Some medical practices have been ingrained in custom for decades, long after “proof” that they were effective was established. It is necessary to periodically reevaluate these practices, as newer theories and research may challenge the evidence upon which they were based. An example is the decades’ old practice of recommending a 4-mg (4,000-µg) supplement of folic acid to women who are at risk for recurrent neural tube defect (NTD) during pregnancy. This recommendation was based on findings from a randomized clinical trial in 1991. Since then, multiple studies have confirmed the utility of 400–800 µg of folic acid in lowering both primary and recurrent risks of NTDs, but no studies have established any further reduction in risk with doses over 1 mg. Current understanding of folic acid metabolism during pregnancy suggests that at higher doses, above ∼1 mg, there is not increased absorption. Recent evidence suggests that 4 mg folic acid supplementation may not be any more effective than lower doses for the prevention of recurrent NTDs. Thus, we recommend that it is time for clinicians to reexamine their reliance on this outdated recommendation and consider using current recommendations of 400–800 µg per day for all patients in conjunction with assessment of maternal folate status.

1.
Practice Bulletin No. 187: Neural tube defects. Obstet Gynecol 2017; 130:e279–e290.
2.
Williams J, Mai CT, Mulinare J, Isenburg J, Flood TJ, Ethen M, et al: Updated estimates of neural tube defects prevented by mandatory folic acid fortification – United States, 1995–2011. MMWR Morb Mortal Wkly Rep 2015; 64: 1–5.
3.
Evans MI, Llurba E, Landsberger EJ, O'Brien JE, Harrison HH: Impact of folic acid fortification in the United States: markedly diminished high maternal serum alpha-fetoprotein values. Obstet Gynecol 2004; 103: 474–479.
4.
Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, Garcia FA, et al: Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. JAMA 2017; 317: 183–189.
5.
Castillo-Lancellotti C, Tur JA, Uauy R: Impact of folic acid fortification of flour on neural tube defects: a systematic review. Public Health Nutr 2013; 16: 901–911.
6.
De-Regil LM, Pena-Rosas JP, Fernandez-Gaxiola AC, Rayco-Solon P: Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2015;Cd007950.
7.
Laurence KM, James N, Miller MH, Tennant GB, Campbell H: Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. Br Med J (Clin Res Ed) 1981; 282: 1509–1511.
8.
Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991; 338: 131–137.
9.
Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R, et al: Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981; 56: 911–918.
10.
Bower C, Stanley FJ: Dietary folate as a risk factor for neural-tube defects: evidence from a case-control study in Western Australia. Med J Aust 1989; 150: 613–619.
11.
Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al: Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262: 2847–2852.
12.
Mulinare J, Cordero JF, Erickson JD, Berry RJ: Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988; 260: 3141–3145.
13.
Use of folic acid for prevention of spina bifida and other neural tube defects – 1983–1991. MMWR Morb Mortal Wkly Rep 1991; 40: 513–516.
14.
Czeizel AE, Dudas I: Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–1835.
15.
Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA: Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995; 6: 219–226.
16.
Werler MM, Shapiro S, Mitchell AA: Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 1993; 269: 1257–1261.
17.
Moore LL, Bradlee ML, Singer MR, Rothman KJ, Milunsky A: Folate intake and the risk of neural tube defects: an estimation of dose-response. Epidemiology 2003; 14: 200–205.
18.
Gropper SS SJ: Advanced Nutrition and Human Metabolism. 6th ed: Belmont: Wadsworth, Cengage Learning; 2013.
19.
Plumptre L, Masih SP, Ly A, Aufreiter S, Sohn KJ, Croxford R, et al: High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood. Am J Clin Nutr 2015; 102: 848–857.
20.
Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM: Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997; 65: 1790–1795.
21.
Crider KS, Devine O, Hao L, Dowling NF, Li S, Molloy AM, et al: Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ 2014; 349:g4554.
22.
WHO Guidelines Approved by the Guidelines Review Committee. Guideline: Optimal Serum and Red Blood Cell Folate Concentrations in Women of Reproductive Age for Prevention of Neural Tube Defects. Geneva: World Health Organization. 2015.
23.
Bonnette RE, Caudill MA, Boddie AM, Hutson AD, Kauwell GP, Bailey LB: Plasma homocyst(e)ine concentrations in pregnant and nonpregnant women with controlled folate intake. Obstet Gynecol 1998; 92: 167–170.
24.
Caudill MA, Cruz AC, Gregory JF 3rd, Hutson AD, Bailey LB: Folate status response to controlled folate intake in pregnant women. J Nutr 1997; 127: 2363–2370.
25.
Institute of Medicine Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998.
26.
Li K, Wahlqvist ML, Li D: Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review. Nutrients 2016; 8.
27.
Mason JB: Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev 2009; 67: 206–212.
28.
Tinker SC, Hamner HC, Qi YP, Crider KS: U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012. Birth Defects Res A Clin Mol Teratol 2015; 103: 517–526.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.