 1.02 to 3.38 ) ; difference , 7.6/1000 . The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group ; relative risk 1.95 ( 1.23 to 3.09 ) ; difference , 13.6/1000 . The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant . CONCLUSIONS --Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities . Further studies are needed to differentiate the chance effect and vitamin dependent effect A double-blind study evaluated the effects of systemic and topical folate on  gingival inflammation during the fourth and eighth months of pregnancy . Thirty women were r and omly divided into three groups . Group A received placebo mouthwash and tablets ; Group B ; placebo mouthwash and 5 mg folate tablets ; Group C : folate mouthwash and placebo tablets . Supplementation lasted for 14 days during months 4 and 8 . Subjects took one tablet daily and rinsed twice daily for 1 min with the mouthwash . At the start and finish of each 14-day period , fasting serum and red cell folate levels were estimated and oral status assessed by a plaque index ( P1I ) , a gingival index ( GI ) , and gingival exu date flow meter ( GEF ) . Subjects completed 1-week diet sheets which were analysed for dietary folate . All groups were similar in each parameter at the start . Correlation was demonstrated between GI and P1I , and between GI and GEF . GI tended to increase throughout pregnancy in all groups except Group C , when in the eighth month there was a highly significant improvement ( 0.001 less than P 0.01 ) despite no significant change in P1I . Although dietary intake of folate was significantly higher during the eighth month in Group C as compared with Groups A and B , ( 0.001 less than P less than 0.01 ) , the folate mouthwash produced highly significantly improvement in gingival health in pregnancy OBJECTIVE To examine the effect of supplemental prenatal folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrients on  maternal morbidity in rural Nepal . METHODS A cluster-r and omized double-masked controlled trial of pregnant women who received daily supplements from early pregnancy through 3 months post partum as per the treatment allocation . Women were interviewed at birth about labor and delivery complications and for 9 days post partum to obtain 24-hour histories of morbidity . RESULTS A total of 3986 ( 97.3 % ) women completed an interview regarding labor and delivery ; morbidity history was available for 3564 ( 87.0 % ) women .  Folic acid-iron reduced the risk of postpartum hemorrhage ( relative risk [ RR ] 0.59 ; 95 % confidence interval [ CI ] 0.35 - 0.98 ) . Risk of dysfunctional labor increased with multiple micronutrient supplementation ( RR 1.28 ; 95 % CI , 1.01 - 1.60 ) , although preterm premature rupture of membrane decreased ( RR 0.40 ; 95 % CI , 0.21 - 0.79 ) . Puerperal sepsis was lower in those receiving folic acid-iron , folic acid-iron-zinc , and multiple micronutrients compared with controls ( P<0.05 ) . CONCLUSION Prenatal folic acid-iron supplementation reduced the risk of obstetric complications in this South Asian setting OBJECTIVE To evaluate the effect of high dose and low dose folic acid on the levels of hemocysteine ( Hcy ) concentration during the first trimester of pregnancy and at delivery , and to examine the association of Hcy serum levels and  preeclampsia .  METHODS In a single blinded r and omized clinical trial , which was conducted in Tabriz , Iran , from 2005 - 2008 , 246 nulliparous pregnant women in 2 similar groups , received folic acid daily from early pregnancy until delivery ( 5 mg/day in group one and 0.5 mg/ day in group 2 ) . The incidence of hypertension and laboratory changes in the levels of serum Hcy , lactate dehydrogenase , and uric acid in addition to the levels of urine creatinine and protein were compared between the groups . RESULTS There was no presence of any type of hypertension in each group . The systolic blood pressures ( BP ) ( mm Hg ) at the first trimester were 114.01 + /- 8.78 for group one , 114.16 + /- 9.05 for group 2 , and at delivery , 117.24 + /- 6.91 for group one , and 117.23 + /- 11.48 for group 2 ( p=0.32 ) . The diastolic BP at the first trimester were 74.90 + /- 7.45 for group one , 73.30 + /- 8.90 for group 2 , and at delivery 76.46 + /- 5.58 for group one , and 76.69 + /- 8.62 for group 2 ( p=0.42 ) . Although the level of Hcy ( micromol/L ) decreased significantly at