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Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies

      Abstract

      Objective

      To provide updated information on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy.

      Evidence

      Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies

      Costs, risks, and benefits

      The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy These associations may require consideration before initiating folic acid supplementation The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications.

      Values

      The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1).

      Keywords

      ABBRIVIATIONS

      aOR
      adjusted odds ratio
      BMI
      body mass index
      CI
      confidence interval
      GI
      gastrointestinal
      MTHFR
      5,10-methylenetetrahydrofolate reductase
      NTD
      neural tube defect
      OR
      odds ratio
      RBC
      red blood cell
      RCT
      randomized controlled trial

      Summary Statement

      In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III)

      Recommendations

      • 1.
        Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A)
      • 2.
        All women in the reproductive age group (12–45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned, this applies to all women who may become pregnant. (III-A)
      • 3.
        Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A)
      • 4.
        Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose (II-2A)
      • 5.
        Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A)
      • 6.
        Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks' gestational age. (1-A) From 12 weeks' gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A)
      • 7.
        Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks' gestational age. From 12 weeks' gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A)
      Table 1Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Forceon Preventive Health Care
      Quality of evidence assessment
      The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive HealthCare.193
      Classification of recommendationst
      Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Forceon Preventive Health Care.193
      I: Evidence obtained from at least one properly randomized controlled trialA. There is good evidence to recommend the clinical preventive action
      II-1: Evidence from well-designed controlled trials without randomizationB. There is fair evidence to recommend the clinical preventive action
      II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research groupC. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making
      II-3:Evidence obtained from comparisons between times or places with or without the intervention Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this categoryD. There is fair evidence to recommend against the clinical preventive action

      E. There is good evidence to recommend against the clinical preventive action
      III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committeesL. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making
      * The quality of evidence reported in here has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive HealthCare.
      • Woolf S.H.
      • Battista R.N.
      • Angerson G.M.
      • Logan A.G.
      • Eel W.
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      Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Forceon Preventive Health Care.
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      • Battista R.N.
      • Angerson G.M.
      • Logan A.G.
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      INTRODUCTION

      It has been estimated that 4% to 5% of babies are born with a serious congenital anomaly
      • Andres J.
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      Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa:.
      ; 2% to 3% will have congenital anomalies (malformations, deformations or disruptions) that can be recognized prenatally by non-invasive ultrasound screening or anticipated through invasive diagnostic testing and 2% will have developmental or functional anomalies and minor congenital anomalies recognized at birth or during the first year of life.
      • Andres J.
      • Evans J.
      • Royle C.
      Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa:.
      Folic acid, taken orally prior to conception and during the early stages of pregnancy, plays a role in preventing neural tube defects
      MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.
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      • Dudas L.
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      • Czeizel A.E.
      Prevention of congenital abnormalities by periconceptional multivitamin supplementation.
      • Czeizel A.E.
      Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities.
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      Reduction of neural-tube defects after folic acid fortification in Canada.
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      • Zimmer P.
      Incidence of open neural tube defects in Nova Scotia after folic acid fortification.
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      • Wang H.
      Prevention of neural-tube defects with folic acid in China.
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      Crohn's disease, folic acid, and neural tube defects (NTD).
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      Periconceptional use of multivitamins and the occurrence of neural tube defects.
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      The absence of a relation between the periconceptional use of vitamins and neural tube defects.
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      • Rothman K.J.
      Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.
      • Centers for Disease Control (CDC)
      Use of folic acid for prevention of spina bifida and other neural tube defects 1983–1991.
      • Bower C.
      • Stanley F.J.
      Dietary folate as a risk factor for neural tube defects: evidence from a case-control study in Western Australia.
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      • Bollano E.
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      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
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      • Ojeda M.E.
      Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile.
      • Boulet S.L.
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      Trends in the postfortification prevalence of spina bifida and anencephaly in the United States.
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      Genetics of human neural tube defects.
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      118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.
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      Neural tube defects and folate: case far from closed.
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      Impact of folic acid fortification of flour on neural tube defects: a systematic review.
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      Neural tube defects in Latin America and the impact of fortification: a literature review.
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      Dietary supplement use and folate status during pregnancy in the United States.
      and has been associated with preventing other folic acid-sensitive congenital anomalies such as heart defects,
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      Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring.
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      Variants of folate metabolism genes and the risk of conotruncal cardiac defects.
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      • Liu Z.
      • Li Y.
      • Lin Y.
      The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China.
      urinary tract anomalies,
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      ,
      • Czeizel A.E.
      Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation.
      ,
      • Li D.K.
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      • Mueller B.A.
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      • Weiss N.S.
      Periconceptional multivitamin use in relation to the risk of congenital urinary tract anomalies.
      oral facial clefts,
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      ,
      MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.
      • Czeizel A.E.
      • Dudas L.
      Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation.
      • Czeizel A.E.
      Prevention of congenital abnormalities by periconceptional multivitamin supplementation.
      • Czeizel A.E.
      Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities.
      • De Wals P.
      • Tairou F.
      • Van Allen M.I.
      • Uh S.H.
      • Lowry R.B.
      • Sibbald B.
      Reduction of neural-tube defects after folic acid fortification in Canada.
      • Persad V.L.
      • Van den Hof M.C.
      • Dube J.M.
      • Zimmer P.
      Incidence of open neural tube defects in Nova Scotia after folic acid fortification.
      • Berry R.J.
      • Li Z.
      • Erickson J.D.
      • Li S.
      • Moore C.A.
      • Wang H.
      Prevention of neural-tube defects with folic acid in China.
      • Martin R.H.
      • Nimrod C.
      Crohn's disease, folic acid, and neural tube defects (NTD).
      • Mulinare J.
      • Cordero J.F.
      • Erickson J.D.
      • Berry R.J.
      Periconceptional use of multivitamins and the occurrence of neural tube defects.
      and limb defects.
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.

      FOLIC ACID SUPPLEMENTATION AND THE PREVENTION OF BIRTH DEFECTS

      The initial NTD translational research study investigated folic acid supplementation for recurrence prevention of NTDs in a randomized double-blind clinical trial involving 1195 completed high risk pregnancies in women from 33 centres.
      MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.
      The NTD recurrence rate decreased from 3.5% in a non-supplemented group to 1% for women randomized to the group receiving an oral 4 mg folic acid supplementation daily prior to pregnancy and throughout the first 6 weeks of pregnancy.
      The second NTD translational research study was a randomized controlled trial for the primary prevention of NTD occurrence.
      • Czeizel A.E.
      • Dudas L.
      Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation.
      The frequency of NTDs was zero in 2471 women receiving 0.8 mg per day of folic acid compared with 6 cases in 2391 women not receiving folic acid. This RCT study supported previous case-control studies that had provided evidence that pregnant women using multivitamins containing folic acid or dietary folic acid had a lower risk of occurrence NTDs than women not taking supplements.
      • Mulinare J.
      • Cordero J.F.
      • Erickson J.D.
      • Berry R.J.
      Periconceptional use of multivitamins and the occurrence of neural tube defects.
      • Mills J.L.
      • Rhoads G.G.
      • Simpson J.L.
      • Cunningham G.C.
      • Conley M.R.
      • Lassman M.R.
      The absence of a relation between the periconceptional use of vitamins and neural tube defects.
      • Milunsky A.
      • Jick H.
      • Jick S.S.
      • Bruell C.L.
      • MacLaughlin D.S.
      • Rothman K.J.
      Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.
      • Centers for Disease Control (CDC)
      Use of folic acid for prevention of spina bifida and other neural tube defects 1983–1991.
      • Bower C.
      • Stanley F.J.
      Dietary folate as a risk factor for neural tube defects: evidence from a case-control study in Western Australia.
      These 2 landmark RCT studies have provided the folic acid supplementation dosing evidence (from initial experimental expert opinion) for NTD primary prevention and recurrence, but they were completed in female populations without the additional exposure or benefit of folic acid food fortification that is at present in the North American food environment. These RCT folic acid dose results may need to be adjusted due to the present food environment “with folic acid fortified white flour products but more research is required for optimization of oral supplementation dose (maximum benefit; minimum or no risk) with non-pregnant pre-conception exposure to fortified food products.
      • Ray J.G.
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      • Vermeulen M.J.
      • Boss S.
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      • Cole D.E.
      Association of neural tube defects and folic acid food fortification in Canada.

