Background: Dietary reference values for folate intake vary widely across Europe. Methods: MEDLINE and Embase through November 2016 were searched for data on the association between folate intake and biomarkers (serum/plasma folate, red blood cell [RBC] folate, plasma homocysteine) from observational studies in healthy adults and elderly. The regression coefficient of biomarkers on intake (β) was extracted from each study, and the overall and stratified pooled β and SE (β) were obtained by random effects meta-analysis on a double log scale. These dose-response estimates may be used to derive folate intake reference values. Results: For every doubling in folate intake, the changes in serum/plasma folate, RBC folate and plasma homocysteine were +22, +21, and –16% respectively. The overall pooled regression coefficients were β = 0.29 (95% CI 0.21–0.37) for serum/plasma folate (26 estimates from 17 studies), β = 0.28 (95% CI 0.21–0.36) for RBC (13 estimates from 11 studies), and β = –0.21 (95% CI –0.31 to –0.11) for plasma homocysteine (10 estimates from 6 studies). Conclusion: These estimates along with those from randomized controlled trials can be used for underpinning dietary recommendations for folate in adults and elderly.

1.
Bermejo LM, Aparicio A, Rodríguez-Rodríguez E, López-Sobaler M, Andrés P, Ortega RM: Dietary strategies for improving folate status in institutionalized elderly persons. Br J Nutr 2009; 101: 1611–1615.
2.
Hoey L, McNulty H, Duffy ME, Hughes CF, Strain JJ: EURRECA-Estimating folate requirements for deriving dietary reference values. Crit Rev Food Sci Nutr 2013; 53: 1041–1050.
3.
Duffy ME, Hoey L, Hughes CF, Strain JJ, Rankin A, Souverein OW, Dullemeijer C, Collings R, Hooper L, McNulty H: Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2014; 99: 96–106.
4.
Fairweather-Tait SJ: Contribution made by biomarkers of status to an FP6 Network of Excellence, EURopean micronutrient RECommendations Aligned (EURRECA). Am J Clin Nutr 2011; 94: 651S–654S.
5.
Souverein OW, Dullemeijer C, van’t Veer P, van der Voet H: Transformations of summary statistics as input in meta-analysis for linear dose-response models on a logarithmic scale: a methodology developed within EURRECA. BMC Med Res Methodol 2012; 12: 57.
6.
Dullemeijer C, Souverein OW, Doets EL, van der Voet H, van Wijngaarden JP, de Boer WJ, Plada M, Dhonukshe-Rutten RA, In ’t Veld PH, Cavelaars AE, de Groot LC, van’t Veer P: Systematic review with dose-response meta-analyses between vitamin B-12 intake and -European Micronutrient Recommendations Aligned’s prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly. Am J Clin Nutr 2013; 97: 390–402.
7.
Moran VH, Stammers AL, Medina MW, Patel S, Dykes F, Souverein OW, Dullemeijer C, Pérez-Rodrigo C, Serra-Majem L, Nissensohn M, Lowe NM: The relationship between zinc intake and serum/plasma zinc concentration in children: a systematic review and dose-response meta-analysis. Nutrients 2012; 4: 841–858.
8.
Fekete K, Berti C, Trovato M, Lohner S, Dullemeijer C, Souverein OW, Cetin I, Decsi T: Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation. Nutr J 2012; 11–75.
9.
Dhonukshe-Rutten RA, Bouwman J, Brown KA, Cavelaars AE, Collings R, Grammatikaki E, de Groot LC, Gurinovic M, Harvey LJ, Hermoso M, Hurst R, Kremer B, Ngo J, Novakovic R, Raats MM, Rollin F, Serra-Majem L, Souverein OW, Timotijevic L, Van’t Veer P: EURRECA-evidence-based methodology for deriving micronutrient recommendations. Crit Rev Food Sci Nutr 2013; 53: 999–1040.
10.