the delivery time in group one ( 11.81+/- 3.85 decreased to 6.44 + /- 1.88 ) , and 2 ( 9.08+/- 3.24 , decreased to 7.44 + /- 2.99 ) , this decrement was more significant in the first group ( p<0.001 ) . CONCLUSION The results show that folic acid supplement throughout pregnancy , irrespective of the dosage , could eliminate hypertensive disorders , and decreases serum level of Hcy , although it is reduced more significant in the first group Objectives : Sulfadoxine-pyrimethamine ( SP ) is an antimalarial drug that acts on the folate metabolism of the malaria parasite . We investigated whether folate ( FA ) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women . Design : This was a r and omized , placebo-controlled , double-blind trial . Setting : The trial was carried out at three hospitals in western Kenya . Participants : The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia ( density of ≥ 500 parasites/μl ) , a haemoglobin level higher than 7 g/dl , a gestational age between 17 and 34 weeks , and no history of antimalarial or FA use , or sulfa allergy . A total of 415 women completed the study . Interventions : All participants received SP and iron supplementation . They were r and omized to the following arms : FA 5 mg , FA 0.4 mg , or FA placebo . After 14 days , all participants continued with FA 5 mg daily as per national guidelines . Participants were followed at days 2 , 3 , 7 , 14 , 21 , and 28 or until treatment failure . Outcome Measures : The outcomes were SP failure rate and change in haemoglobin at day 14 . Results : The proportion of treatment failure at day 14 was 13.9 % ( 19/137 ) in the placebo group , 14.5 % ( 20/138 ) in the FA 0.4 mg arm ( adjusted hazard ratio [ AHR ] , 1.07 ; 98.7 % confidence interval [ CI ] , 0.48 to 2.37 ; p = 0.8 ) , and 27.1 % ( 38/140 ) in the FA 5 mg arm ( AHR , 2.19 ; 98.7 % CI , 1.09 to 4.40 ; p = 0.005 ) . The haemoglobin levels at day 14 were not different relative to placebo ( mean difference for FA 5 mg , 0.17 g/dl ; 98.7 % CI , −0.19 to 0.52 ; and for FA 0.4 mg , 0.14 g/dl ; 98.7 % CI , −0.21 to 0.49 ) . Conclusions : Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women . Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation CONTEXT Iron and zinc are important for the development of both intellectual and motor skills . Few studies have examined whether iron and zinc supplementation during gestation , a critical period of central nervous system development , affects children 's later functioning . OBJECTIVE To examine intellectual and motor functioning of children whose mothers received micronutrient supplementation during pregnancy . DESIGN , SETTING , AND PARTICIPANTS Cohort follow-up of 676 children aged 7 to 9 years in June 2007-April 2009 who had been born to women in 4 of 5 groups of a community-based , double-blind , r and omized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal . Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial . INTERVENTIONS Women whose children were followed up had been r and omly assigned to receive daily iron/folic acid , iron/folic acid/zinc , or multiple micronutrients containing these plus 11 other micronutrients , all with vitamin A , vs a control group of vitamin A alone from early pregnancy through 3 months postpartum . These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation . MAIN OUTCOME MEASURES Children 's intellectual functioning , assessed using the Universal Nonverbal Intelligence Test ( UNIT ) ; tests of executive function , including go/no-go , the Stroop test , and backward digit span ; and motor function , assessed using the Movement Assessment Battery for Children ( MABC ) and finger-tapping test . RESULTS The difference across outcomes was significant ( Bonferroni-adjusted P < .001 ) for iron/folic acid vs control but not for other supplement groups . The mean UNIT T score in the iron/folic acid group was 51.7 ( SD , 8.5 ) and in the control group was 48.2 ( SD , 10.2 ) , with an adjusted mean difference of 2.38 ( 95 % confidence interval [ CI ] , 0.06 - 4.70 ; P = .04 ) . Differences were not significant between the control group and either the iron/folic acid/zinc ( 0.73 ; 95 % CI , -0.95 to 2.42 ) or multiple micronutrient ( 1.00 ; 95 % CI , -0.55 to 2.56 ) groups . In tests of executive function , scores were better in the iron/folic acid group relative to the control group for the Stroop test ( adjusted mean difference in proportion who failed , -0.14 ; 95 % CI , -0.23 to -0.04 ) and backward digit span ( adjusted mean difference , 0.36 ; 95 % CI , 0.01 - 0.71 ) but not for the go/no-go test . The MABC score was lower ( better ) in the iron/folic acid group compared with the control group but not after adjustment for confounders ( mean difference , -1.47 ; 95 % CI , -3.06 to 0.12 ; P = .07 ) . Finger-tapping test scores were higher ( mean difference , 2.05 ; 95 % CI , 0.87 - 3.24 ; P = .001 ) in the iron/folic acid group . CONCLUSION Aspects of intellectual functioning including working memory , inhibitory control , and fine motor functioning among offspring were positively associated with prenatal iron/folic acid supplementation in an area where iron deficiency is prevalent . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00115271 The long-term benefits of antenatal iron supplementation in child survival are not known . In 1999 - 2001 , 4,926 pregnant women in rural Nepal participated in a cluster-r and omized , double-masked , controlled trial involving 4 alternative combinations of micronutrient supplements , each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls , who received vitamin A only . They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival . Of 4,130 livebirths , 209 infants died in the first 3 months and 8 were lost to follow-up . Of those remaining , 3,761 were followed , 150 died between ages 3 months and 7 years , and 152 were lost to follow-up . Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group , as follows : folic acid , 13.4 ; folic acid-iron , 10.3 ; folic acid-iron-zinc , 12.0 ; multiple micronutrients ; 14.0 ; and controls , 15.2 . Hazard ratios were 0.90 ( 95 % confidence interval ( CI ) : 0.65 , 1.22 ) , 0.69 ( 95 % CI : 0.49 , 0.99 ) , 0.80 ( 95 % CI : 0.58 , 1.11 ) , and 0.93 ( 95 % CI : 0.66 , 1.31 ) , respectively , in the 4 supplementation groups . Maternal iron-folic acid supplementation  reduced mortality among these children by 31 % between birth and age 7 years . These results provide additional motivation for strengthening antenatal iron-folic acid programs BACKGROUND Zinc and folate are important for fetal growth . However , the relationship between the dietary intake of these nutrients and pregnancy outcome is not settled . METHODS A prospect i ve study was conducted to ascertain the relationship between  maternal dietary zinc and folate intake  ( n = 1398 ) , serum zinc and folate levels ( n = 289 ) , and infant birthweight .  Twenty-four hour recalls were used to measure energy , zinc , folate and other nutrient intakes at 18 and 30 weeks of gestation . Subjects in the study were offered daily folic acid ( 1.0 mg ) and iron ( 60 mg as ferrous sulfate ) at enrollment . RESULTS Maternal zinc nutriture as assessed by serum and dietary intake was not associated with birthweight or length of gestation . There was a small but significant positive association between maternal folate intake and adjusted infant birthweight ( beta = 0.05 , p = 0.03 ) . The indirect measures of maternal nutritional status including maternal pre-pregnancy weight ( beta = 8.0 , p = 0.0001 ) and weight gain during pregnancy ( beta = 18.1 , p = 0.0001 ) were stronger predictors of adjusted infant birthweight as compared to energy intake and intake of zinc and folate . An increase of 320 , 290 , and 48 g in infant birthweight was associated with the 90th-10th percentile difference for pre-pregnancy weight , weight gain during pregnancy , and folate intake respectively . CONCLUSION These results indicate that pre-pregnancy weight and weight gain during pregnancy are both strong predictors of infant birthweight .  Folate intake , although significantly associated with birthweight , was a weak predictor while maternal intake of zinc and other nutrients was not associated with birthweight Our interest in the problem of folic acid and pregnancy was aroused by the work of Hibbard and Hibbard : “ Aetiological factors in abruptio placentae ” 1963 ( 12 ) . Though the frequency of abruptio placentae at our department is by no means so high as that at Millroad Maternity Hospital , Liverpool , the complication is serious because of its foetal mortality . We therefore thought it advisable to try folic acid prophylaxis during pregnancy in an attempt to decrease the frequency of abruptio placentae . Later