      ORAL FOLIC ACID SUPPLEMENTATION PREGNANCY CARE

      Oral pre-conception folic acid dietary intake or supplementation is required as it is the primary source for the trans-placental transfer of folate/folic acid to the embryo/fetus. No specific studies have been published looking at the embryonic cell folate availability in humans during this embryonic target period of 0 to 8 weeks (conception to 10 gestational weeks). Canadian researchers have made strong contributions in this area of prevention.
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      Public Health Agency of Canada. Preconception health: folic acid for the primary prevention of neural tube defects. A resource document for health professionals, Ottawa ON: PHAC.
      Health Canada. Prenatal nutrition guidelines for health professionals–background on Canada's food guide.
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      Vitamin supplements and the risk for congenital anomalies other than neural tube defects.
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      The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia.
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      Vitamin B12 and the risk of neural tube defects in a folic-acid-fortified population.
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      Motherisk Update 2007. Study on circadian variation in folate pharmacokinetics.
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      Motherisk Update 2007. Compliance with prenatal vitamins. Patients with morning sickness sometimes find it difficult.
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      One third of pregnant and lactating women may not be meeting their folate requirements from diet alone based on mandated levels of folic acid fortification.
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      Folic acid fortification above mandated levels results in a low prevalence of folate inadequacy among Canadians.
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      Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.
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      Hospitalizations of newborns with folate-sensitive birth defects before and after fortification of foods with folic acid.
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      Should folic acid fortification be mandatory?.
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      Periconceptional multivitamin supplementation and multimalformed offspring.
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      Folic acid supplement use is the most significant predictor of folate concentrations in Canadian women of childbearing age.
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      • Walker M.
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      • Ferreira E.
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      Concordance between periconceptional folic acid supplementation and Canadian clinical guidelines.
      • Anderson C.A.
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      • Feng Z.
      Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial.
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      Circulating unmetabolized folic acid: relationship to folate status and effect of supplementation.
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      • Pietrzik K.
      Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?.
      Women should be advised to maintain a nutritionally healthy diet, as recommended in Eating Well with Canada’s Food Guide.
      Health Canada. Prenatal nutrition guidelines for health professionals–background on Canada's food guide.
      Good or excellent sources of natural folate include broccoli, spinach, peas, Brussels sprouts, corn, lentils, and oranges.
      Counselling should emphasize that the recurrence risk for a fetus with an NTD is shared by both mother’s and father’s personal reproductive history, but only the mother is treated with the supplemental dose of pre-conception/first trimester folic acid.

      Folic Acid Food Fortification and Oral Supplementation

      In Canada, since 1998, in an effort to reduce the rate of NTDs, there has been mandatory folic acid fortification of white flour, enriched pasta, and cornmeal. Food fortification coincided with an observed decrease in NTDs in live-born infants,
      • Andres J.
      • Evans J.
      • Royle C.
      Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa:.
      • De Wals P.
      • Tairou F.
      • Van Allen M.I.
      • Uh S.H.
      • Lowry R.B.
      • Sibbald B.
      Reduction of neural-tube defects after folic acid fortification in Canada.
      • Ray J.G.
      • Meier C.
      • Vermeulen M.J.
      • Boss S.
      • Wyatt P.R.
      • Cole D.E.
      Association of neural tube defects and folic acid food fortification in Canada.
      but a proportion of the documented NTD decrease may also be related to an increased use of prenatal tests and subsequent pregnancy termination (secondary prevention) rather than to fortification alone.
      • Peller A.J.
      • Westgate M.N.
      • Holmes L.
      Trends in congenital malformations, 174–1999: effect of prenatal diagnosis and elective termination.
      ,
      • Van Allen M.I.
      • Boyle E.
      • Thiessen P.
      • McFadden D.
      • Cochrane D.
      • Chambers G.K.
      The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia.
      It is possible that certain prevalence data populations may not have included termination of pregnancy prior to the 20 weeks’ gestation information in their reported rate.
      Sherwood et al. assessed the dietary folate intake of pregnant and lactating women at the presently mandated and predicted folic acid fortification levels to determine the prevalence of inadequate and excessive intakes. The conclusion was, at the present mandated levels of food fortification, many pregnant and lactating women are still unlikely to meet their appropriate folate requirements from dietary sources alone, however the actual level of inadequacy cannot be determined until the level of folic acid in the food supply is known with greater precision.
      • Sherwood L.K.
      • Houghton L.A.
      • Tarasuk V.
      • O'Connor D.L.
      One third of pregnant and lactating women may not be meeting their folate requirements from diet alone based on mandated levels of folic acid fortification.
      RBC folate testing/screening for the prevention of birth defects in certain co-existing maternal health conditions requires more investigation to determine the actual effectiveness and use of this testing.

      Factors that may affect the ability to achieve adequate maternal folic acid tissue levels

      Optimization of oral maternal folic acid supplementation is difficult because it relies on folic acid dose, type of folate supplement, bio-availability of the folate from foods, timing of supplementation initiation, maternal metabolism/genetic factors, and many other factors.
      • Colapinto C.K.
      • O'Connor D.L.
      • Dubois L.
      • Tremblay M.S.
      Folic acid supplement use is the most significant predictor of folate concentrations in Canadian women of childbearing age.
      • Miller E.C.
      • Liu N.
      • Wen S.W.
      • Walker M.
      Why do Canadian women fail to achieve optimal pre-conceptional folic acid supplementation? An observational study.
      • Richard-Tremblay A-A.
      • Sheehy O.
      • Audibert F.
      • Ferreira E.
      • Bérard A.
      Concordance between periconceptional folic acid supplementation and Canadian clinical guidelines.
      • Anderson C.A.
      • Beresford S.A.
      • McLerran D.
      • Lampe J.W.
      • Deeb S.
      • Feng Z.
      Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial.
      • Tam C.
      • O'Connor D.
      • Koren G.
      Circulating unmetabolized folic acid: relationship to folate status and effect of supplementation.
      • Obeid R.
      • Holzgreve W.
      • Pietrzik K.
      Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?.

      Recommendations

      • 1.
        Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A)
      • 2.
        All women in the reproductive age group(12–45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned this applies to all women who may become pregnant. (III-A)