HigginsJP, Green S: Cochrane Handbook for Systematic Reviews for Interventions, version 5.1.0 (updated March 2011); The Cochrane Collaboration, 2011. http://handbook-5–1.cochrane.org/(accessedonFebruary1, 2018).
11.
Arnaud J, Fleites-Mestre P, Chassagne M, Verdura T, Garcia Garcia I, Hernandez-Fernandez T, Gautier H, Favier A, Pérez-Cristià R, Barnouin J: Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy epidemic. Br J Nutr 2001; 85: 741–748.
12.
Ashfield-Watt PA, Whiting JM, Clark ZE, Moat SJ, Newcombe RG, Burr ML, McDowell IF: A comparison of the effect of advice to eat either “5-a-day” fruit and vegetables or folic acid-fortified foods on plasma folate and homocysteine. Eur J Clin Nutr 2003; 57: 316–323.
13.
Chew SC, Khor GL, Loh SP: Association between dietary folate intake and blood status of folate and homocysteine in Malaysian adults. J Nutr Sci Vitaminol 2011; 57: 150–155.
14.
Colić Barić I, Satalić Z, Keser I, Cecić I, Sucić M: Validation of the folate food frequency questionnaire with serum and erythrocyte folate and plasma homocysteine. Int J Food Sci Nutr 2009; 60(suppl 5): 10–8.
15.
de Bree A, Verschuren WM, Bjørke-Monsen AL, van der Put NM, Heil SG, Trijbels FJ, Blom HJ: Effect of the methylenetetrahydrofolatereductase 677C–>T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample. Am J ClinNutr 2003; 77: 687–693.
16.
Drogan D, Klipstein-Grobusch K, Wans S, Luley C, Boeing H, Dierkes J: Plasma folate as marker of folate status in epidemiological studies: the European Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Br J Nutr 2004; 92: 489–496.
17.
Fukuda N, Hamajima N, Wakai K, Suzuki K: A cross-sectional study to find out the relationship of methylenetetrahydrofolate reductase (MTHFR) C677T genotype with plasma levels of folate and total homocysteine by daily folate intake in Japanese. J Nutr Sci Vitaminol (Tokyo) 2014; 60: 231–238.
18.
Glynn SA, Albanes D, Pietinen P, Brown CC, Rautalahti M, Tangrea JA, Gunter EW, Barrett MJ, Virtamo J, Taylor PR: Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev 1996; 5: 487–494.
19.
Johansson I, Van Guelpen B, Hultdin J, Johansson M, Hallmans G, Stattin P: Validity of food frequency questionnaire estimated intakes of folate and other B vitamins in a region without folic acid fortification. Eur J ClinNutr 2010; 64: 905–913.
20.
Melse-Boonstra A, de Bree A, Verhoef P, Bjørke-Monsen AL, Verschuren WM: Dietary monoglutamate and polyglutamatefolate are associated with plasma folate concentrations in Dutch men and women aged 20–65 years. J Nutr 2002; 132: 1307–1312.
21.
Sedjo RL, Inserra P, Abrahamsen M, Harris RB, Roe DJ, Baldwin S, Giuliano AR: Human papillomavirus persistence and nutrients involved in the methylation pathway among a cohort of young women. Cancer Epidemiol Biomarkers Prev 2002; 11: 353–359.
22.
Shuaibi AM, Sevenhuysen GP, House JD: Validation of a food choice map with a 3-day food record and serum values to assess folate and vitamin B-12 intake in college-aged women. J Am Diet Assoc 2008; 108: 2041–2050.
23.
Schüpbach R, Wegmüller R, Berguerand C, Bui M, Herter-Aeberli I: Micronutrient status and intake in omnivores, vegetarians and vegans in Switzerland. Eur J Nutr 2017; 56: 283–293.
24.
Sivaprasad M, Shalini T, Balakrishna N, -Sudarshan M, Lopamudra P, Suryanarayana P, Arlappa N, Ravikumar BP, Radhika MS, Reddy GB: Status of vitamin B12 and folate among the Urban adult population in South India. Ann Nutr Metab 2016; 68: 94–102.
