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

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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 Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline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).

Section snippets

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

INTRODUCTION

It has been estimated that 4% to 5% of babies are born with a serious congenital anomaly1; 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.1 Folic acid, taken orally prior to conception and during the

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.2 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

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.41., 42., 43., 44., 45., 46., 47., 48., 49., 50.,

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).77

In Canada, the prevalence of NTDs in newborns has declined since 1998 due to food fortification and increased vitamin supplementation,78., 79., 80. as well as to an increase of prenatal diagnosis/termination.45., 46.

Recurrence risks may reflect the genetic

Benefit

Folic acid, in a 0.4 to 1.0 mg daily dose60., 150., 151., 152. 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.153., 154., 155.

Ovarian cancer studies suggest

Benefit

Pediatric ongoing health benefits have been identified following prenatal multivitamin supplementation before and in early pregnancy.40., 128. 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),40., 146., 180. neuroblastoma (OR 0.53, 95% CI 0.42 to 0.68),40 leukemia (OR 0.61, 95% CI 0.50 to 0.74),40., 147. Wilms’ tumour,142 primitive neuroectodermal tumours,145 and ependymomas.145 It was stated that it is not

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.189

Han

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

ACKNOWLEDGEMENTS

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

REFERENCES (193)

  • P. Nguyen et al.

    Steady state folate concentrations achieved with 5 compared with 1.1 mg folic acid supplementation among women of childbearing age

    Am J Clin Nutr

    (2009)
  • A. Han et al.

    Pre-conceptional folic acid supplement use according to maternal country of birth

    J Obstet Gynecol Can

    (2009)
  • E.C. Miller et al.

    Why do Canadian women fail to achieve optimal pre-conceptional folic acid supplementation? An observational study

    J Obstet Gynaecol Can

    (2011)
  • K. Chambers et al.

    Neural tube defects in British Columbia

    Lancet

    (1994)
  • G.P. Oakley

    The scientific basis for eliminating folic acid-preventable spina bifida: a modern miracle from epidemiology

    Ann Epidemiol

    (2009)
  • G.P. Oakley

    Folic acid-preventable spina bifida. A good start but much to be done

    Am J Prev Med

    (2010)
  • R.D. Wilson 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

    J Obstet Gynaecol Can

    (2007)
  • J. Andres et al.

    Prevalence of congenital anomalies. Canadian Perinatal Health Report, 2008 ed. Ottawa:

    Public Health Agency of Canada

    (2008)
  • MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study

    Lancet

    (1991)
  • CzeizelA.E. et al.

    Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation

    N Engl J Med

    (1992)
  • A.E. Czeizel

    Prevention of congenital abnormalities by periconceptional multivitamin supplementation

    BMJ

    (1993)
  • A.E. Czeizel

    Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities

    Birth Defects Res A Clin Mol Teratol

    (2009)
  • De WalsP. et al.

    Reduction of neural-tube defects after folic acid fortification in Canada

    N Engl J Med

    (2007)
  • V.L. Persad et al.

    Incidence of open neural tube defects in Nova Scotia after folic acid fortification

    CMAJ

    (2002)
  • R.J. Berry et al.

    Prevention of neural-tube defects with folic acid in China

    N Engl J Med

    (1999)
  • MartinR.H. et al.

    Crohn's disease, folic acid, and neural tube defects (NTD)

    BMJ

    (1984)
  • MulinareJ. et al.

    Periconceptional use of multivitamins and the occurrence of neural tube defects

    JAMA

    (1988)
  • MillsJ.L. et al.

    The absence of a relation between the periconceptional use of vitamins and neural tube defects

    N Engl J Med

    (1989)
  • A. Milunsky et al.

    Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects

    JAMA

    (1989)
  • Centers for Disease Control (CDC)

    Use of folic acid for prevention of spina bifida and other neural tube defects 1983–1991

    MMWR Morb Mortal Wkly Rep

    (1991)
  • BowerC. et al.

    Dietary folate as a risk factor for neural tube defects: evidence from a case-control study in Western Australia

    Med J Aust

    (1989)
  • Y.I. Goh et al.

    Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis

    J Obstet Gynaecol Can

    (2006)
  • Lopez-CameloJ.S. et al.

    Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile

    Am J Med Genet

    (2005)
  • S.L. Boulet et al.

    Trends in the postfortification prevalence of spina bifida and anencephaly in the United States

    Birth Defects Res A Clin Mol Teratol

    (2008)
  • GreeneN.D.E. et al.

    Genetics of human neural tube defects

    Hum Mol Genet

    (2009)
  • G.M. Shaw et al.

    118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

    BMC Medical Genet

    (2009)
  • BlomH.K. et al.

    Neural tube defects and folate: case far from closed

    Nat Rev Neurosci

    (2006)
  • H.J. Blom

    Folic acid, methylation and neural tube closure in humans

    Birth Defects Res A Clin Mol Teratol

    (2009)
  • Castillo-LancellottiC. et al.

    Impact of folic acid fortification of flour on neural tube defects: a systematic review

    Pub Health Nutr

    (2013)
  • J. Rosenthal et al.

    Neural tube defects in Latin America and the impact of fortification: a literature review

    Latin America. Pub Health Nutr

    (2014)
  • G.M. Shaw et al.

    Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring

    Am J Med Genet

    (1995)
  • BottoL.D. et al.

    Periconceptional multivitamin use and the occurrence of conotruncal heart defects:results from a population-based, case-control study

    Pediatr

    (1996)
  • A.E. Czeizel

    Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation

    Am J Med Genet

    (1996)
  • E. Goldmuntz et al.

    Variants of folate metabolism genes and the risk of conotruncal cardiac defects

    Cir Cardiovasc Genet

    (2008)
  • LiD.K. et al.

    Periconceptional multivitamin use in relation to the risk of congenital urinary tract anomalies

    Epidemiology

    (1995)
  • HayesC. et al.

    Case-control study of periconceptional folic acid supplementation and oral clefts

    Am J Epidemiol

    (1996)
  • TolarovaM. et al.

    Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins

    Teratology

    (1995)
  • BadovinacR.L. et al.

    Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis

    Birth Defects Res A Clin Mol Teratol

    (2007)
  • M.M. Yazdy et al.

    Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply

    Birth Defects Res A Clin Mol Teratol

    (2007)
  • O'NeillJ.

    Do folic acid supplements reduce facial clefts?

    Evid Based Dentistry

    (2008)
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    This Clinical Practice Guideline was prepared by the Genetics Committee, reviewed by the Family Physician Advisory Committee, and approved by the Executive and Board of the Society of Obstetricians and Gynaecologists of Canada.

    Disclosure statements have been received from all contributors.

    This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC.

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