      FOLIC ACID FOR CONGENITAL ANOMALIES PREVENTION AND EVALUATIONS

      Background for NTD Prevention

      Neural tube defects are severe congenital anomalies that occur due to a lack of neural tube closure at either the upper, middle, or lower portion of the spine in the third to fourth week after conception (day 26 to day 28 post-conception).
      • Firth H.V.
      • Hurst J.A.
      • Hall J.G.
      Oxford desk reference. Clinical genetics.
      In Canada, the prevalence of NTDs in newborns has declined since 1998 due to food fortification and increased vitamin supplementation,
      Health Canada. Canadian perinatal health report 2003. Canadian Perinatal Surveillance System.
      • Hall J.G.
      • Friedman J.M.
      • Kenna B.A.
      • Popkin J.
      • Jawanda M.
      • Arnold W.
      Clinical, genetic, and epidemiological factors in neural tube defects.
      • Chambers K.
      • Popkin J.
      • Arnold W.
      • Irwin B.
      • Hall J.G.
      Neural tube defects in British Columbia.
      as well as to an increase of prenatal diagnosis/termination.
      • Peller A.J.
      • Westgate M.N.
      • Holmes L.
      Trends in congenital malformations, 174–1999: effect of prenatal diagnosis and elective termination.
      • Van Allen M.I.
      • Boyle E.
      • Thiessen P.
      • McFadden D.
      • Cochrane D.
      • Chambers G.K.
      The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia.
      Recurrence risks may reflect the genetic contribution in different regional or population incidence and folic acid NTD sensitivity (Table 2), as there is still an estimated 1% recurrence rate even with the 4 to 5 mg folic acid prophylaxis supplementation approach.
      • Andres J.
      • Evans J.
      • Royle C.
      Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa:.
      • De Wals P.
      • Tairou F.
      • Van Allen M.I.
      • Uh S.H.
      • Lowry R.B.
      • Sibbald B.
      Reduction of neural-tube defects after folic acid fortification in Canada.
      • Persad V.L.
      • Van den Hof M.C.
      • Dube J.M.
      • Zimmer P.
      Incidence of open neural tube defects in Nova Scotia after folic acid fortification.
      • Hall J.G.
      Folic acid: the opportunity that still exists.
      Neural tube defects.
      • Little J.
      • Elwood J.M.
      eds. Epidemiology and control of neural tube defects. In: Monograph in epidemiology and biostatistics.
      • Baird P.A.
      Neural tube defects in the Sikhs.
      • Hunter AGW.
      Neural tube defects in eastern Ontario and western Quebec: demography and family data.
      • Frecker M.
      • Fraser F.C.
      Epidemiological studies of neural tube defects in Newfoundland.
      • Dallaire L.
      • Melancon S.B.
      • Potier M.
      • Matthiew M-P.
      • Ducharme G.
      Date of conception and prevention of neural tube defects.
      • McBride M.L.
      Sib risks of anencephaly and spina bifida in British Columbia.
      • Dallaire L.
      • Michaud J.
      • Melancon S.B.
      • Potier M.
      • Lambert M.
      • Mitchell G.
      et al. Prenatal diagnosis of fetal anomalies during the second trimester of pregnancy: their characterization and delineation of defects in pregnancies at risk.
      • Gucciardi E.
      • Pietrusiak M.A.
      • Reynolds D.L.
      • Rouleau J.
      Incidence of neural tube defects in Ontario, 1986–1999.
      • Trimble B.K.
      • Baird P.A.
      Congenital anomalies of the central nervous system. Incidence in British Columbia 1952–1972.
      Table 2Anencephaly and spina bifida approximate recurrence risk with no food folic acid fortification or folate supplementation
      Adapted from Firth HV, Hurst JA, Hall JG. Oxford desk reference. Clinical genetics. Oxford: Oxford University Press; 2006.
      • Firth H.V.
      • Hurst J.A.
      • Hall J.G.
      Oxford desk reference. Clinical genetics.
      Recurrence risk, % based on population NTD incidence
      Relationship of NTD affected individual to the at-risk fetusPopulation incidence 5 per 1000Population incidence 2 per 1000Population incidence 1 per 1000
      One sibling522
      Two siblings121010
      One parent444
      One second-degree relative211
      One third degree relative10.750.5
      NTD: neural tube defect
      Table 2 summarizes the increasing NTD clinical risk groups, based on the family relationship of the affected individual to the “at-risk” fetus and the specific NTD population background risk (based on ethnic/genetic population demographics). The Canadian population risk varies across the country, with the highest NTD risk in Newfoundland and the lowest NTD risk in British Columbia.
      • Firth H.V.
      • Hurst J.A.
      • Hall J.G.
      Oxford desk reference. Clinical genetics.
      Table 3 summarizes the evidence-based risk factors for low maternal RBC or serum folate status that are associated specifically with neural tube defects.
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      • Greene N.D.E.
      • Stanier P.
      • Copp A.J.
      Genetics of human neural tube defects.
      • Shaw G.M.
      • Lu W.
      • Zhu H.
      • Yang W.
      • Briggs F.S.B.
      • Carmichael S.L.
      118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.
      • Blom H.K.
      • Shaw G.M.
      • den Heijer M.
      • Finnell R.H.
      Neural tube defects and folate: case far from closed.
      • Blom H.J.
      Folic acid, methylation and neural tube closure in humans.
      • Van Allen M.I.
      • McCourt C.
      • Lee N.S.
      Public Health Agency of Canada. Preconception health: folic acid for the primary prevention of neural tube defects. A resource document for health professionals, Ottawa ON: PHAC.
      • Firth H.V.
      • Hurst J.A.
      • Hall J.G.
      Oxford desk reference. Clinical genetics.
      Health Canada. Canadian perinatal health report 2003. Canadian Perinatal Surveillance System.
      • Hall J.G.
      • Friedman J.M.
      • Kenna B.A.
      • Popkin J.
      • Jawanda M.
      • Arnold W.
      Clinical, genetic, and epidemiological factors in neural tube defects.
      • Hall J.G.
      Folic acid: the opportunity that still exists.
      Neural tube defects.
      • Oakley G.P.
      Folate deficiency is an "imminent health hazard" causing a worldwide birth defects epidemic.
      • Eichholzer M.
      • Tonz O.
      • Zimmerman R.
      Folic acid: a public-health challenge.
      • Oakley G.P.
      The scientific basis for eliminating folic acid-preventable spina bifida: a modern miracle from epidemiology.
      • Oakley G.P.
      Folic acid-preventable spina bifida. A good start but much to be done.
      • Wilson R.D.
      • Désilets V.
      • Wyatt P.
      • Langlois S.
      • Gagnon A.
      • Allen V.
      • et al.
      Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; The Motherrisk Program. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. SOGC Clinical Practice Guidelines, No. 201, December 2007.
      • Evans J.A.
      Pre-conceptional vitamin/folic acid supplementation 2007.
      • Health Canada
      Prenatal nutrition guidelines for health professionals.
      • Health Canada
      High dose folic acid supplementation – questions and answers for health professionals. Ottawa: Health Canada.
      • Lammer E.J.
      • Sever L.E.
      • Oakley Jr., G.P.
      Teratogen updates: valproic acid.
      • Rosa F.W.
      Spina bifida in infants of women treated with carbamazepine during pregnancy.
      • Warkany J.
      Amniopterin and methotrexate: folic acid deficiency.
      • Briggs G.G.
      • Freeman R.K.
      • Yaffe S.J.
      Drugs in pregnancy and lactation, 9th ed. A reference guide to fetal and neonatal risk.
      • American College of Obstetricians and Gynecologists (ACOG)
      ACOG education pamphlet AP 056.
      • American College of Obstetricians and Gynecologists (ACOG)
      ACOG education pamphlet AP 146.
      US Preventative Services Task Force. Folic acid for the prevention of neural tube defects. US Preventive Services Task Force recommendation statement.
      Table 3Identified increased risk factors for fetal NTD or low maternal RBC folate status
      Personal/family history or ethnic risk
      • Andres J.
      • Evans J.
      • Royle C.
      Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa:.
      MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.
      • Czeizel A.E.
      • Dudas L.
      Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation.
      • Czeizel A.E.
      Prevention of congenital abnormalities by periconceptional multivitamin supplementation.
      • Czeizel A.E.
      Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities.
      ,
      • Greene N.D.E.
      • Stanier P.
      • Copp A.J.
      Genetics of human neural tube defects.
      • Shaw G.M.
      • Lu W.
      • Zhu H.
      • Yang W.
      • Briggs F.S.B.
      • Carmichael S.L.
      118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.
      • Blom H.K.
      • Shaw G.M.
      • den Heijer M.
      • Finnell R.H.
      Neural tube defects and folate: case far from closed.
      • Blom H.J.
      Folic acid, methylation and neural tube closure in humans.
      NTD: maternal or paternal affected, previous affected fetus for either parent, child, sibling, or second/third degree relative

      MTHFR genotype 677TT carrier homozygous

      677CST carrier heterozygous
      Medical/surgical condition
      • Van Allen M.I.
      • McCourt C.
      • Lee N.S.
      Public Health Agency of Canada. Preconception health: folic acid for the primary prevention of neural tube defects. A resource document for health professionals, Ottawa ON: PHAC.
      ,
      • Firth H.V.
      • Hurst J.A.
      • Hall J.G.
      Oxford desk reference. Clinical genetics.
      Health Canada. Canadian perinatal health report 2003. Canadian Perinatal Surveillance System.
      • Hall J.G.
      • Friedman J.M.
      • Kenna B.A.
      • Popkin J.
      • Jawanda M.
      • Arnold W.
      Clinical, genetic, and epidemiological factors in neural tube defects.
      ,
      • Lammer E.J.
      • Sever L.E.
      • Oakley Jr., G.P.
      Teratogen updates: valproic acid.
      • Warkany J.
      Amniopterin and methotrexate: folic acid deficiency.
      • Briggs G.G.
      • Freeman R.K.
      • Yaffe S.J.
      Drugs in pregnancy and lactation, 9th ed. A reference guide to fetal and neonatal risk.
      GI: malabsorption/inflammatory bowel, Crohn's, active Celiac disease, gastric bypass surgery, advanced liver disease

      Renal: kidney dialysis

      Pre-gestational diabetes (type I or II)