25.
Van Guelpen B, Hultdin J, Johansson I, Witthöft C, Weinehall L, Eliasson M, Hallmans G, Palmqvist R, Jansson JH, Winkvist A: Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function. J Intern Med 2009; 266: 182–195.
26.
Verkleij-Hagoort AC, de Vries JH, Stegers MP, Lindemans J, Ursem NT, Steegers-Theunissen RP: Validation of the assessment of folate and vitamin B12 intake in women of reproductive age: the method of triads. Eur J Clin Nutr 2007; 61: 610–615.
27.
Weinstein SJ, Albanes D, Selhub J, Graubard B, Lim U, Taylor PR, Virtamo J, Stolzenberg-Solomon R: One-carbon metabolism biomarkers and risk of colon and rectal cancers. Cancer Epidemiol Biomarkers Prev 2008; 17: 3233–3240.
28.
Fayet F, Flood V, Petocz P, Samman S: Relative and biomarker-based validity of a food frequency questionnaire that measures the intakes of vitamin B(12), folate, iron, and zinc in young women. Nutr Res 2011; 31: 14–20.
29.
Fraser GE, Jaceldo-Siegl K, Henning SM, Fan J, Knutsen SF, Haddad EH, Sabaté J, Beeson WL, Bennett H: Biomarkers of dietary intake are correlated with corresponding measures from repeated dietary recalls and food-frequency questionnaires in the adventist health study-2. J Nutr 2016; 146: 586–594.
30.
Hoey L, McNulty H, Askin N, Dunne A, Ward M, Pentieva K, Strain J, Molloy AM, Flynn CA, Scott JM: Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults. Am J Clin Nutr 2007; 86: 1405–1413.
31.
Hopkins SM, Gibney MJ, Nugent AP, McNulty H, Molloy AM, Scott JM, Flynn A, Strain JJ, Ward M, Walton J, McNulty BA: Impact of voluntary fortification and supplement use on dietary intakes and biomarker status of folate and vitamin B-12 in Irish adults. Am J Clin Nutr 2015; 101: 1163–1172.
32.
Knutsen SF, Fraser GE, Linsted KD, Beeson WL, Shavlik DJ: Comparing biological measurements of vitamin C, folate, alpha-tocopherol and carotene with 24-hour dietary recall information in nonhispanic blacks and whites. Ann Epidemiol 2001; 11: 406–416.
33.
Mendonça N, Mathers JC, Adamson AJ, Martin-Ruiz C, Seal CJ, Jagger C, Hill TR: Intakes of folate and vitamin B12 and biomarkers of status in the very old: the newcastle 85+ study. Nutrients 2016; 8:pii:E604.
34.
Owens JE, Holstege DM, Clifford AJ: Comparison of two dietary folate intake instruments and their validation by RBC folate. J Agric Food Chem 2007; 2: 3737–3740.
35.
Berti C, Fekete K, Dullemeijer C, Trovato M, Souverein OW, Cavelaars A, Dhonukshe-Rutten R, Massari M, Decsi T, Van’t Veer P, Cetin I: Folate intake and markers of folate status in women of reproductive age, pregnant and lactating women: a meta-analysis. J NutrMetab 2012; 2012: 470656.
36.
DerSimonian R, Laird N: Meta-analysis in clinical trials. Controlled Clin Trials 1986; 7: 177–188.
37.
Suitor CW, Bailey LB: Dietary folate equivalents: Interpretation and application. J Am Diet Assoc 2000; 100: 88–94.
38.
Öhrvik V, Lemming EW, Nälsén C, Becker W, Ridefelt P, Lindroos AK: Dietary intake and biomarker status of folate in Swedish adults. Eur J Nutr 2016,Epub ahead of print.
39.
Dodd KW, Guenther PM, Freedman LS, et al: Statistical methods for estimating usual intake of nutrients and foods: a review of the theory. J Am Diet Assoc 2006; 106: 1640–1650.