investigations ( 14 , 20 ) have , however , shown that if folic acid treatment is not started until pregnancy has been diagnosed , it will hardly be able to reduce the frequency of abruptio placentae and abortion . In Great Britain megaloblastic anaemia due to folic acid deficiency is common during pregnancy ( 4 , 5 , 6 , 7 , 8 , 13 , 15 , 16 , IS ) , while in Sweden only a few cases have been reported . This discrepancy can be explained only partly by differences in interest in the diagnosis and diagnostic facilities available . In a thoroughly examined series Hansen found megaloblastic anaemia in less than 0.1 % of all pregnant women during a 3 1/2-year-period in Gothenburg ( 9 ) . A poor composition of the diet was thought to be a main causal factor of folic acid deficiency in the series reported from Background / Objectives : Little is known about the long-term effects of maternal multi-micronutrient supplementation on the growth of children during early childhood . In this follow-up study , the effects of maternal supplementation with multi-micronutrients in pregnancy on postnatal child growth are examined . Subjects/ Methods : A longitudinal follow-up of a subset of newborns ( n=1388 ) whose mothers were r and omly assigned to receive the supplements of folic acid , iron – folic acid or multi-micronutrients daily during pregnancy in the original trial was conducted . Children ’s weight and length were measured and assessed during monthly home visits from birth to 30 months of age . Results : The pooled prevalence rate of stunting over different time points during the first 30 months was 13.5 , 14.9 and 12.1 % for the folic acid group , iron – folic acid group and multi-micronutrient group , respectively . However , there were no significant differences in the pooled odds of stunting in children between the multi-micronutrient group and the folic acid ( odds ratio ( OR ) 0.97 , 95 % confidence interval ( CI ) : 0.74–1.26 ) , and between the multi-micronutrient group and the iron – folic acid group ( OR 0.82 , 95 % CI : 0.63–1.07 ) . Similar results for the three groups were found for the occurrences of underweight and wasting in children . Furthermore , no significant differences were observed in length , weight , length-for-age , weight-for-age and weight-for-length Z-scores among the three treatment groups . Conclusions : Currently , available evidence is insufficient to support a greater advantage of the effect of maternal multi-micronutrient supplementation on child growth over iron – folic acid or folic acid only supplementation during the first 30 months Objective Elevated plasma homocysteine has been implicated in vascular changes compatible with atherosis and endothelial dysfunction similar to the vascular changes of the placenta in preeclampsia . Previous reports have indicated an increased incidence of hyperohomocysteinemia in preeclamptic patients . The aim of this study was to examine the association of homocysteine levels and preeclampsia in our patients . Study design Prospect i ve study of 28 preeclamptic patients that were matched with 26 normal controls of the same gestational age . Results The preeclamptic group had an increased incidence of cesarean sections ( 75 % ) , of growth retarded fetuses ( 50 % ) , intrauterine deaths ( 7 % ) and placental abruptions ( 7 % ) . Mean levels of homocysteine were significantly elevated in the preeclamptic than in control group ( 11.11 vs. 6.40 μmol/l , P < 0.001 ) . There were no differences between the groups regarding the levels of folic acid ( 11.12 vs. 9.73 ng/ml , P = 0.55 ) and vitamin B12 ( 295.76 vs. 356.15 pg/ml , P = 0.43 ) . Conclusion It is concluded that in our study homocysteine levels are significantly elevated in patients with preeclampsia compared with control group , while no vitamin deficiencies were observed BACKGROUND We previously reported that a r and omized controlled trial of antenatal micronutrient supplements in rural Nepal decreased the risk of low birth weight by approximately 15 % . OBJECTIVE The objective was to examine the effects of micronutrient supplementation on growth and body composition in children of supplemented mothers through school age . DESIGN Mothers received 1 of 5 micronutrient supplements daily : folic acid , folic acid + iron , folic acid + iron + zinc , multiple micronutrients , or a control . All of the supplements contained vitamin A.  