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Food and Nutrition

High Dose Folic Acid Supplementation - Questions and Answers for Health Professionals

1. When should women be advised to take more than 400 mcg (0.4 mg) folic acid per day from a supplement to reduce their risk of a pregnancy affected by a neural tube defect (NTD)?

In determining whether a higher dose of folic acid supplementation is warranted, a woman's health care provider should first ascertain whether the woman has personal characteristics or health conditions associated with an elevated risk of having a baby with a NTD.

After this is established, the health care provider should assess whether the elevated risk is related to a woman's:

  1. Low dietary intake of folate or
  2. Elevated folate requirement or
  3. Uncertain disease etiology where the role of altered folate metabolism is unclear.

Situation A: Low dietary intake of folate

Risk factors for a NTD associated with low dietary intakes of folate (in the absence of elevated folate requirements)Footnote 1:

  • Poor dietary quality
  • Chronic dieting, and/or avoidance of folic acid fortified foods (e.g. low carbohydrate diets)
  • Low socio-economic status
  • Food selection and preparation methods that may be more common in specific ethnic groups (e.g. use of non-fortified rice as a staple; use of maize flour (masa) versus folic acid fortified wheat flour among certain Hispanic-Canadians; and prolonged stewing, a common practice among some South Asian-Canadians that destroys naturally occurring folate)
  • Smoking

Situation B: Elevated folate requirement

Risk factors for a NTD that may be associated with elevated folate requirementsFootnote 1:

  • Personal or family history of NTDs or other congenital anomalies
  • Medications that interfere with folate metabolism Footnote 1,Footnote 2,Footnote 3
  • Alcohol abuse
  • Malabsorption and gastric bypass surgeryFootnote 4
  • Liver Disease
  • Kidney dialysis

Situation C: Uncertain disease etiology

Risk factors for a NTD in which it is uncertain whether altered folate metabolism (and specifically an elevated folate requirement) plays a role in the etiology of the birth defectFootnote 5,Footnote 6,Footnote 7,Footnote 8,Footnote 9,Footnote 10:

  • Obesity
  • Diabetes
  • Impaired glucose metabolism
  • Hyperinsulinemia

If the indicator of risk for a NTD is associated with low dietary folate intake (situation A), in the absence of an elevated requirement, it is not necessary to advise more than 0.4 mg per day of supplemental folic acid.

If the indicator of a NTD risk is associated with an elevated folate requirement (situation B), a higher dose of folic acid (greater than 0.4 mg/d) should be recommended. However, clear instructions should be given to the woman on when this higher dose should be started, and transitioned to a lower dose supplement or stopped. (See response to question 2 for details on how to provide a higher dose of folic acid.)

In the case of situation C, the health care provider may wish to measure a woman's red blood cell (RBC) folate concentration in order to determine the most appropriate dose of folic acid to recommendFootnote 11. It has been shown that RBC folate concentrations greater than 906 nmol/L are maximally protective against folate-dependent NTDsFootnote 12.

  • If her RBC folate concentration is greater than 906 nmol/L, and she typically takes up to 0.4 mg of supplemental folic acid each day, she can be advised to use or continue using a daily multivitamin containing 0.4 mg of folic acid for the prevention of a NTD-affected pregnancy.
  • If her RBC folate concentration is below 906 nmol/L, and she regularly takes 0.4 to 1 mg of supplemental folic acid each day, a higher dose (in combination with a multivitamin supplement) may be beneficial. (See response to question 2 for details on how to provide a higher dose of folic acid.)
  • A large number of drugs are known to alter folate metabolism. Several of these have been shown to increase NTD risks (e.g. valproic acid, carbamazeprine, trimethoprim). Other drugs such as phenobarbitol, primidone, diphenylhydantoin, oxcarbamazepine, sulfonamides and methotrexate may increase the risk for other potentially folate-sensitive anomalies (e.g. orofacial clefts and heart defects) or potentiate NTD risks when combined with other drugsFootnote 1,Footnote 2,Footnote 3. Other medications that are known to elevate folate requirements but whose impact on NTD risk is unknown include metformin, triamterene and barbituratesFootnote 1.
  • While beyond the scope of these questions and answers focusing on folic acid, health care professionals are reminded that impaired glucose metabolism, high glycemic index diets and hyperinsulinemia are thought to be independently related to the risk of birth defects, including NTDsFootnote 5,Footnote 6,Footnote 7.

2. If it is determined that a woman may benefit from a higher level of supplemental folic acid, how should it be provided?

A woman with personal characteristics or health conditions that put her at risk of a pregnancy affected by a neural tube defect (NTD) due to elevated folate requirements (situation B, or in situation C, when RBC folate concentration is less than 906 nmol/L) should consume 4 to 5 mg per day of folic acid in combination with a B12-containing multivitamin supplement. She should be advised to start taking this supplemental dose at least 3 months before conception and to continue until 10 to12 weeks into her pregnancyFootnote 13. At 10 to12 weeks, she can be advised to transition to a daily multivitamin supplement containing 0.4 mg of folic acid for the duration of pregnancy and lactation.

If it is determined that a woman may benefit from a higher level of supplemental folic acid, a health care provider can recommend that a woman:

  1. consume a multivitamin supplement and add single folic acid tablets as necessary to achieve the desired daily dose of folic acid, or
  2. consume a multivitamin containing more than 1 mg of folic acid.

With both approaches, the multivitamin supplement should contain vitamin B12; most multivitamin supplements available in Canada contain vitamin B12.

Women should be advised not to take more than one multivitamin supplement each day in an attempt to consume a higher dose of supplemental folic acid. In large doses some substances in multivitamins could be harmful. This is especially true of Vitamin A in the retinol form (including retinyl palmitate and retinyl acetate). The Tolerable Upper Intake Level (UL) for vitamin A is 3,000 mcg retinol activity equivalent (RAE) or 10,000 IU.

In the event that a woman doesn't conceive after 3 or 4 months and adherence in taking supplements daily is good, a lower level of folic acid supplementation (0.4 to1.0 mg) should be considered. By this time, the blood folate concentrations of most women will be within the maximally protective rangeFootnote 14. Red blood cell (RBC) folate concentrations should be determined after 4 months on a lower dose of folic acid. Her RBC folate concentration will decrease, but it is important to ensure it remains above 906 nmol/L to provide maximal protection against NTDsFootnote 12. The health care provider should have the woman re-tested after an additional 4 months to confirm that a new plateau for RBC folate concentration above 906 nmol/L has been achieved.

3. If a woman' s only risk factor for a pregnancy affected by a neural tube defect (NTD) is poor dietary intake of folate (situation A) and it is determined that her adherence to taking supplements is poor, should a higher dose of folic acid be recommended?

Again, in this instance, the woman's red blood cell (RBC) folate concentration can be used to guide the most appropriate dose of folic acid to recommendFootnote 11. It has been shown that RBC folate concentrations above 906 nmol/L are maximally protective against folate-dependent NTDsFootnote 12.

  • If her RBC folate concentration is greater than 906 nmol/L, it is not necessary to advise more than 0.4 mg/d of supplemental folic acid.  However, the health care provider should encourage the woman to take her supplement on a daily basis.
  • If her RBC folate concentration is below 906 nmol/L, a higher dose of folic acid should be recommended.  The dose of folic acid recommended (1 to 5 mg) should be guided by the woman's level of adherence to supplement intake and how far below the 906 nmol/L cut-off her RBC folate concentration is.   

Women should be advised not to take more than one multivitamin supplement each day in an attempt to consume a higher dose of supplemental folic acid. In large doses some substances in multivitamins could be harmful. This is especially true of Vitamin A in the retinol form (including retinyl palmitate and retinyl acetate). The Tolerable Upper Intake Level (UL) for vitamin A is 3,000 mcg retinol activity equivalent (RAE) or 10,000 IU.

References

Footnote 1

Institute of Medicine. Food and Nutrition Board. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin b6, folate, vitamin b12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press 1998.

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Footnote 2

Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000; 343(22): 1608-14.

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Footnote 3

Ornoy A. Neuroteratogens in man: An overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol 2006; 22(2): 214-26.

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Footnote 4

Gasteyger C, Suter M, Gaillard RC, Giusti V. Nutritional deficiencies after roux-en-y gastric bypass for morbid obesity often cannot be prevented by standard multivitamin supplementation. Am J Clin Nutr 2008; 87(5): 1128-33.

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Footnote 5

Rasmussen SA, Chu SY, Kim SY, Schmid CH, Lau J. Maternal obesity and risk of neural tube defects: A meta-analysis. Am J Obstet Gynecol 2008; 198(6): 611-9.

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Footnote 6

Ray JG, Wyatt PR, Vermeulen MJ, Meier C, Cole DE. Greater maternal weight and the ongoing risk of neural tube defects after folic acid flour fortification. Obstet Gynecol 2005; 105(2): 261-5.

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Footnote 7

Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: A systematic review and meta-analysis. JAMA 2009; 301(6): 636-50.

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Footnote 8

Shaw GM, Velie EM, Schaffer D. Risk of neural tube defect-affected pregnancies among obese women. JAMA 1996; 275(14): 1093-6.

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Footnote 9

Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA. Maternal obesity and risk for birth defects. Pediatrics 2003; 111(5 Part 2): 1152-8.

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Footnote 10

Werler MM, Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to risk of neural tube defects. JAMA 1996; 275(14): 1089-92.

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Footnote 11

Tam C, McKenna K, Ingrid Goh Y, Klieger-Grossman C, O'Connor D L, Einarson A, Koren G. Periconceptional folic acid supplementation: A new indication for therapeutic drug monitoring. Ther Drug Monit 2009;31(3):319-26.

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Footnote 12

Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA 1995; 274(21): 1698-702.

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Footnote 13

Prevention of neural tube defects: Results of the medical research council vitamin study. Mrc vitamin study research group. Lancet 1991; 338(8760): 131-7.

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Footnote 14

Nguyen P, Tam C, O'Connor DL, Kapur B, Koren G. 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; 89(3): 844-52.

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Acknowledgements

These questions and answers for health professionals were prepared by:

  • Dr. Deborah L. O'Connor, RD, PhD, Director of Clinical Dietetics at the Hospital for Sick Children and Associate Professor at the University of Toronto's Department of Nutritional Sciences.

Additional expert advice was provided by:

  • Dr. Jane Evans, PhD, FCCMG, Professor of Biochemistry and Medical Genetics, Pediatrics and Child Health, and Community Health Sciences at the University of Manitoba, and Chair of the Advisory Group of the Canadian Congenital Anomalies Surveillance Network, as well as
  • Dr. Gideon Koren, MD, FRCPC, Founder and Director of the Motherisk Program at the Hospital for Sick Children, and Professor of Pediatrics, Pharmacology, Pharmacy, and Medical Genetics at the University of Toronto.

Members of the Expert Advisory Group on National Nutrition Pregnancy Guidelines also contributed to this work.