      Anti-epilepsy or folate-inhibiting medications (see Table 4)
      Maternal co-morbidities
      • Hall J.G.
      Folic acid: the opportunity that still exists.
      ,
      • Oakley G.P.
      Folate deficiency is an "imminent health hazard" causing a worldwide birth defects epidemic.
      • Eichholzer M.
      • Tonz O.
      • Zimmerman R.
      Folic acid: a public-health challenge.
      • Oakley G.P.
      The scientific basis for eliminating folic acid-preventable spina bifida: a modern miracle from epidemiology.
      • Oakley G.P.
      Folic acid-preventable spina bifida. A good start but much to be done.
      • Wilson R.D.
      • Désilets V.
      • Wyatt P.
      • Langlois S.
      • Gagnon A.
      • Allen V.
      • et al.
      Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; The Motherrisk Program. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. SOGC Clinical Practice Guidelines, No. 201, December 2007.
      • Evans J.A.
      Pre-conceptional vitamin/folic acid supplementation 2007.
      Maternal obesity: BMI > 30 kg/m2 or 80 kg (pre-pregnancy weight)
      Maternal lifestyle factors
      Neural tube defects.
      • Health Canada
      Prenatal nutrition guidelines for health professionals.
      • Health Canada
      High dose folic acid supplementation – questions and answers for health professionals. Ottawa: Health Canada.
      • Wang M.
      • Wang Z.P.
      • Gao L.J.
      • Gong R.
      • Sun X.H.
      • Zhao Z.T.
      Maternal body mass index and the association between folic acid supplements and neural tube defects.
      • Nguyen P.
      • Thomas M.
      • Koren G.
      Predictors of prenatal multivitamin adherence in pregnant women.
      • Kennedy D.
      • Koren G.
      Motherisk update 2012. Identifying women who might benefit from higher doses of folic acid in pregnancy.
      Smoking

      Alcohol overuse

      Non-prescription drug use/abuse

      Low socio-economic status

      Poor/restricted diet
      NTD: neural tube defect; RBC: red blood cell; MTHFR: methylenete trahydrofolate reductase
      Table 4 summarizes the commonly used medications/drugs prescribed for certain medical therapies that have been shown to have interactions with folate metabolism and may alter RBC folate levels with a resulting increased risk for congenital anomaly outcomes.
      • Rosa F.W.
      Spina bifida in infants of women treated with carbamazepine during pregnancy.
      • Warkany J.
      Amniopterin and methotrexate: folic acid deficiency.
      • Briggs G.G.
      • Freeman R.K.
      • Yaffe S.J.
      Drugs in pregnancy and lactation, 9th ed. A reference guide to fetal and neonatal risk.
      • American College of Obstetricians and Gynecologists (ACOG)
      ACOG education pamphlet AP 056.
      Table 4Interactions between drugs or medications and folic acid
      1. Biology reduced folic acid activityInterference with erythrocyte maturation