Children born during this trial were revisited at age 6 - 8 y to measure height , weight , midupper arm circumference , waist circumference , and triceps and subscapular skinfold thicknesses . Arm fat and muscle area were estimated by using st and ard formulas , and height-for-age , weight-for-age , and body mass index-for-age z scores were calculated by using the World Health Organization growth st and ard . RESULTS Of the 3771 surviving children , 3324 were revisited and consented to anthropometric measurements . Maternal supplementation with folic acid + iron + zinc result ed in an increase in mean height ( 0.64 cm ; 95 % CI : 0.04 , 1.25 ) and a reduction in mean triceps skinfold thickness ( -0.25 mm ; 95 % CI : -0.44 , -0.06 ) , subscapular skinfold thickness ( -0.20 mm ; 95 % CI : -0.33 , -0.06 ) , and arm fat area ( -0.18 cm(2 ) ; -0.34 , -0.01 ) . No significant differences were found between groups in mean weight or body mass index-for-age z scores , waist circumference , or arm muscle area . Other micronutrient combinations including a multiple micronutrient formulation failed to show a growth benefit . CONCLUSION Antenatal supplementation with zinc may benefit child growth , particularly in areas where a deficiency of this nutrient is common It has been shown that the incidence of megaloblastic anaemia in a group of 463 r and omly selected pregnant women receiving iron  was 12 times as high as in a control group of 235 pregnant women receiving iron and folic acid .  The incidence of all types of anaemia in the women receiving iron alone was more than three times the incidence in those having iron and folic acid . Some women who were not anaemic or who had normoblastic anaemia had serum folate levels in the same range as the women with megaloblastic anaemia , but none of the women with megaloblastic anaemia had high serum folate levels . The labile fraction of the serum folate was no more reliable than the total serum folate as a diagnostic criterion of megaloblastic erythropoiesis in the individual case . The blood group distribution in the women with megaloblastic anaemia was the same as in the general population . Babies born to mothers with megaloblastic anaemia tended to be smaller than the rest , although there was no difference in the placental weights . The significance of these findings is discussed In this placebo controlled , r and omised , double blind trial , pregnant women received from the 20th week of gestation onwards either 500 mg docosahexaenoic acid ( DHA ) , 400 mg 5-methyl-tetra-hydro-folate ( 5-MTHF ) , or placebo , or a combination of 500 mg DHA and 400 mg 5-MTHF . The dietary supplements were well tolerated ; the dropout rates did not differ significantly in the active arms of the study ( 10 % to 19 % ) from that seen in the placebo group ( 13 % ) . DHA supplementation result ed in significant enhancement of the contribution of DHA to maternal , placental and venous cord blood lipids The objective in the Hungarian r and omised double-blind controlled trial was to study the preventive effect of periconceptional multivitamin supplementation on  neural tube-defects and other congenital abnormalities .  There were 2,471 and 2,391 informative offspring ( prenatally diagnosed and terminated malformed fetuses , stillborn fetuses , and liveborn infants ) in the multivitamin and placebo-like trace element groups , respectively . A single tablet either of a multivitamin containing 0.8 mg of folic acid or trace element supplement was given daily for at least one month before conception and at least until the date of the second missed menstrual period . The total rate of major congenital abnormalities was 20.6/1,000 in the multivitamin and 40.6/1,000 in the trace element group . After the exclusion of six cases of neural-tube defects in the trace element group the difference was very highly significant [ P = 0.0003 ; relative risk of 0.54 ( 95 % CI 0.39 , 0.76 ) ] . Multivitamin supplementation appeared to result in a significant reduction in the rate of urinary tract abnormalities , mainly obstructive defects , and in the rate of sporadic cardiovascular malformations , mainly ventricular septal defects . This report is regarded as a hypothesis-generating study encouraging others to see if the result can be repeated Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron  increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation  increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic OBJECTIVE The preventive efficacy of the periconceptional use of multivitamins is well established for neural tube defects , much less so for other birth defects . We conducted a population -based , case-control study to assess the effects of multivitamin use on the risk for conotruncal defects , a group of severe heart defects that includes transposition of the great arteries , tetralogy of Fallot , and truncus arteriosus . METHODS From the population -based Atlanta Birth Defects Case-Control Study , we identified 158 case infants with conotruncal defects and 3026 unaffected , r and omly chosen control infants , born from 1968 through 1980 to mothers residing in metropolitan Atlanta .  Periconceptional multivitamin use was defined as reported regular use from 3 months before conception through the third month of pregnancy . We present the results of the crude analysis , because the multivariate model yielded essentially identical results . RESULTS Mothers who reported periconceptional multivitamin use had a 43 % lower risk of having infants with conotruncal defects ( odds ratio [ OR ] , 0.57 ; 95 % confidence interval [ CI ] , 0.33 to 1.00 ) than did mothers who reported no use . The estimated relative risk was lowest for isolated conotruncal defects ( OR , 0.41 ; 95 % CI , 0.20 to 0.84 ) compared with those associated with noncardiac defects ( OR , 0.91 ; 95 % CI , 0.33 to 2.52 ) or a recognized syndrome ( OR , 1.82 ; 95 % CI , 0.31 to 10.67 ) . Among anatomic subgroups of defects , transposition of the great arteries showed the greatest reduction in risk ( OR , 0.36 ; 95 % CI , 0.15 to 0.89 ) . CONCLUSIONS Periconceptional multivitamin use is associated with a reduced risk for conotruncal defects . These findings could have major implication s for the prevention of these birth defects The efficacy of prophylactic treatment with ferrous sulfate ( 80 mg Fe++ ) and the combination of ferrous sulfate with folic acid ( 80 mg Fe++ and 350 microgram folic acid ) were studied in a double blind trial in the 20th , and again in the 30th and 36th week of pregnancy ( 29 patients ) . At the beginning of the treatment ( 20th week ) 29 % of the patients showed a pathologically reduced serum folic acid level . Combined therapy has a favorable effect on the folic acid levels in the serum and red blood cells ; this was confirmed statistically . At the end of pregnancy , 69 % of the patients of the control group ( ferrous sulfate ) showed a pathologically reduced serum level and 23 % a subnormal level in erythrocytes . These results un question ably justify the prophylactic prescription of folic acid during pregnancy An open , r and omised multicentre study was carried out to compare pregnant women , treated with calcium folinate ( Citofolin Bracco S.p . A. ) 15 mg/day per os starting from the 12th or 20th week of gestation , with an untreated group .  The results obtained confirm the efficacy of calcium folinate treatment on the trends of parameters analysed ( serum and endoerythrocytic folatemia , hemoglobin and sideremia ) which remained within the normal range . Moreover , no adverse effects of any type were reported during the study BACKGROUND The influence of prenatal long-chain polyunsaturated fatty acids ( LC-PUFAs ) and folate on neurologic development remains controversial . OBJECTIVE The objective was to assess the long-term effects of n-3 ( omega-3 ) LC-PUFA supplementation , 5-methyltetrahydrofolate ( 5-MTHF ) supplementation , or both in pregnant women on cognitive development of offspring at 6.5 y of age . DESIGN This was a follow-up study of the NUHEAL ( Nutraceuticals for a Healthier Life ) cohort . Healthy pregnant women in 3 European centers were r and omly assigned to 4 intervention groups . From the 20th week of pregnancy until delivery , they received a daily supplement of 500 mg docosahexaenoic acid ( DHA ) + 150 mg eicosapentaenoic acid [ fish oil ( FO ) ] , 400 μg 5-MTHF , or both or a placebo .  