40.
Brevik A, Vollset SE, Tell GS, Refsum H, Ueland PM, Loeken EB, Drevon CA, Andersen LF: Plasma concentration of folate as a biomarker for the intake of fruit and vegetables: the Hordaland Homocysteine Study. Am J Clin Nutr 2005; 81: 434–439.
41.
Marchetta CM, Devine OJ, Crider KS, Tsang BL, Cordero AM, Qi YP, Guo J, Berry RJ, Rosenthal J, Mulinare J, Mersereau P, Hamner HC: Assessing the association between natural food folate intake and blood folate concentrations: a systematic review and Bayesian meta-analysis of trials and observational studies. Nutrients 2015; 7: 2663–2686.
42.
Pfeiffer CM, Schleicher RL, Johnson CL, Coates PM: Assessing vitamin status in large population surveys by measuring biomarkers and dietary intake – two case studies: folate and vitamin D. Food Nutr Res 2012; 56.
43.
Vitamin and Mineral Requirements in Human Nutrition. Second Edition of Report of A Joint FAO/WHO Expert Consultation, Bangkok, Thailand. World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO). 2004. (ISBN 92 4 1546123).
44.
Elmadfa I, Meyer A, Nowak V, Hasenegger V, Putz P, Verstraeten R, Remaut-DeWinter AM, Kolsteren P, Dostálová J, Dlouhý P, Trolle E, Fagt S, Biltoft-Jensen A, Mathiessen J, Velsing Groth M, Kambek L, Gluskova N, Voutilainen N, Erkkilä A, Vernay M, Krems C, Strassburg A, Vasquez-Caicedo AL, Urban C, Naska A, Efstathopoulou E, Oikonomou E, Tsiotas K, Bountziouka V, Benetou V, Trichopoulou A, Zajkás G, Kovács V, Martos E, Heavey P, Kelleher C, Kennedy J, Turrini A, Selga G, Sauka M, Petkeviciene J, Klumbiene J, Holm Totland T, Andersen LF, Halicka E, Rejman K, Kowrygo B, Rodrigues S, Pinhão S, Ferreira LS, Lopes C, Ramos E, Vaz Almeida MD, Vlad M, Simcic M, Podgrajsek K, Serra Majem L, Román Viñas B, Ngo J, Ribas Barba L, Becker V, Fransen H, Van Rossum C, Ocké M, Margetts B: European nutrition and health report 2009. Forum Nutr 2009; 62: 1–405.
45.
Park JY, Nicolas G, Freisling H, Biessy C, Scalbert A, Romieu I, Chajès V, Chuang SC, Ericson U, Wallström P, Ros MM, Peeters PH, Mattiello A, Palli D, María Huerta J, Amiano P, Halkjær J, Dahm CC, Trichopoulou A, Orfanos P, Teucher B, Feller S, Skeie G, Engeset D, Boutron-Ruault MC, Clavel-Chapelon F, Crowe F, Khaw KT, Vineis P, Slimani N: Comparison of standardised dietary folate intake across ten countries participating in the European Prospective Investigation into Cancer and Nutrition. Br J Nutr 2012; 108: 552–569.
46.
Novaković R, Cavelaars AE, Bekkering GE, Roman-Viñas B, et al: Micronutrients intake and status in Central and Eastern Europe as compared to other European countries, results from the EURRECA network. Public Health Nutr 2013; 16: 824–840.
47.
Nordic Nutrition Recommendations 2004, ed 4. Copenhagen, Nordic Council of Ministers, Nord, 2004, p 13.
48.
Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.  -Washington, Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Washington (DC): National Academies Press (US); 1998. ISBN-10: 0–309–06411–2ISBN-13: 978–0-309-06411-8.
49.
Requirements of Vitamin A, Iron, Folate and Vitamin B12. FAO/WHO expert consultation. World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), 1998, pp 51–61.
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.