      Other
      Chloramphenicol

      Methotrexate

      Metformin
      2. Reduced folic acid levelsImpaired absorption

      Increased metabolism
      Sulfasalazine

      Phenobarbital

      Phenytoin
      3. Other interactionsNot reportedPrimidone

      Triamterene

      Barbiturates
      Table 5 summarizes the studies with case–control, cohort, or RCT comparisons (odds ratio) and decreased, increased, or no effects on specific congenital anomalies.
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      • Li X.
      • Li S.
      • Mu D.
      • Liu Z.
      • Li Y.
      • Lin Y.
      The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China.
      • O'Neill J.
      Do folic acid supplements reduce facial clefts?.
      • Johnson C.Y.
      • Little J.
      Folate intake, markers of folate status and oral clefts: is the evidence converging?.
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      • Canfield M.A.
      • Collins J.S.
      • Boto L.D.
      • Williams L.J.
      • Mai C.T.
      • Kirby R.S.
      Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.
      Folic acid in combination with multivitamin supplements has been shown to reduce certain other congenital anomalies such as heart defects,
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      • Shaw G.M.
      • O'Malley C.D.
      • Wasserman C.R.
      • TolarovaM M.M.
      • Lammer E.J.
      Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring.
      • Botto L.D.
      • Khoury M.J.
      • Mulinara J.
      • Erickson J.D.
      Periconceptional multivitamin use and the occurrence of conotruncal heart defects:results from a population-based, case-control study.
      • Czeizel A.E.
      Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation.
      • Goldmuntz E.
      • Woyciechowski S.
      • Renstrom D.
      • Lupo P.J.
      • Mitchell L.E.
      Variants of folate metabolism genes and the risk of conotruncal cardiac defects.
      • Li X.
      • Li S.
      • Mu D.
      • Liu Z.
      • Li Y.
      • Lin Y.
      The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China.
      urinary tract anomalies,
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      • Czeizel A.E.
      Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation.
      • Li D.K.
      • Daling J.R.
      • Mueller B.A.
      • Hickok D.E.
      • Fantel A.G.
      • Weiss N.S.
      Periconceptional multivitamin use in relation to the risk of congenital urinary tract anomalies.
      oral facial clefts,
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      • Hayes C.
      • Werler M.M.
      • Willett W.C.
      • Mitchell A.A.
      Case-control study of periconceptional folic acid supplementation and oral clefts.
      • Shaw G.M.
      • Lammer E.J.
      • Wasserman C.R.
      • O'Malley C.D.
      • Tolarova M.M.
      Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally.
      • Tolarova M.
      • Harris J.
      Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins.
      • Badovinac R.L.
      • Werler M.M.
      • Williams P.L.
      • Kelsey K.T.
      • Hayes C.
      Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis.
      • Yazdy M.M.
      • Honein M.A.
      • Xing J.
      Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply.
      • O'Neill J.
      Do folic acid supplements reduce facial clefts?.
      • Johnson C.Y.
      • Little J.
      Folate intake, markers of folate status and oral clefts: is the evidence converging?.
      • Wehby G.L.
      • Félix T.M.
      • Goco N.
      • Richieri-Costa A.
      • Chakraborty H.
      • Souza J.
      High dose folic acid supplementation, oral cleft recurrence and fetal growth.
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      and limb defects.
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      At present, multifactorial inheritance (genetic and environmental factors)
      • Hall J.G.
      • Friedman J.M.
      • Kenna B.A.
      • Popkin J.
      • Jawanda M.
      • Arnold W.
      Clinical, genetic, and epidemiological factors in neural tube defects.
      • Holmes L.B.
      • Driscoll S.G.
      • Atkins L.A.
      Etiologic heterogeneity of neural tube defects.
      • Khoury M.J.
      • Erickson J.D.
      • James L.M.
      Etiologic heterogeneity of neural tube defects: clues from epidemiology.
      is the most commonly reported etiology for NTDs, but monogenic, chromosomal, and teratogenic etiologies have specific effects and have not been well studied in their association with folic acid deprivation or supplementation.
      • Jones K.L.
      Smith's recognizable patterns of human malformation, 6th ed.
      Table 5Summary of congenital anomalies (decreased or increased or no effect) following folic acid food fortification
      Study referenceAnomalyCase–Control (95% CI)Cohort/RCT (95% CI)
      Meta-analysis
      Goh et al. (2006)
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      Neural tube defect0.67 (0.58–0.77)0.52 (0.39–0.69)
      Oral facial cleft0.63 (0.54–0.73)0.58 (0.28–1.19)
      Cardiovascular defects0.78 (0.67–0.92)0.61 (0.40–0.92)
      Limb reduction defects0.48 (0.30–0.76)0.57 (0.38–0.85)
      Cleft palate0.76 (0.62–0.93)0.42 (0.06–2.84)
      Urinary tract defects0.48 (0.30–0.76)0.68 (0.35–1.31)
      Congenital hydrocephalus0.37 (0.24–0.56)1.54 (0.53–4.50)
      Johnson and Little (2008)
      • Johnson C.Y.
      • Little J.
      Folate intake, markers of folate status and oral clefts: is the evidence converging?.
      Cleft lip and palate0.75 (0.65–0.88)
      Cleft palate only0.88 (0.76–1.01)
      Single Population
      Li et al. (2013)
      • Li X.
      • Li S.
      • Mu D.
      • Liu Z.
      • Li Y.
      • Lin Y.
      The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China.
      Heart defects isolated0.52 (0.34–0.78)
      and complex0.27 (0.14–0.55)
      Godwin et al. (2008)
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      Spina bifida0.51 (0.36–0.73)
      OS atrial septal defects0.80 (0.69–0.93)
      Ureteric obstruction1.45 (1.24–1.70)
      Abdominal wall defect1.40 (1.04–1.88)
      Pyloric stenosis1.49 (1.18–1.89)
      Canfield et al. (2005)
      • Canfield M.A.
      • Collins J.S.
      • Boto L.D.
      • Williams L.J.
      • Mai C.T.
      • Kirby R.S.
      Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.
      Anencephaly0.84 (0.76–0.94)
      Spina bifida0.66 (0.61–0.71)
      TGA0.88 (0.81–0.96)
      Cleft palate only0.88 (0.82–0.95)
      Pyloric stenosis0.95 (0.90–0.99)
      Omphalocele0.79 (0.66–0.95)
      Upper limb reduction0.89 (0.80–0.99)
      O'Neill (2007)
      • O'Neill J.
      Do folic acid supplements reduce facial clefts?.
      Cleft lip ± palate0.61 (0.39–0.96)Folic acid 0.4 mg daily
      0.75 (0.50–1.11)Folate diet only
      0.36 (0.17–0.77)Supplement + diet
      Cleft palate only1.07 (0.56–2.03)
      Goh et al (2006)
      • Goh Y.I.
      • Bollano E.
      • Einarson T.R.
      • Koren G.
      Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.
      No effect identified forTrisomy 21
      Pyloric stenosis
      Undescended testis
      Hypospadias
      RCT: randomized control trial; OS: ostium secunda; TGA: transposition of the great arteries
      The risk categories for fetal NTD outcome should consider the 2 major effect pathways:
      • 1.
        Genetic factors including gene polymorphisms that affect the efficiency of folate metabolism, gene mutations, affects related to DNA methylation/epigenetics, and associated chromosomal anomalies, and
      • 2.
        Environmental factors such as dietary folate intake (food fortification and/or dietary supplementation), gastrointestinal absorption efficiency, teratogenic medication exposure (epilepsy or folate antagonist medications), glucose metabolism (obesity, diabetes type I and II), drugs, smoking, alcohol, and “proposed” folate receptor auto-antibodies. Details for the genetic and environmental factors/considerations with fetal and pediatric outcomes are available in the references.
        • Greene N.D.E.
        • Stanier P.
        • Copp A.J.
        Genetics of human neural tube defects.
        • Shaw G.M.
        • Lu W.
        • Zhu H.
        • Yang W.
        • Briggs F.S.B.
        • Carmichael S.L.
        118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects.
        • Blom H.K.
        • Shaw G.M.
        • den Heijer M.
        • Finnell R.H.
        Neural tube defects and folate: case far from closed.
        • Blom H.J.
        Folic acid, methylation and neural tube closure in humans.
        • Pietrzik K.
        • Bailey L.
        • Shane B.
        Folic acid and L-5 methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics.
        • Bodnar L.M.
        • Himes K.P.
        • Venkataramanan R.
        • Chen J.Y.
        • Evans R.W.
        • Meyer J.L.
        Maternal serum folate species in early pregnancy and risk of preterm birth.
        • Suh J.R.
        • Herbig A.K.
        • Stover P.J.
        New perspectives on folate catabolism.
        • van der Linden I.J.
        • Den Heijer M.
        • Alman L.A.
        • Gellekink H.
        • Vermeulen S.H.
        • Kluijtmans L.A.
        The methionine synthase reductase 66A to G polymorphism is a maternal risk factor for spina bifida.
        • Wallingford J.B.
        • Niswander L.A.
        • Shaw G.M.
        • Finnell R.H.
        The continuing challenge of understanding, preventing, and treating neural tube defects.
        • Burdge G.C.
        • Lillycrop K.A.
        Folic acid supplementation in pregnancy: are there devils in the detail?.
        • Salbaum J.M.
        • Kappen C.
        Genetic and epigenomic footprints of folate.
        • Greenburg J.A.
        • Bell S.J.
        • Guan Y.
        • Yu Y-H.
        Folic acid supplementation and pregnancy: more than just neural tube defect prevention.
        • Vasquez K.
        • Kuizon S.
        • Junaid M.
        • El Idrissi A.
        Chapter 8. The effect of folic acid on GABA(A)-B 1 receptor subunit. In: El Idrissi A, L'Amoreaux WJ, editors. Taurine 8. Advances in experimental medicine and biology 775.
        • Hoyo C.
        • Murtha A.P.
        • Schildkraut J.M.
        • Forman M.R.
        • Calingaert B.
        • Demark-Wahnefried W.
        Folic acid supplementation before and during pregnancy in the Newborn Epigenetics Study (NEST).
        • Sie K.K.
        • Li J.
        • Ly A.
        • Sohn K.J.
        • Croxford R.
        • Kim Y.I.
        Effect of maternal and postweaning folic acid supplementation on global and gene-specific DNA methylation in the liver of the rat offspring.
        • Babcook C.J.
        • Ball R.H.
        • Feldkamp M.L.
        Prevalence of aneuploidy and additional anatomic abnormalities in fetuses with open spina bifida: population based study in Utah.
        • Kumar V.
        • Singh A.
        • Sharma S.P.
        • Srivastava A.
        • Saxena A.
        • Gangopadhyay A.N.
        Clinical spectrum of neural tube defects with special reference to karyotyping study.
        • Donnelly J.C.
        • Platt L.D.
        • Rebarber A.
        • Zachary J.
        • Grobman W.A.
        • Wapner R.J.
        Association of copy number variants with specific ultrasonographically detected fetal anomalies.
        • Desilets V.
        • Oligny L.L.
        Genetics Committee of the Society of Obstetricians and Gynaecology Canada; Family Physicians Advisory Committee; Medico–Legal Committee of the SOGC. Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype. SOGC Technical Update, No. 267, October 2011.
        • Mills J.L.
        • Carter T.C.
        • Kay D.M.
        • Browne M.
        • Brody L.C.
        • Liu A.
        Folate and vitamin B12 related genes and risk for omphalocele.
        • Hollis N.D.
        • Allen E.G.
        • Oliver T.R.
        • Tinker S.W.
        • Druschel C.
        • Hobbs C.A.
        Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project.
        • Goh Y.I.
        • Bollano E.
        • Einarson T.R.
        • Koren G.
        Motherisk Update 2007. Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis.
        • Olshan A.F.
        • Smith J.C.
        • Bondy M.L.
        • Neglia J.P.
        • Pollock B.H.
        Maternal vitamin use and the reduced risk of neuroblastoma.
        • Allen V.M.
        • Armson B.A.
        Genetics Committee and Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada. Teratogenicity associated with pre-existing and gestational diabetes. SOGC Clinical Practice Guideline, No. 200, November 2007.
        • Wentzel P.
        Can we prevent diabetic birth defects with micronutrients?.
        • Bánhidy F.
        • Dakhlaoui A.
        • Puhó E.H.
        • Czeizel AAE.
        Is there a reduction of congenital abnormalities in the offspring of diabetic pregnant women after folic acid supplementation? A population-based case-control study.
        • Matok I.
        • Gorodischer R.
        • Koren G.
        • Landau D.
        • Wiznitzer A.
        • Levy A.
        Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations.
        • Ray J.G.
        • Langman L.J.
        • Mamdani M.M.
        • Cole DEC.
        Absence of effect of folic acid flour fortification on anticolvulsant drug levels.
        • Morrow J.I.
        • Hunt S.J.
        • Russell A.J.
        • Smithson W.H.
        • Parsons L.
        • Robertson I.
        Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register.
        • Hauser W.A.
        Folic acid supplementation: too much of a good thing?.
        • Kjaer D.
        • Horvath-Puhó E.
        • Christensen J.
        • Vestergaard M.
        • Czeizel A.E.
        • Sørensen H.T.
        Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study.
        • Werler M.M.
        • Ahrens K.A.
        • Bosco JLF.
        • Mitchell A.A.
        • Anderka M.T.
        • Gilboa S.M.
        Use of antiepileptic medications in pregnancy in relation to risks of birth defects.
        • Meijer W.M.
        • de Walle H.E.
        • Kerstjens-Frederikse W.S.
        • de Jong-van den Berg L.T.
        Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists.
        • Harden C.L.
        • Pennell P.B.
        • Koppel B.S.
        • Hovinga C.A.
        • Gidal B.
        • Meador K.J.
        Management issues for women with epilepsy—focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
        • Emes R.D.
        • Clifford H.
        • Haworth K.E.
        • Farrell W.E.
        • Fryer A.A.
        • Carroll W.D.
        Antiepileptic drugs and the fetal epigenome.
        • Czeizel A.E.
        • Puhó E.H.
        • Langmar Z.
        • Ács N.
        • Bánhidy F.
        Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study.
        • van Uitert E.M.
        Steegers-Theunissen RPM. Influence of maternal folate status on human fetal growth parameters.
        • Kim M.W.
        • Hong S.C.
        • Choi J.S.
        • Han J-Y.
        • Oh M.J.
        • Kim H.J.
        Homocysteine, folate, and pregnancy outcomes.
        • Li Z.
        • Ye R.
        • Zhang L.
        • Li H.
        • Liu J.
        • Ren A.
        Folic acid supplementation during early pregnancy and the risk of gestational hypertension and preeclampsia.
        • Linabery A.M.
        • Johnson K.J.
        • Ross J.A.
        Childhood cancer incidence trends in association with US folic acid fortification (1986–2008).
        • Milne E.
        • Greenop K.R.
        • Bower C.
        • Miller M.
        • van Bockxmeer F.M.
        • Scott R.J.
        Maternal use of folic acid and other supplements and risk of childhood brain tumors.
        • Amigou A.
        • Rudant J.
        • Orsi L.
        • Goujon-Bellec S.
        • Leverger G.
        • Baruchel A.
        Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE).
        • Surén P.
        • Roth C.
        • Bresnahan M.
        • Haugen M.
        • Hornig M.
        • Hirtz D.
        Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children.
        • Berry R.J.
        • Crider K.S.
        • Yeargin-Allsopp M.
        Periconceptional folic acid and risk of autism spectrum disorders.

      POTENTIAL CAUTION FOR MATERNAL, FETAL, CHILDHOOD, OR GENERAL POPULATION WITH FOLIC ACID SUPPLEMENTATION

      Benefit

      Folic acid, in a 0.4 to 1.0 mg daily dose
      • Brown J.E.
      • Jacobs D.
      • Hartman T.
      • Barosso G.
      • Stang J.
      • Gross M.
      Predictors of red cell folate level in women attempting pregnancy.
      • Simpson J.L.
      • Bailey L.B.
      • Pietrzik K.
      • Shane B.
      • Holzgreve W.
      Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I—folate, vitamin B12, vitamin B6.
      • Ahn E.
      • Nava-Ocampo A.A.
      • Motherisk Koren G.
      Multivitamin supplement for pregnant women. New insights.
      • Simpson J.L.
      • Shulman L.P.
      • Brown H.
      • Holzgreve W.
      Closing the folate gap in reproductive-age women.
      is not known to cause demonstrable harm to the developing fetus or to the pregnant woman. The risk of maternal or fetal toxicity from oral folic acid intake due to vitamin supplements and/or fortified foods is low. Folic acid is a water soluble vitamin, so any excess intake is anticipated to be excreted in the urine.
      Folic acid has not been shown to promote or to prevent breast cancer.
      • Ravdin P.M.
      • Cronin K.A.
      • Howlader N.
      • Ber C.D.
      • Chlebowski R.T.
      • Feuer E.J.
      The decrease in breast-cancer incidence in 2003 in the United States.
      • Kim Y.I.
      Does a high folate intake increase the risk of breast cancer?.
      • Lubecka-Pietruszewska K.
      • Kaufman-Szymczyk A.
      • Stefanska B.
      • Fabianowska-Majewska K.
      Folic acid enforces DNA methylation-mediated transcriptional silencing of PTEN, APC and RARbeta2 tumour suppressor genes in breast cancer.
      Ovarian cancer studies suggest (but not with statistical significance) that relatively high dietary folate intake may be associated with a reduction in ovarian cancer risk among woman with high alcohol and methionine intake.
      • Navarro-Silvera S.A.
      • Jain M.
      • Howe G.R.
      • Miller A.B.
      • Rohan T.E.
      Dietary folate consumption and risk of ovarian cancer: a prospective cohort study.
      Evidence has been reported for a decreased pre-valence of preeclampsia with maternal folic acid supplementation.
      • Kim M.W.
      • Hong S.C.
      • Choi J.S.
      • Han J-Y.
      • Oh M.J.
      • Kim H.J.
      Homocysteine, folate, and pregnancy outcomes.
      • Kim M.W.
      • Ahn K.H.
      • Ryu J.H.
      • Hong S.C.
      • Lee J.S.
      • Nava-Ocampo A.A.
      Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes.
      • Dekker G.A.
      • de Vries J.I.
      • Doelitzsch P.M.
      • Huijgens P.C.
      • von Blomberg B.M.
      • Jakobs C.
      Underlying disorders associated with severe early-onset preeclampsia.
      • Rajkovic A.
      • Mahomed K.
      • Malinow M.R.
      • Sorenson T.K.
      • Woelk G.B.
      • Williams M.A.
      Plasma homocyst(e)ine concentration in eclamptic and pre-eclamptic African women postpartum.
      • Wen S.W.
      • Chen X.K.
      • Rodger M.
      • White R.R.
      • Yanag Q.
      • Smith G.N.
      Folic acid supplementation in early second trimester and the risk of preeclampsia.
      An Australian study found that high serum folate did not mask the macrocytosis of cobalamin (vitamin B12) deficiency of pernicious anemia.
      • Metz J.
      • McNel A.R.
      • Levin M.
      The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate.
      A Cochrane Review found no conclusive evidence of benefit of folic acid supplementation on pregnancy outcomes (preterm birth, stillbirths, neonatal deaths, low birth weight babies, pre-delivery anemia, or low pre-delivery red cell folate).
      • Lassi Z.S.
      • Salam R.A.
      • Haider B.A.
      • Bhutta Z.A.
      Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes.

      Risks and Cautions

      Folic acid dosing above the recommended supplement-ation amounts (supra-physiologic doses) has not been shown to have any added fetal/maternal health or developmental benefits, although recent epigenetic/methylation studies in animals and humans have indicated that some caution and research is required. The folic acid doses of 5 mg have not been reported to have maternal or fetal risks, but long-term high-dose 5 mg folic acid use has not been well studied in a prenatal population.
      • Czeizel A.E.
      • Dudas L.
      Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation.
      • Mulinare J.
      • Cordero J.F.
      • Erickson J.D.
      • Berry R.J.
      Periconceptional use of multivitamins and the occurrence of neural tube defects.
      • Mills J.L.
      • Rhoads G.G.
      • Simpson J.L.
      • Cunningham G.C.
      • Conley M.R.
      • Lassman M.R.
      The absence of a relation between the periconceptional use of vitamins and neural tube defects.
      • Milunsky A.
      • Jick H.
      • Jick S.S.
      • Bruell C.L.
      • MacLaughlin D.S.
      • Rothman K.J.
      Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.
      • Centers for Disease Control (CDC)
      Use of folic acid for prevention of spina bifida and other neural tube defects 1983–1991.
      • Bower C.
      • Stanley F.J.
      Dietary folate as a risk factor for neural tube defects: evidence from a case-control study in Western Australia.
      • Badovinac R.L.
      • Werler M.M.
      • Williams P.L.
      • Kelsey K.T.
      • Hayes C.
      Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis.
      • Yazdy M.M.
      • Honein M.A.
      • Xing J.
      Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply.
      • Robbins J.M.
      • Tilford J.M.
      • Bird T.M.
      • Cleves M.A.
      • Reading A.
      • Hobbs C.A.
      Hospitalizations of newborns with folate-sensitive birth defects before and after fortification of foods with folic acid.
      • Bell K.N.
      • Oakley G.P.
      Tracking the prevention of folic acid-preventable spina bifida and anencephaly.
      • Duffy T.P.
      Hematologic aspects of pregnancy. In: Barrow GN, Duffy TP, eds. Medical complications during pregnancy, 5th ed.
      Recent summary conclusions from colorectal cancer reviews of the topic are still cautionary.
      • Kennedy D.A.
      • Stern S.J.
      • Moretti M.
      • Matok I.
      • Sarkar M.
      • Nickel C.
      Folate intake and the risk of colorectal cancer: a systemic review and meta-analysis.
      • Mason J.B.
      • Dickstein A.
      • Jacques P.
      • Haggarty P.
      • Selhub J.
      • Dallal G.
      A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.
      • Lucock M.
      • Yates Z.
      Folic acid fortification: a double-edged sword.
      • Sauer J.
      • Mason J.B.
      • Choi S-W.
      Too much folate—a risk factor for cancer and cardiovascular disease?.
      • Fife J.
      • Raniga S.
      • Hider P.N.
      • Frizelle F.A.
      Folic acid supplementation and colorectal risk: a meta-analysis.
      • Figueiredo J.C.
      • Mott L.A.
      • Giovannucci E.
      • Wu K.
      • Cole B.
      • Grainge M.J.
      Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials.
      • Burh G.
      • Bales C.W.
      Nutritional supplements for older adults: review and recommendations—Part II.
      • Dunlap B.
      • Shelke K.
      • Salem S.A.
      • Keith L.G.
      Folic acid and human reproduction—ten important issues for clinicians.
      • Toriello H.V.
      Policy statement on folic acid and neural tube defects.
      • Tulauliker V.S.
      • Arulkumaran S.
      Folic Acid in obstetric practice: a review.
      • Curtin K.
      • Samowitz W.S.
      • Ulrich C.M.
      • Wolff R.K.
      • Herrick J.S.
      • Caan B.J.
      Nutrients in folate-mediated, one-carbon metabolism and the risk of rectal tumors in men and women.
      • Miller J.W.
      • Ulrich C.M.
      Folic acid and cancer—where are we today?.
      • Vollset S.E.
      • Clarke R.
      • Lewington S.
      • Ebbing M.
      • Halsey J.
      • Lonn E.
      Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals.
      No evidence of cancer risk from folate supplements.
      Two studies show no association of folic acid with colorectal adenoma or recurrence.
      • Song Y.
      • Manson J.E.
      • Lee I.M.
      • Cook N.R.
      • Paul L.
      • Selhub J.
      Effect of combined folic acid, vitamin B(6), and vitamin B(12) on colorectal adenoma.
      • Castillo-Lancellotti C.
      • Tur Mari J.A.
      • Uauy Dagach R.
      Folic acid supplementation and colorectal adenoma recurrence: systematic review.

      FETAL AND PEDIATRIC ISSUES

      Benefit

      Pediatric ongoing health benefits have been identified following prenatal multivitamin supplementation before and in early pregnancy.
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      • Olshan A.F.
      • Smith J.C.
      • Bondy M.L.
      • Neglia J.P.
      • Pollock B.H.
      Maternal vitamin use and the reduced risk of neuroblastoma.
      Maternal use of prenatal multivitamins is associated with a decreased risk for pediatric brain tumours (OR 0.73, 95% CI 0.60 to 0.88),
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      • Milne E.
      • Greenop K.R.
      • Bower C.
      • Miller M.
      • van Bockxmeer F.M.
      • Scott R.J.
      Maternal use of folic acid and other supplements and risk of childhood brain tumors.
      • Greenop K.R.
      • Miller M.
      • de Klerk N.H.
      • Scott R.J.
      • Attia J.
      • Ashton L.J.
      Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and risk of childhood brain tumors.
      neuroblastoma (OR 0.53, 95% CI 0.42 to 0.68),
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      leukemia (OR 0.61, 95% CI 0.50 to 0.74),
      • Godwin K.A.
      • Sibbald B.
      • Bedard T.
      • Kuzeljevic B.
      • Lowry R.B.
      • Arbour L.
      Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.
      • Amigou A.
      • Rudant J.
      • Orsi L.
      • Goujon-Bellec S.
      • Leverger G.
      • Baruchel A.
      Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE).
      Wilms’ tumour,
      • van Uitert E.M.
      Steegers-Theunissen RPM. Influence of maternal folate status on human fetal growth parameters.
      primitive neuroectodermal tumours,
      • Linabery A.M.
      • Johnson K.J.
      • Ross J.A.
      Childhood cancer incidence trends in association with US folic acid fortification (1986–2008).
      and ependymomas.
      • Linabery A.M.
      • Johnson K.J.
      • Ross J.A.
      Childhood cancer incidence trends in association with US folic acid fortification (1986–2008).
      It was stated that it is not known which constituent(s) among the multivitamins confers this protective effect.
      A study looking at maternal use of folic acid supplementation and the diagnosis of childhood autism found that folic acid supplementation around the time of conception was associated with lower risk of autistic disorder in a Norwegian cohort. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI 0.41 to 0.90). These findings cannot establish causality but they do support the use of prenatal folic acid supplementation.
      • Surén P.
      • Roth C.
      • Bresnahan M.
      • Haugen M.
      • Hornig M.
      • Hirtz D.
      Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children.
      • Berry R.J.
      • Crider K.S.
      • Yeargin-Allsopp M.
      Periconceptional folic acid and risk of autism spectrum disorders.

      Risks and Cautions

      Folic acid and multivitamin supplementation is possibly associated with an increased incidence of twins, although positive and negative twinning findings have been reported with the possible confounders of in vitro fertilization and ovarian stimulation or other environmental hormones. A clear relationship between folic acid supplementation and twinning has not been confirmed.
      • Brown J.E.
      • Jacobs D.
      • Hartman T.
      • Barosso G.
      • Stang J.
      • Gross M.
      Predictors of red cell folate level in women attempting pregnancy.
      • Czeizel A.E.
      • Vargha P.
      Periconceptional folic acid/multivitamin supplementation and twin pregnancy.
      • Steinman G.
      Can the chance of having twins be modified by diet?.
      • Haggarty P.
      • McCallum H.
      • McBain H.
      • Andrews K.
      • Duthie S.
      • McNeill G.
      Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study.
      A slightly increased risk of wheeze and respiratory infection was found in the offspring whose mothers took folic acid supplements during pregnancy.
      • Hågberg S.E.
      • London S.J.
      • Stigum H.
      • Nafstad P.
      • Nystad W.
      Folic acid supplements in pregnancy and early childhood respiratory health.
      It was suggested that methyl donors in the maternal diet during pregnancy may influence respiratory health in children consistent with epigenetic mechanisms. Zetstra-van der Woude et al. reported maternal high-dose folic acid (5 mg) was associated with an increased rate of asthma medication among children (recurrent asthma medication IRR [incidence rate ratio] = 1.14, 1.04 to 1.30 and recurrent inhaled corticosteroids IRR = 1.26, 1.07 to 1.47). In the cohort of 39 602 pregnancies, 2.9% were exposed to high-dose folic acid.
      • Zetstra-van der Woude P.A.
      • De Walle H.E.
      • Hoek A.
      • Bos H.J.
      • Boezen H.M.
      • Koppelman G.H.
      Maternal high-dose folic acid during pregnancy and asthma medication in the offspring.
      Associations were clustered on the mother and adjusted for maternal age, maternal asthma medication, and dispensing of benzodiazepines during pregnancy.
      • Veeranki S.P.
      • Gebretsadik T.
      • Dorris S.L.
      • Mitchel E.F.
      • Hartert T.V.
      • Cooper W.O.
      Association of folic acid supplementation during pregnancy and infant bronchiolitis.
      Veeranki et al. used a retrospective cohort of 167 333 mother–infant pairs to compare no prenatal folic acid exposure with first trimester only folic acid exposure and reported higher relative odds of bronchiolitis diagnosis (aOR 1.17, 1.11 to 1.22) and greater severity (aOR 1.16, 1.11 to 1.22). The effect was not significant in the other 2 exposed groups of “after the first trimester” or “both first trimester and after the first trimester”.
      • Veeranki S.P.
      • Gebretsadik T.
      • Dorris S.L.
      • Mitchel E.F.
      • Hartert T.V.
      • Cooper W.O.
      Association of folic acid supplementation during pregnancy and infant bronchiolitis.
      Magdelijns et al.
      • Magdelijns FJH.
      • Mommers M.
      • Penders J.
      • Smits L.
      • Thijs C.
      Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood.
      and Crider
      • Crider K.S.
      • Cordero A.M.
      • Qi Y.P.
      • Mulinare J.
      • Fowling N.F.
      • Berry R.J.
      Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis.
      et al. did not confirm any meaningful association between folic acid supplementation during pregnancy with atopic diseases in the offspring.
      More population studies are required to understand whether there is an exposure and an effect risk for pediatric outcomes, but for now some caution in favour of using the lowest effective folic acid supplementation dose is required.

      Recommendations

      • 3.
        Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A)
      • 4.
        Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose. (II-2A)

      COUNSELLING AND FOLIC ACID SUPPLEMENTATION

      Canadian data indicates clear socio-demographic differences among women with respect to their knowledge and use of folic acid. Although most women understood the benefits of folic acid supplementation, greater than 33% did not take folic acid supplements prior to becoming pregnant and less than 50% supplemented according to national guidelines. Targeted education and other interventions to improve folic acid use in younger women and women with lower socio-economic status is recommended.
      • Nelson CRM.
      • Loen J.A.
      • Evans J.
      The relationship between awareness and supplementation: which Canadian women know about folic acid and how does that translate into use?.
      Han et al. reported that certain groups of women (from the Caribbean, Latin America, North Africa, Middle East, China, and South Pacific) who are immigrants to Canada take fewer folic acid supplements than Canadian-born women. This immigrant group may benefit from enhanced or directed pre-conception education and counselling.
      • Han A.
      • Rotermann M.
      • Fuller-Thomson E.
      • Ray J.G.
      Pre-conceptional folic acid supplement use according to maternal country of birth.
      Folic acid supplementation and the NTD risk stratified for maternal BMI requires more consideration. A recent Chinese cohort study reported the association between folic acid supplementation and the reduced NTDs risk was weaker in overweight/obese mothers (overweight/obese was defined as BMI ≥ 24.0 kg/m2) than in underweight/normal mothers (BMI < 24.0 kg/m2).
      • Wang M.
      • Wang Z.P.
      • Gao L.J.
      • Gong R.
      • Sun X.H.
      • Zhao Z.T.
      Maternal body mass index and the association between folic acid supplements and neural tube defects.
      Oral supplementation success may be variable because of compliance issues with daily oral tablet use (nausea, “forgot,” “don’t like to take pills”) but as a result of food fortification with folic acid, Canada has almost eliminated folate deficiency.
      • Nguyen P.
      • Thomas M.
      • Koren G.
      Predictors of prenatal multivitamin adherence in pregnant women.
      The best predictor of prenatal multivitamin adherence in pregnant women is related to the women’s previous experiences with multivitamin use. The most important factors inhibiting prenatal vitamin use are fear or the experience of nausea, vomiting, and gagging. For women who took the supplemental vitamins, the most important factors were the dosing regimen, health care provider advice, and the mode of product distribution (prescription, over-the-counter, covered by insurance).
      • Nguyen P.
      • Thomas M.
      • Koren G.
      Predictors of prenatal multivitamin adherence in pregnant women.
      The limited RCT data for folic acid supplementation in certain clinical scenarios requires the use of cohort and case–control evaluation and expert opinion extrapolation. Alternate opinions regarding oral supplemental dosing have been published by Motherisk.
      • Kennedy D.
      • Koren G.
      Motherisk update 2012. Identifying women who might benefit from higher doses of folic acid in pregnancy.
      Other long-term uses for folic acid in the other clinical use context (alcoholics, anemia, liver disease, kidney disease, malabsorption, cardiac disease, cancer treatment, regular multivitamin wellness use) are not considered or discussed in this guideline.

      Summary Statement

      In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III)
      The 3 clinically at-risk groups that will benefit from folic acid supplementation are derived from evidence-based review and expert opinion, and are based on the folic acid-sensitive risk of teratogenic or genetic congenital anomaly, or the estimated risk of maternal folic acid deficiency. The supplemental folic acid requirements for the best benefit-to-risk outcome have used the published Canadian female population (post fortification) RBC folate values.
      It is important to emphasize that all 3 risk recommendations for the clinically “at-risk” groups have pregnant women returning to or continuing the oral low dose 1.0 mg folic acid multivitamin supplementation at 12 weeks’ gestational age and continuing to minimize any unknown or potential risk for folic acid supplementation and the exposed mother or fetus/newborn.
      LOW risk group: Women or their male partners with no personal or family history of health risks for folic acid-sensitive birth defects.
      MODERATE risk group: Women with the following personal or co-morbidity scenarios (1 to 5) or their male partner with a personal scenario (1 and 2):
      • 1.
        Personal positive or family history of other folate sensitive congenital anomalies (limited to specific anomalies for cardiac, limb, cleft palate, urinary tract, congenital hydrocephaly)
      • 2.
        Family history of NTD in a first or second-degree relative
      • 3.
        Maternal diabetes (type I or II) with secondary fetal teratogenic risk. Measurement of red blood cell folate levels could be part of the pre-conception evaluation to determine the multivitamin and folic acid supplementation dose strategy (1.0 mg with RBC folate < 906 and 0.4 to 0.6 mg with RBC folate > 906) with a multivitamin)
      • 4.
        Teratogenic medications with secondary fetal teratogenic effects by folate inhibition via anticonvulsant medications (carbamazepine, valproic acid, phenytoin, primidone, phenobarbital), metformin, methotrexate, sulfasalazine, triamterene, trimethoprim (as in cotrimoxazole), and cholestyramine
      • 5.
        Maternal GI malabsorption conditions secondary to co-existing medical or surgical conditions that have been shown to result in decreased RBC folate levels (Crohn’s or active Celiac disease, gastric bypass surgery, advanced liver disease, kidney dialysis, alcohol overuse)
      INCREASED/HIGH risk group: Women or their male partners with a personal NTD history or a previous neural tube defect pregnancy

      Recommendations

      • 5.
        Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mgfolic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A)
      • 6.
        Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks’ gestational age. (1-A) From 12 weeks’ gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A)
      • 7.
        Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks’ gestational age. From 12 weeks’ gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A)
      To achieve a dose of 4.0 mg/day folic acid, women should consume a multivitamin containing 1.0 mg folic acid and add 3 single 1.0 mg folic acid tablets. (See the appendix for a summary of the risk statuses, risk groups, and appropriate folic acid dosing.)
      Recognizing the challenge some clinical offices might face implementing the above recommendations based on the mode of product distribution (prescription, over-the-counter, covered by insurance) and compliance issues with taking daily multiple oral tablets,
      • Crider K.S.
      • Cordero A.M.
      • Qi Y.P.
      • Mulinare J.
      • Fowling N.F.
      • Berry R.J.
      Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis.
      the following simplified regimen could be considered. However, it is important to keep in mind that the folic acid intake should be at the lowest effective and safest dose.
      Low or moderate risk group: a diet of folate-rich foods in addition to pre-conception and first trimester folic acid supplementation with an over-the-counter daily prenatal multivitamin containing 1.0 mg of folic acid.
      Increased/high risk group: a diet of folate-rich foods in addition to preconception and first trimester folic acid supplementation with a prescription daily multivitamin containing 5.0 mg of folic acid.
      See the Figure for a detailed decision tree.

      SUMMARY

      Folic acid (in the diet and/or as a prenatal oral supplement) with a multivitamin/micronutrient has been shown to decrease or minimize specific congenital anomalies including neural tube defects with associated hydrocephalus, oral facial clefts with or without cleft palate, congenital heart disease, urinary tract anomalies, and limb defects, as well as some pediatric cancers. The 1998 public health initiative for fortification of flour has been very beneficial with respect to primary prevention of certain folic acid-sensitive birth defects. The comprehensive Canadian analysis of neural tube reduction after folic acid flour fortification has reported a 46% reduction. The observed reduction was greater for spina bifida (53%) than for anencephaly (38%) and encephalocele (31%). Further reductions in the incidence of other congenital anomalies sensitive to folic acid and multivitamins should be possible with the participation of key stakeholders. Public health surveillance strategies should be implemented to look for any adverse health outcomes (maternal; pediatric) that could possibly be related to folic acid food fortification and additional folic acid supplementation recommendations.

      Decision tree for folic acid supplementation

      ACKNOWLEDGEMENTS

      Expert opinion and guideline review were obtained from the Public Health Agency of Canada and Motherisk.

      Appendix. FOLIC ACID SUPPLEMENTATION

      Tabled 1
      Risk statusFemale partnerMale partnerFolic acid dosing: A healthy folate-rich diet AND:
      LowNo personal or family risk for NTD or folic acid-sensitive birth defectsNo personal or family risk for NTD or folic acid-sensitive birth defectsMultivitamin with 0.4 to 1.0 mg folic acid for 2 to 3 months before conception, throughout pregnancy and for 6 weeks postpartum or to completion of lactation
      ModeratePersonal history positive for folate sensitive anomalies.

      Family history for NTD in first- or second-degree relative.

      Diabetes type I or II

      Teratogenic medications by folate inhibition

      GI malabsorption that decreases RBC folate
      Personal history positive for folate sensitive anomalies

      Family history for NTD in first- or second-degree relative
      Multivitamin including 1. 0 mg folic acid for at least 3 months before conception to 12 weeks and then for remainder of pregnancy and 6 weeks postpartum or to completion of lactation
      HighPersonal NTD history.

      Previous NTD pregnancy
      Personal NTD history.

      Previous NTD pregnancy
      Multivitamin including 1.0 mg folic acid plus 3 × 1.0 mg folic acid (for total of 4.0 mg) OR prescription multivitamin including 5.0 mg folic acid
      It is important to keep in mind that folic acid intake should be at the safest and lowest effective dose (4 mg/daily). However, clinical offices that face a challenge in implementing the recommended dose because of the mode of product distribution (prescription vs. over-the-counter, covered by insurance or not) and compliance issues with taking multiple oral tablets daily could consider the simplified regimen of the 5.0 mg folic acid prescription multivitamin.
      at least 3 months before conception until 12 weeks’ gestation, then a multivitamin including 0.4 to 1.0 mg folic acid for remainder of pregnancy and 6 weeks postpartum or to completion of lactation
      NTD: neural tube defect; GI: gastrointestinal; RBC: red blood cell
      * It is important to keep in mind that folic acid intake should be at the safest and lowest effective dose (4 mg/daily). However, clinical offices that face a challenge in implementing the recommended dose because of the mode of product distribution (prescription vs. over-the-counter, covered by insurance or not) and compliance issues with taking multiple oral tablets daily could consider the simplified regimen of the 5.0 mg folic acid prescription multivitamin.

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