Infants received formula containing 0.5 % DHA and 0.4 % arachidonic acid ( AA ) if they were born to mothers receiving FO supplements or were virtually free of DHA and AA until the age of 6 mo if they belonged to the groups that were not supplemented with FO . Fatty acids and folate concentrations were determined in maternal blood at weeks 20 and 30 of pregnancy , at delivery , and in cord blood . Cognitive function was assessed at 6.5 y of age with the Kaufman Assessment Battery for Children ( K-ABC ) . RESULTS We observed no significant differences in K-ABC scores between intervention groups . Higher DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring . CONCLUSION We observed no significant effect of supplementation on the cognitive function of children , but maternal DHA status may be related to later cognitive function in children . This trial was registered at clinical trials.gov as NCT01180933 IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal 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 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 Maternal supplementation with long-chain PUFA , to improve infant neurological development , might cause additional increase of oxidative stress . Pregnant women aged 18 - 41 years were r and omised into one of four supplementation groups . From week 22 on , they received supplements containing either modified fish oil ( n 69 ) , 5-methyl-tetrahydro-folate ( n 65 ) , both ( n 64 ) , or placebo ( n 72 ) . Plasma Trolox-equivalent antioxidative capacity ( TEAC ) , concentrations of alpha-tocopherol , retinol , beta-carotene , free thiol groups , uric acid and thiobarbituric acid-reactive substances ( TBARS ) were determined at weeks 20 and 30 and at delivery . The studied antioxidants showed no significant differences between the four supplementation groups . At week 30 plasma TBARS levels were found to be significantly higher in the fish oil group ( 0.80 ( sem 0.04 ) micromol/l ) than in the folate ( 0.67 ( sem 0.03 ) micromol/l ; P = 0.024 ) and control ( 0.69 ( sem 0.04 ) micromol/l ; P = 0.01 ) groups . Concentrations of retinol and free thiol groups decreased during pregnancy , whereas uric acid increased and beta-carotene as well as TEAC showed only minor changes . Fish oil supplementation during the second half of pregnancy appears not to decrease antioxidant status . The increased TBARS levels at week 30 may indicate a period of increased oxidative stress in plasma at this time Objective : Micronutrient deficiencies during pregnancy may be linked to poor newborn health and poor host defences against infection . We assessed newborn morbidity to determine the effect of four combinations of antenatal micronutrient supplements . Design : Cluster-r and omised , double-masked , controlled trial . Setting : Rural community in Nepal . Interventions : Women received daily supplements from early pregnancy through to 3 months postpartum of vitamin A alone ( control ) or vitamin A with folic acid , folic acid plus iron , folic acid plus iron plus zinc or a multiple micronutrient supplement containing these and 11 other nutrients . Main outcome measures : Infants were visited in their home at birth ( n = 3927 ) and for each of 9 days thereafter to elicit a 24-h history of nine infant morbidity symptoms , measure infant respiratory rate and axial temperature , and assess the infant for chest indrawing . At 6 weeks of age , infants were visited again in their homes to elicit a 30-day and 7-day history of 10 morbidity symptoms using parental recall . Results : Maternal micronutrient supplementation had no effect on 10-day morbidity or morbidity 30-day and 7-day morbidity assessed at 6 weeks of age all relative risks were close to 1 . Symptoms of birth asphyxia increased by about 60 % ( p<0.05 ) in infants of women who received the multiple micronutrient supplement compared with the control . Symptoms of combinations of sepsis , preterm and birth asphyxia were associated with 8- to 14-fold increased odds of 6-month infant mortality . Conclusions : None of the combinations of antenatal micronutrient supplements tested improved symptoms of neonatal morbidity in the first 10 days of life or at 6 weeks of age . Further research is needed to eluci date the association and mechanism of increased risk of birth asphyxia following maternal multiple micronutrient supplementation . Trial registration numbers : NCT00115271 A former double-blind study evaluated the effect of a 14-day period of systemic and topical folate supplementation on  gingival inflammation during pregnancy ( Pack & Thomson 1980 ) . The current experiment was similar to the earlier one except that supplementation was for 28 days during the eighth month only . Thirty women during their 32nd week of pregnancy were r and omly divided into three equal groups . Control Group A received placebo mouthwash ( MW ) and placebo tablets ; Group B received placebo MW and one 5 mg folate tablet daily ; Group C received placebo tablets and rinsed with folate MW twice daily for 1 min . At the beginning and end of the experimental period , oral status was determined using a plaque index ( PlI ) and a gingival index ( GI ) . Each subject furnished a 1-week diet record which was analysed for dietary folate . No differences in parameters existed between groups at the commencement of the study except for folate levels which were lower in Group B. Results confirmed the findings of the former experiment . Group C showed highly significant improvement in GI despite no significant changes in PlI ( 0.001 less than P less than 0.01 ) , whilst in Group B , changes in gingival health were not statistically significant ( 0.05 less than P less than 0.10 ) . No significant changes were demonstrated in Group A. Folate levels increased significantly in Groups B and C. Dietary folate was similar in all groups Hemoglobin ( Hb ) concentration , serum iron level , iron binding capacity and blood folate ( Lactobacillus casei ) activity were determined in 310 unselected pregnant Burmese women .  Hb concentration was less than 11 g/dl in 72 % of the women ; the serum iron level was less than 50 mug/dl in 33 % ; serum folate activity was less than 3ng/ml in 13 % ; and red cell folate activity was less than 100 ng/ml in 17 % of the women . Ninety-six of the women in our study were r and omly divided into four groups , treated from the 22nd to the 25th week of pregnancy until full term with either ferrous sulfate containing 60 mg elemental iron twice daily , 5 mg folic acid twice daily , a combination of both , or a placebo only . At full term , Hb concentration fell in the groups given placebo or folic acid . On the other h and , in the groups given iron alone or iron plus folic acid there was an increase in Hb of 0.4 and 0.7 g/dl , respectively ( intergroup difference not statistically significant ) . Serum iron and blood folate levels fell in the groups not receiving the appropriate hematinic . In spite of deficient serum and red cell folate levels in 30 and 40 % , respectively , of the group on iron alone , the mean Hb concentration increased at full term and none of the women had a Hb concentration lower than 10 g/dl . Blood folate levels were lower in the iron-supplemented group than in the placebo group , indicating that iron deficiency does not aggravate the folate nutritional status The serial trends of the  whole blood folate level  in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those  receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid .  Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium Investigations on 114 anaemic pregnant women revealed that megaloblastosis  occurred in more than half . A therapeutic follow-up approach clearly indicated that vitamin B12-deficiency was fairly common in such patients ; the need of iron supplementation in many of them for achieving complete remission emphasized the poor status of iron stores . All patients with normoblastic marrow achieved full remission with iron therapy alone . The deficiency of haematinic factors appears to be largely due to poor nutrition Questions have been raised about potentially negative effects of antenatal folic acid use in population s 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 r and omized 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 sub sample ( 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 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
BACKGROUND During pregnancy , fetal growth causes an increase in the total number of rapidly dividing cells , which leads to increased requirements for folate .
Inadequate folate intake leads to a decrease in serum folate concentration , result ing in a decrease in erythrocyte folate concentration , a rise in homocysteine concentration , and megaloblastic changes in the bone marrow and other tissues with rapidly dividing cells OBJECTIVES To assess the effectiveness of oral folic acid supplementation alone or with other micronutrients versus no folic acid ( placebo or same micronutrients but no folic acid ) during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes .