Acessibilidade / Reportar erro
Review Article • Rev. Bras. Hematol. Hemoter. 36 (4) • Jul-Aug 2014 • https://doi.org/10.1016/j.bjhh.2014.03.018   copy

Concentrations of blood folate in Brazilian studies prior to and after fortification of wheat and cornmeal (maize flour) with folic acid: a review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

BACKGROUND:

In July 2004, the Brazilian Ministry of Health through the National Health Surveillance Agency made the fortification of wheat flour and cornmeal (maize flour) with iron and folic acid mandatory, with the intention of reducing the rate of diseases such as neural tube defects.

OBJECTIVE:

The aim of the study was to investigate the impact of the folic acid fortified wheat flour and cornmeal on serum and red blood cell folate levels and on the reduction of neural tube defects in different Brazilian studies.

METHODS:

In order to compare folate concentrations in the Brazilian population prior to and following the implementation of mandatory fortification of wheat and cornmeal, studies that involved blood draws between January 1997 and May 2004 (pre-fortification period), and from June 2004 to the present (post-fortification period) were chosen. The data search included PubMed and Scopus databases as well as the Brazilian Digital Library of Theses and Dissertations. The following keywords were employed for the query: folate, folic acid, fortification, Brazil, healthy population, the elderly, children and pregnant women.

RESULTS:

A total of 47 Brazilian studies were selected; 26 from the pre-fortification period and 22 after the fortification implementation. The studies were classified according to the cohort investigated (pregnant women, children, adolescents, adults and the elderly). After the implementation of flour fortification with folic acid in Brazil, serum folate concentrations increased in healthy populations (57% in children and adolescents and 174% in adults), and the incidence of neural tube defects dropped.

CONCLUSION:

Folic acid fortification of wheat flour and cornmeal increased the blood folate concentrations and reduced the incidence of neural tube defects.

Adult; Blood; Brazil; Food; fortification; Folic acid

Introduction

Folic acid (FA) is a hydrosoluble vitamin essential for human health; its main roles in cell metabolism involve DNA synthesis and supplying methyl groups for homocysteine (Hcy), DNA, protein and lipid methylation reactions.11. Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med. 2009;11:e4.

The term folate is used to designate the polyglutamate form of water-soluble B vitamin present in edibles, while the term folic acid corresponds to the monoglutamate form used in supplements and in the fortification of food.22. Sanderson P, McNulty H, Mastroiacovo P, McDowell IF, Melse-Boonstra A, Finglas PM, Gregory JF 3rd; UK Food Standards Agency. Folate bioavailability: UK Food Standards Agency workshop report. Br J Nutr. 2003;90(2):473-9. Folate rich foods include: green vegetables (broccolis, lettuce, spinach and asparagus), beans, fruit (lemons, bananas and melons), dry cereals, whole-grains, liver, kidney and mushrooms.33. Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res. 2007;51(3):267-92. The physiological folate requirements increase when there is a corresponding increase in cell division such as during pregnancy, lactation and in early childhood; or whenever individuals are afflicted with certain diseases, such as hemolytic anemia, leukemia and other malignant diseases, as well as in alcoholism.44. Green, R. Folate, cobalamin, and megaloblastic anemias (capítulo 41). Kaushansky, K; Lichtman M., Beutler E., et al. (eds). Williams Hematology, Oitava Edição, 2010.

It is believed to be difficult to obtain the required intake of this vitamin by means of a balanced diet alone (without fortified foods) when there is an increase in physiological necessities. A normal diet supplies around 0.25 mg of folate/ day, considering a diet of 2200 calories per day. The difficulty in fulfilling the requirements may be explained by the low bioavailability of folate in foods and the low dietary intake of foods that are natural sources of this vitamin. Furthermore, high temperature processing of foods results in considerable loss of folate, reducing its content by 50%.55. Santos LM, Pereira MZ. [The effect of folic acid fortification on the reduction of neural tube defects]. Cad Saude Publica. 2007;23(1):17-24.

The recommended dietary allowance (RDA), estimated average requirement (EAR) and the tolerable upper intake level (UL) reference values for folate differ according to age (children, adolescents and adults) remembering that intake requirements are higher for pregnant (RDA 600 μg/day and EAR 520 μg/day) and breast-feeding women (RDA 500 μg/day and EAR 450 μg/day).66. Institute of Medicine. In Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington: National Academy Press; 1998. pp. 196-305. During pregnancy, cells multiply intensively due to the widening of the uterus, placental development, increase in blood volume and fetal development, which increases folate and B12 vitamin necessities accordingly.77. Guerra-Shinohara EM, Morita OE, Peres S, Pagliusi RA, Sampaio Neto LF, D'Almeida V, et al. Low ratio of S-adenosylmethionine to S-adenosylhomocysteine is associated with vitamin deficiency in Brazilian pregnant women and newborns. Am J Clin Nutr. 2004;80(5):1312-21.

Adequate intake of these vitamins is essential, since folate insufficiency has been identified as a risk factor for congenital disorders especially neural tube defects (NTDs). They result from neural tube closing failure during the early development of the embryo, typically between the 21st and 28th day after conception, most frequently resulting in anencephaly and spina bifida.

Since pregnancy is not always planned, it is important that women of child-bearing age have access to a suitable quantity of FA, at least one month prior to becoming pregnant.

Accordingly, it is recommended that women of child-bearing age consume 400 μg of FA daily, via fortified foods, supplements or both, in addition to the quantity they acquire from their normal daily diet.66. Institute of Medicine. In Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington: National Academy Press; 1998. pp. 196-305. Considering the difficulties to obtain the folate requirements from a normal balanced diet, several countries decided to implement mandatory FA fortification of foods, starting with the United States in 1998, followed shortly by Canada, Chile and several others.

In Brazil, the Ministry of Health through the National Health Surveillance Agency (ANVISA) made the iron and FA fortification of wheat and cornmeal mandatory in July 2004, with the intention of reducing the rate of pathologies, like NTDs, nationally. When the RDC Resolution no. 344 was issued on December 13, 2002, ANVISA dictated that all wheat flour and cornmeal, whether sold directly to consumers or to the food industry for the manufacture of edibles, must be enriched with iron and FA. It was established that every 100 g of wheat flour and cornmeal must contain at least 4.2 mg of iron and 150 μg of FA.88. Brasil. Ministério da Saúde. ANVISA - Agência Nacional de Vigilância Sanitária. Resolução RDC nº 344, de 13 de dezembro de 2002. Aprova o Regulamento Técnico para a fortificação das farinhas de trigo e das farinhas de milho com ferro e ácido fólico, constante do anexo desta Resolução. D.O.U. - Diário Oficial da União; Poder Executivo, de 18 de dezembro de 2002. However, no nationwide studies have been carried out to evaluate the concentrations of folate consumed by the Brazilian population prior to and following the mandatory implementation of fortified wheat flour and cornmeal. Accordingly, the purpose of this review is to investigate the impact of the FA fortification of wheat flour and cornmeal on serum and red blood cell folate levels, and to evaluate the reduction of NTDs in different strata of the Brazilian population.

Methods

In order to compare folate concentrations in the Brazilian population prior to and following the implementation of mandatory fortification of wheat flour and cornmeal, studies that involved blood draws between January 1997 and May 2004 (the pre-fortification period), and from June 2004 to the present (the post-fortification period) were chosen. Data reviewed included PubMed and Scopus databases as well as the Brazilian Digital Library of Theses and Dissertations. The following keywords were employed in the query: folate, folic acid, fortification, Brazil, healthy population, the elderly, children and pregnant women.

Studies in which the sample collection included both time periods were classified as "pre-fortification studies", as long as the sample collection period prior to June 2004 was longer than the period after June 2004. Likewise, studies in which the collection period after June 2004 was greater than the period prior to mandatory fortification were classified as "post-fortification studies". A number of studies did not specify the sample collection period; in these cases, emails were sent to the respective corresponding authors in order to determine this information.

Transversal and/or prospective studies were selected, without interventions, carried out on different cohorts of the Brazilian population, such as pregnant women, neonates, children and adolescents, adults and the elderly. The studies that evaluated the concentrations of folate in unhealthy populations were also selected and the data are presented in the Tables below but were not taken into consideration in the whole evaluation between the pre- and post-fortification periods. For consistency purposes , studies that presented folate concentrations expressed in ng/mL had their values converted into nmol/L using a conversion factor of 2.26699. Chisholm-Burns MA, et al. Pharmacotherapy Principles and Practice. New York: McGraw-Hill Medical Publishing Division; 2008. 1671 p. for this review.

In order to evaluate the concentrations of serum folate between the pre- and post-fortification periods, the increase of serum concentrations was estimated in children and adolescents and adults. Pregnant women were not considered for this evaluation, because the studies found presented great variations in the gestational age of the subjects within this cohort. Neonates and the elderly were not evaluated either, because few studies involving these cohorts were found for the two periods considered.

Results

A total of 47 Brazilian studies were selected, including 26 from the pre-fortification and 22 from the post-fortification periods. The studies were classified according to the cohort investigated (pregnant women, children, adolescents, adults and the elderly). Several articles analyzed more than one type of population in the same study and so that these studies may appear in more than one Table in the results section.

Tables 1 to 7 present the characteristics of the selected studies, including where they were carried out, the period of the sample collection, the characteristics of the evaluated cohort, the number of individuals involved in the study (n) and the method used for quantifying the folate.

Tables 1 to 3 present the characteristics of the studies that evaluated the concentrations of serum folate on different healthy populations, while Tables 4 and 5 present the characteristics of the studies involving unhealthy populations. Tables 6 and 7 present the characteristics of the studies that evaluate the total blood or red blood cell folate concentrations among healthy and unhealthy populations, respectively.

Thumbnail
Table 1
Serum folate concentrations in healthy pregnant women and neonates.
Thumbnail
Table 2
Serum folate concentrations in healthy pregnant women and neonates.

Increases of 57% and 174% of the serum folate concentration were observed between the pre- and post-fortification periods for the children and adolescents cohort and for the healthy adults cohort, respectively.

Of the total number of studies encountered, 32 (68%) were held at southeastern geographical region of Brazil, while 6 (13%), 1 (2%), 2 (4%) and 6 (13%) studies were conducted in the southern, mid-west, northern and northeastern geographical regions, respectively.

Discussion

The need to reduce the incidence of congenital disorders in the population has led some countries to adopt a program to fortify foods with FA. Other countries, especially in Europe, have implemented special women's healthcare initiatives, including the introduction of FA supplementation and the monitoring of women's health conditions, with the purpose of ensuring adequate folate blood concentrations prior to pregnancy.

Thumbnail
Table 3
Serum folate concentrations in healthy adults.
Thumbnail
Table 4
Serum folate concentrations in unhealthy populations.
Thumbnail
Table 5
Serum folate concentrations in unhealthy populations.

One of the purposes of this review was to assess the impact of the FA fortification of wheat flour and cornmeal on serum and on red blood cell folate concentrations by comparing the pre- and post-fortification periods in Brazil.

The analysis shows that most of the studies were carried out in the southeastern geographical region of the country; and there is a relative scarcity of studies covering the other regions, especially the mid-west and the northern areas; thus, the results presented herein cannot be considered to be representative of the country as a whole.

In healthy populations, an increase in serum folate concentrations was observed (57% in children and adolescents and 174% in adults). The observation that serum folate concentrations increased since fortification is a common characteristic with similar studies carried out with North American5656. Dietrich M, Brown CJ, Block G. The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr. 2005;24(4):266-74. , 5757. Enquobahrie DA, Feldman HA, Hoelscher DH, Steffen LM, Webber LS, Zive MM, et al. Serum homocysteine and folate concentrations among a US cohort of adolescents before and after folic acid fortification. Public Health Nutr. 2012;15(10):1818-26. and Chilean5858. Hertrampf E, Cortés F, Erickson JD, Cayazzo M, Freire W, Bailey LB, et al. Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J Nutr. 2003;133(10):3166-9. populations. It is important to emphasize that the difference in blood folate concentrations between the pre- and post-fortification periods in Brazil may be greater than that observed in this review, since few studies that involved blood draws in the last three to four years were encountered.

Although this review presents folate concentrations (serum and red blood cell) among pregnant women and the elderly, it was not possible to make a comparison between the pre- and post-fortification values for pregnant women, due to the small number of post-fortification studies involving this cohort, but also because of the diversity of the gestational ages of pregnant women presented in these studies. It is known that there is a reduction in blood folate from the beginning to the end of pregnancy1414. Kubota AM. Efeito das concentrações das vitaminas (séricas e da dieta) e do polimorfismo MTHFR C677T na taxa de metilação global do DNA durante o período gestacional [thesis]. São Paulo: Universidade de São Paulo; 2008. 103f. , 5959. Pereira PM. Consumo de cobalamina e folato por gestantes: relação com o metabolismo da homocisteína e com os polimorfismos nos genes da metionina sintase, metilenotetraidrofolato redutase e metionina sintase redutase [thesis]. São Paulo: Universidade de São Paulo; 2007. 109p. and, accordingly, the comparison of values among different gestational ages could result in biased data. Among the elderly, there is a lack of studies during the pre-fortification period; as only one study involving 8 individuals was found for this period, no comparison is possible.

Thumbnail
Table 6
Red blood cell folate concentrations in healthy pregnant women, neonates, adolescents and adults.
Thumbnail
Table 7
Red blood cell folate concentrations in unhealthy populations.

Another point to be considered is the difference in results when different methods are used for the quantification of folate. This fact was brought to our attention in a study in which enzyme immunoassay and chemiluminescent methods were used to quantify folate concentration in pregnant women.1010. Thame G, Guerra-Shinohara EM, Moron AF. Serum folate by two methods in pregnant women carrying fetuses with neural tube defects. Clin Chem. 2002;48(7):1094-5. Recently, we analyzed the serum folate content in 108 samples using two methods: one microbiological method and one chemiluminescent method (Immulite(r) Kit, DPC Med Lab). The results showed that the two methods presented different means, with higher values of folate recorded using the microbiological method [median (25-75 percentiles): 34.7; range: 21.3-46.2 nmol/L] compared to the chemiluminescent method (median: 30.2; range: 19.3-37.6 nmol/L; Wilcoxon signed-rank test: p-value < 0.001); however, there was a significant correlation between the results of the two tests (r = 0.901; Spearman Correlation: p-value < 0.001). The different results obtained in the dosages of serum folate are the result of a lack of a specific ligand for folate or anti-folate monoclonal antibodies that could be used in the enzyme immunoassay or chemiluminescence kits.

Accordingly, if we consider the differences (14.5%) between the two methods (microbiological and chemiluminescent), this difference is much smaller than the difference found between the post- and pre-fortification periods in the groups of children and adolescents (57%) and adults (174%), leaving no doubt that there has been an increase in the concentration of serum folate since mandatory fortification.

In this review, it was not possible to evaluate the difference of red blood cell folate concentrations between the pre- and post-fortification periods, because different kits were used in the studies that evaluated similar population groups. It has already been described in the literature that different quantification methods may generate different results for red blood cell folate concentration.6060. Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci U S A. 1998;95(22):13217-20. , 6161. Molloy AM, Mills JL, Kirke PN, Whitehead AS, Weir DG, Scott JM. Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radioassay and microbiological assays. Clin Chem. 1998;44(1):186-8. It is known that TT genotype carriers of the MTHFR c.677C>T polymorphism present elevated red blood cell folate values compared to CC and CT genotype carriers, when folate is quantified by means of methods that use milk proteins as folate ligands (enzyme immunoassay or chemiluminescence and radio assay). However, TT genotype carriers present lower red blood cell folate values compared to other genotypes if the microbiological method is used. One possible explanation for this finding is that individuals with the TT genotype may accumulate formylated forms of folate or degradation products due to the decreased activity of the MTHFR enzyme, so that these forms may be quantified by methods that use milk proteins as ligands, rather than being quantified by the microbiological method, as they are not active forms of folate.6161. Molloy AM, Mills JL, Kirke PN, Whitehead AS, Weir DG, Scott JM. Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radioassay and microbiological assays. Clin Chem. 1998;44(1):186-8.

Regarding the impact of FA fortification of flour on the rate of NTDs, several countries that have adopted the program have demonstrated a reduction in the occurrence of NTDs. In Latin America, a 33% to 59% reduction in the occurrence of NTDs has been observed.6262. Rosenthal J, Casas J, Taren D, Alverson CJ, Flores A, Frias J. Neural tube defects in Latin America and the impact of fortification: a literature review. Public Health Nutr. 2013:1-14. Furthermore, a collaborative study conducted in Chile, Argentina and Brazil observed that the incidence of anencephaly and spina bifida per 1000 births in Brazil alone dropped from 1.12 to 0.69 and from 1.45 to 1.42, respectively.6363. López-Camelo JS, Castilla EE, Orioli IM; INAGEMP (Instituto Nacional de Genética Médica Populacional); ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas). Folic acid flour fortification: impact on the frequencies of 52 congenital anomaly types in three South American countries. Am J Med Genet A. 2010;152(10):2444-58.

In Brazil, one study found no significant differences between the incidence of anencephaly, encephalocele and spina bifida between the two periods;6464. Pacheco SS, Braga C, Souza AI, Figueiroa JN. Effects of folic acid fortification on the prevalence of neural tube defects. Rev Saude Publica. 2009;43(4):565-71. another study found a significant reduction (39%) in the incidence of spina bifida.6565. Orioli IM, Lima do Nascimento R, López-Camelo JS, Castilla EE.Effects of folic acid fortification on spina bifida prevalence in Brazil. Birth Defects Res A Clin Mol Teratol. 2011;91(9):831-5. Recently a transversal study has shown that the incidences of anencephaly and spina bifida were reduced by 22% and 48%, respectively, with no reduction in the incidence of encephalocele in municipals of the state of São Paulo following mandatory fortification. In total, the incidence of NTDs has dropped 35%, from 0.57 to 0.37 cases per 1000 live births.6666. Fujimori E, Baldino CF, Sato AP, Borges AL, Gomes MN. [Prevalence and spatial distribution of neural tube defects in São Paulo State, Brazil, before and after folic acid flour fortification]. Cad Saude Publica. 2013;29(1):145-54.

Besides these studies, a systematic review in nine countries (Brazil, Chile, Argentina, Canada, the USA, Costa Rica, Iran, Jordan and South Africa) observed that the FA fortification of foods has had a considerable impact, with reductions in the incidence of NTDs varying between 15.5% and 58.0%.6767. 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(5):901-11.

Another way of evaluating the impact of fortification is by means of dietary folate intake, such that a significant decline in the rate of inadequate folate intake has been observed in the countries that have adopted mandatory FA fortification.6868. Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr. 2010;91(1):231-7. Comment in: Am J Clin Nutr. 2010;91(5):1408-9. Am J Clin Nutr. 2010;91(1):3-4. and 7070. Abdollahi Z, Elmadfa I, Djazayery A, Golalipour MJ, Sadighi J, Salehi F, et al. Efficacy of flour fortification with folic acid in women of childbearing age in Iran. Ann Nutr Metab. 2011;58(3):188-96. In Brazil, transversal studies have shown inadequate folate intake among pregnant women,7171. Lima HT, Saunders C, Ramalho A. Ingestão dietética de folato em gestantes do município do Rio de Janeiro. Rev Bras Saúde Matern Infant. 2002;2:303-11. and 7373. Azevedo DV, Sampaio HA. Consumo alimentar de gestantes adolescentes atendidas em serviço de assistência pré-natal. Rev Nutr. 2003;16(3):273-80. teenagers7474. Vitolo MR, Canal Q, Campagnolo PD, Gama CM. Factors associated with risk of low folate intake among adolescents. J Pediatr (Rio J). 2006;82(2):121-6.and adults7575. Tomita LY, Cardoso MA. Avaliação da lista de alimentos e porções alimentares de Questionário Quantitativo de Freqüência Alimentar em população adulta. Cad Saúde Pública. 2002;18(6):1747-56. in the pre-fortification period.

However, in the post-fortification period, no inadequate folate intake has been observed among pre-school children.7676. Bernardi JR, De Cezaro C, Fisberg RM, Fisberg M, Rodrigues GP, Vitolo MR. Consumo alimentar de micronutrientes entre pré-escolares no domicílio e em escolas de educação infantil do município de Caxias do Sul (RS). Rev Nutr. 2011;24(2):253-61. An inadequate intake of FA was observed in 15.2% adolescents in the town of Indaiatuba (state of São Paulo).2121. Steluti J, Martini LA, Peters BS, Marchioni DM. Folate, vitamin B6 and vitamin B12 in adolescence: serum concentrations, prevalence of inadequate intakes and sources in food. J Pediatr (Rio J). 2011;87(1):43-9.

Finally, one factor that must be taken into consideration when evaluating the FA fortification of flour is the level of compliance with legislation by flour mills. ANVISA RDC Resolution no. 344 mandates the addition of 150 μg of FA to every 100 g of wheat flour and cornmeal; however, a maximum limit for the quantity of FA has not been established. Non-compliant FA concentrations regarding RDC no. 344 have been observed in cornmeal (from 96 to 558 μg per 100 g) and in wheat flour (73 to 233 μg per 100 g).7777. Boen TR, Soeiro BT, Pereira-Filho ER, Lima-Pallone JA. Folic acid and iron evaluation in Brazilian enriched corn and wheat flours. J Braz Chem Soc. [Internet]. 2008;19(1):53-9. Available from: http://www.scielo.br/pdf/jbchs/v19n1/ a09v19n1.pdf
http://www.scielo.br/pdf/jbchs/v19n1/ a0... Since both lack and excess of folate can be harmful, these data emphasize the need for constant monitoring of the FA content in flour products by health authorities, especially as several studies have observed supraphysiological concentrations of this vitamin (serum folate > 45 nmol/L) among several populations. In conclusion, the studies show an increase in the serum concentrations of folate and a reduction in the incidence of NTDs in Brazil. However, national wide-range evaluations are necessary, in order to be able to monitor blood concentrations in the Brazilian population and the FA content of fortified foods.

REFERENCES

  • 1
    Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med. 2009;11:e4.
  • 2
    Sanderson P, McNulty H, Mastroiacovo P, McDowell IF, Melse-Boonstra A, Finglas PM, Gregory JF 3rd; UK Food Standards Agency. Folate bioavailability: UK Food Standards Agency workshop report. Br J Nutr. 2003;90(2):473-9.
  • 3
    Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res. 2007;51(3):267-92.
  • 4
    Green, R. Folate, cobalamin, and megaloblastic anemias (capítulo 41). Kaushansky, K; Lichtman M., Beutler E., et al. (eds). Williams Hematology, Oitava Edição, 2010.
  • 5
    Santos LM, Pereira MZ. [The effect of folic acid fortification on the reduction of neural tube defects]. Cad Saude Publica. 2007;23(1):17-24.
  • 6
    Institute of Medicine. In Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington: National Academy Press; 1998. pp. 196-305.
  • 7
    Guerra-Shinohara EM, Morita OE, Peres S, Pagliusi RA, Sampaio Neto LF, D'Almeida V, et al. Low ratio of S-adenosylmethionine to S-adenosylhomocysteine is associated with vitamin deficiency in Brazilian pregnant women and newborns. Am J Clin Nutr. 2004;80(5):1312-21.
  • 8
    Brasil. Ministério da Saúde. ANVISA - Agência Nacional de Vigilância Sanitária. Resolução RDC nº 344, de 13 de dezembro de 2002. Aprova o Regulamento Técnico para a fortificação das farinhas de trigo e das farinhas de milho com ferro e ácido fólico, constante do anexo desta Resolução. D.O.U. - Diário Oficial da União; Poder Executivo, de 18 de dezembro de 2002.
  • 9
    Chisholm-Burns MA, et al. Pharmacotherapy Principles and Practice. New York: McGraw-Hill Medical Publishing Division; 2008. 1671 p.
  • 10
    Thame G, Guerra-Shinohara EM, Moron AF. Serum folate by two methods in pregnant women carrying fetuses with neural tube defects. Clin Chem. 2002;48(7):1094-5.
  • 11
    Guerra-Shinohara EM, Paiva AA, Rondo PH, Yamasaki K, Terzi CA, D'Almeida V. Relationship between total homocysteine and folate levels in pregnant women and their newborn babies according to maternal serum levels of vitamin B12. BJOG. 2002;109(7):784-91.
  • 12
    Barbosa PR, Stabler SP, Machado AL, Braga RC, Hirata RD, Hirata MH. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur J Clin Nutr. 2008;62(8):1010-21.
  • 13
    Guerra-Shinohara EM, Pereira PM, Kubota AM, Silva TA, Reis JL, Miyashita GS. Increased MMA concentration and body mass index are associated with spontaneous abortion in Brazilian women: a pilot study. Clin Chim Acta. 2010;411(5-6):423-7.
  • 14
    Kubota AM. Efeito das concentrações das vitaminas (séricas e da dieta) e do polimorfismo MTHFR C677T na taxa de metilação global do DNA durante o período gestacional [thesis]. São Paulo: Universidade de São Paulo; 2008. 103f.
  • 15
    Couto FD, Moreira LM, Dos Santos DB, Reis MG, Gonçalves MS. Folate, vitamin B12 and total homocysteine levels in neonates from Brazil. Eur J Clin Nutr. 2007;61(3):382-6.
  • 16
    Félix TM, Leistner S, Giugliani R. Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil. Birth Defects Res A Clin Mol Teratol. 2004;70(7):459-63.
  • 17
    do Prado R, D'Almeida VM, Guerra-Shinohara E, Galdieri LC, Terreri MT, Hilário MO. Increased concentration of plasma homocysteine in children with systemic lupus erythematosus. Clin Exp Rheumatol. 2006;24(5):594-8.
  • 18
    Galdieri LC, Arrieta SR, Silva CM, Pedra CA, D'Almeida V. Homocysteine concentrations and molecular analysis in patients with congenital heart defects. Arch Med Res. 2007;38(2):212-8.
  • 19
    Gonçalves M, D'Almeida V, Guerra-Shinohara EM, Galdieri LC, Len CA, Hilário MO. Homocysteine and lipid profile in children with Juvenile Idiopathic Arthritis. Pediatr Rheumatol Online J. 2007;5:2.
  • 20
    Hadler MC, Sigulem DM, Alves Mde F, Torres VM. Treatment and prevention of anemia with ferrous sulfate plus folic acid in children attending daycare centers in Goiânia, Goiás State, Brazil: a randomized controlled trial. Cad Saude Publica. 2008;24 Suppl 2:S259-71.
  • 21
    Steluti J, Martini LA, Peters BS, Marchioni DM. Folate, vitamin B6 and vitamin B12 in adolescence: serum concentrations, prevalence of inadequate intakes and sources in food. J Pediatr (Rio J). 2011;87(1):43-9.
  • 22
    Cardoso MA, Scopel KK, Muniz PT, Villamor E, Ferreira MU. Underlying factors associated with anemia in Amazonian children: a population-based, cross-sectional study. PLoS One. 2012;7(5):e36341.
  • 23
    Fialho ABCB. Helicobacter pylori, níveis séricos de ferritina, vitamina B12, ácido fólico e a dinâmica da infecção em indivíduos de uma comunidade de baixa renda. 2012. Dissertação (Mestrado - Programa de Pós-Graduação em Cirurgia) - Universidade Federal do Ceará, Faculdade de Medicina, Fortaleza, 2012.
  • 24
    Bigio RS. Consumo de frutas, legumes e verduras: relação com os níveis sanguíneos de homocisteína entre adolescentes [thesis]. São Paulo: Universidade de São Paulo; 2011. 82p.
  • 25
    da Costa NF, Schtscherbyna A, Soares EA, Ribeiro BG. Disordered eating among adolescent female swimmers: dietary, biochemical, and body composition factors. Nutrition. 2013;29(1):172-7.
  • 26
    Moriguti JC, Ferriolli E, Marchini JS. Urinary calcium loss in elderly men on a vegetable:animal (1:1) high-protein diet. Gerontology. 1999;45(5):274-8.
  • 27
    Tassino M, Campos TF, Guerra RO. Homocysteine (Hcy) and cognitive performance in a population sample of elderly Brazilians. Arch Gerontol Geriatr. 2009;48(2):142-5.
  • 28
    Xavier JM, Costa FF, Annichino-Bizzacchi JM, Saad ST. High frequency of vitamin B12 deficiency in a Brazilian population. Public Health Nutr. 2010;13(8):1191-7.
  • 29
    Coussirat C. Prevalência de deficiência de vitamina B12 e ácido fólico e sua associação com anemia em idosos atendidos em um hospital universitário [thesis] Porto Alegre: Pontifícia Universidade Católica Do Rio Grande Do Sul; 2010. 64p.
  • 30
    Martins PJ, D'Almeida V, Vergani N, Perez AB, Tufik S. Increased plasma homocysteine levels in shift working bus drivers. Occup Environ Med. 2003;60(9):662-6.
  • 31
    Pereira AC, Schettert IT, Morandini Filho AA, Guerra-Shinohara EM, Krieger JE. Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population. Clin Chim Acta. 2004;340(1-2):99-105.
  • 32
    Tavares EF, Vieira-Filho JP, Andriolo A, et al. Serum total homocysteine levels and the prevalence of folic acid deficiency and C677T mutation at the MTHFR gene in an indigenous population of Amazonia: the relationship of homocysteine with other cardiovascular risk factors. Ethn Dis. 2004;14(1):49-56.
  • 33
    Helfenstein T, Fonseca FA, Relvas WG, et al. Prevalence of myocardial infarction is related to hyperhomocysteinemia but not influenced by C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms in diabetic and non-diabetic subjects. Clin Chim Acta. 2005;355(1-2):165-172. Comment in: Ethn Dis. 2004 Winter; 14(1):159.
  • 34
    Muniz MT, Siqueira ER, Fonseca RA, D'Almeida V, Hotta JK, dos Santos JE. [Evaluation of MTHFR C677T gene polymorphism and homocysteine level in coronary atherosclerotic disease]. Arq Bras Endocrinol Metabol. 2006;50(6):1059-65.
  • 35
    Faria-Neto JR, Chagas AC, Bydlowski SP, Lemos Neto PA, Chamone DA, Ramirez JA. Hyperhomocystinemia in patients with coronary artery disease. Braz J Med Biol Res. 2006;39(4):455-63.
  • 36
    Almeida LC, Tomita LY, D'Almeida V, Cardoso MA. [Socio-demographic, lifestyle, gynecological, and obstetric predictors of serum or plasma concentrations of homocysteine, folic acid, and vitamins B12 and B6 among low-income women in São Paulo, Brazil]. Cad Saude Publica. 2008;24(3):587-96.
  • 37
    Barbosa PR, Stabler SP, Trentin R, Carvalho FR, Luchessi AD, Hirata RD. Evaluation of nutritional and genetic determinants of total homocysteine, methylmalonic acid and S-adenosylmethionine/S-adenosylhomocysteine values in Brazilian childbearing-age women. Clin Chim Acta. 2008;388(1-2):139-47.
  • 38
    Biselli PM, Guerzoni AR, de Godoy MF, Eberlin MN, Haddad R, Carvalho VM, et al. Genetic polymorphisms involved in folate metabolism and concentrations of methylmalonic acid and folate on plasma homocysteine and risk of coronary artery disease. J Thromb Thrombolysis. 2010;29(1):32-40.
  • 39
    Blume CA, Boni CC, Casagrande DS, Rizzolli J, Padoin AV, Mottin CC. Nutritional profile of patients before and after Roux-en-Y gastric bypass: 3-year follow-up. Obes Surg. 2012;22(11):1676-85.
  • 40
    Mendes CC, Biselli JM, Zampieri BL, Goloni-Bertollo EM, Eberlin MN, Haddad R, et al. 19-base pair deletion polymorphism of the dihydrofolate reductase (DHFR) gene: maternal risk of Down syndrome and folate metabolism. Sao Paulo Med J. 2010;128(4):215-8.
  • 41
    Barnabé A. Avaliação da concentração de 2,3-difosfoglicerato, homocisteína plasmática, ácido fólico, vitamina B12 e polimorfismos no gene da MTHFR em pacientes com doença pulmonar obstrutiva crônica [thesis]. Campinas: Universidade Estadual de Campinas; 2010. 110p.
  • 42
    Minozzo R, Deimling LI, Santos-Mello R. Cytokinesis-blocked micronucleus cytome and comet assays in peripheral blood lymphocytes of workers exposed to lead considering folate and vitamin B12 status. Mutat Res. 2010;697(1-2):24-32.
  • 43
    Braga CB, Vannucchi H, Freire CM, Marchini JS, Jordão AA, da Cunha SF. Serum vitamins in adult patients with short bowel syndrome receiving intermittent parenteral nutrition. JPEN J Parenter Enteral Nutr. 2011;35(4):493-8.
  • 44
    Vinha PP, Jordão AA, Farina JA Jr, Vannucchi H, Marchini JS, Cunha SF. Inflammatory and oxidative stress after surgery for the small area corrections of burn sequelae. Acta Cir Bras. 2011;26(4):320-4.
  • 45
    Chiarani F. Avaliação de biomarcadores de risco cardiovascular em pacientes com transtorno de humor bipolar [Thesis]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2012. 132p.
  • 46
    Giusti KC. Associação entre polimorfismos em genes relacionados ao metabolismo de folato (RFC1, GCP2, MTHFR e MTHFD1) e alterações nas concentrações de folato, cobalamina e homocisteína em mulheres com história de abortos espontâneos recorrentes [thesis]. São Paulo: Universidade de São Paulo; 2012. 106p.
  • 47
    de Carvalho SC, Muniz MT, Siqueira MD, Siqueira ER, Gomes AV, Silva KA, et al. Plasmatic higher levels of homocysteine in non-alcoholic fatty liver disease (NAFLD). Nutr J. 2013;12:37.
  • 48
    Cunha AL, Hirata MH, Kim CA, Guerra-Shinohara EM, Nonoyama K, Hirata RD. Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects. Clin Chim Acta. 2002;318(1-2):139-43.
  • 49
    Melo SS, Persuhn DC, Meirelles MS, Jordao AA, Vannucchi H. G1793A polymorphisms in the methylene-tetrahydrofolate gene: effect of folic acid on homocysteine levels. Mol Nutr Food Res. 2006;50(8):769-74.
  • 50
    Uehara SK, Rosa G. Association of homocysteinemia with high concentrations of serum insulin and uric acid in Brazilian subjects with metabolic syndrome genotyped for C677T polymorphism in the methylenetetrahydrofolate reductase gene. Nutr Res. 2008;28(11):760-6.
  • 51
    Scorsatto M, Uehara SK, Luiz RR, de Oliveira GM, Rosa G. Fortification of flours with folic acid reduces homocysteine levels in Brazilian women. Nutr Res. 2011;31(12):889-95.
  • 52
    Vianna AC, Mocelin AJ, Matsuo T, Morais-Filho D, Largura A, Delfino VA, et al. Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events. Hemodial Int. 2007;11(2):210-6.
  • 53
    Chiarello PG, Penaforte FR, Japur CC, Souza CD, Vannucchi H, Troncon LE. Increased folate intake with no changes in serum homocysteine and decreased levels of C-reactive protein in patients with inflammatory bowel diseases. Dig Dis Sci. 2009;54(3):627-33.
  • 54
    Santos IS, Scazufca M, Lotufo PA, Menezes PR, Benseñor IM. Causes of recurrent or persistent anemia in older people from the results of the São Paulo Ageing & Health Study. Geriatr Gerontol Int. 2013;13(1):204-8.
  • 55
    Almeida Dantas J, de Arruda Ada S. [Folate food intake and red blood cell folate concentrations in women from Recife, Northeast of Brazil]. Arch Latinoam Nutr. 2010;60(3):227-34.
  • 56
    Dietrich M, Brown CJ, Block G. The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr. 2005;24(4):266-74.
  • 57
    Enquobahrie DA, Feldman HA, Hoelscher DH, Steffen LM, Webber LS, Zive MM, et al. Serum homocysteine and folate concentrations among a US cohort of adolescents before and after folic acid fortification. Public Health Nutr. 2012;15(10):1818-26.
  • 58
    Hertrampf E, Cortés F, Erickson JD, Cayazzo M, Freire W, Bailey LB, et al. Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile. J Nutr. 2003;133(10):3166-9.
  • 59
    Pereira PM. Consumo de cobalamina e folato por gestantes: relação com o metabolismo da homocisteína e com os polimorfismos nos genes da metionina sintase, metilenotetraidrofolato redutase e metionina sintase redutase [thesis]. São Paulo: Universidade de São Paulo; 2007. 109p.
  • 60
    Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci U S A. 1998;95(22):13217-20.
  • 61
    Molloy AM, Mills JL, Kirke PN, Whitehead AS, Weir DG, Scott JM. Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radioassay and microbiological assays. Clin Chem. 1998;44(1):186-8.
  • 62
    Rosenthal J, Casas J, Taren D, Alverson CJ, Flores A, Frias J. Neural tube defects in Latin America and the impact of fortification: a literature review. Public Health Nutr. 2013:1-14.
  • 63
    López-Camelo JS, Castilla EE, Orioli IM; INAGEMP (Instituto Nacional de Genética Médica Populacional); ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas). Folic acid flour fortification: impact on the frequencies of 52 congenital anomaly types in three South American countries. Am J Med Genet A. 2010;152(10):2444-58.
  • 64
    Pacheco SS, Braga C, Souza AI, Figueiroa JN. Effects of folic acid fortification on the prevalence of neural tube defects. Rev Saude Publica. 2009;43(4):565-71.
  • 65
    Orioli IM, Lima do Nascimento R, López-Camelo JS, Castilla EE.Effects of folic acid fortification on spina bifida prevalence in Brazil. Birth Defects Res A Clin Mol Teratol. 2011;91(9):831-5.
  • 66
    Fujimori E, Baldino CF, Sato AP, Borges AL, Gomes MN. [Prevalence and spatial distribution of neural tube defects in São Paulo State, Brazil, before and after folic acid flour fortification]. Cad Saude Publica. 2013;29(1):145-54.
  • 67
    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(5):901-11.
  • 68
    Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr. 2010;91(1):231-7. Comment in: Am J Clin Nutr. 2010;91(5):1408-9. Am J Clin Nutr. 2010;91(1):3-4.
  • 69
    Shakur YA, Garriguet D, Corey P, O'Connor DL. Folic acid fortification above mandated levels results in a low prevalence of folate inadequacy among Canadians. Am J Clin Nutr. 2010;92(4):818-25.
  • 70
    Abdollahi Z, Elmadfa I, Djazayery A, Golalipour MJ, Sadighi J, Salehi F, et al. Efficacy of flour fortification with folic acid in women of childbearing age in Iran. Ann Nutr Metab. 2011;58(3):188-96.
  • 71
    Lima HT, Saunders C, Ramalho A. Ingestão dietética de folato em gestantes do município do Rio de Janeiro. Rev Bras Saúde Matern Infant. 2002;2:303-11.
  • 72
    Fonseca VM, Sichieri R, Basilio L, Ribeiro LV. Consumo de folato em gestantes de um hospital público do Rio de Janeiro. Rev Bras Epidemiol. 2003;6:319-27.
  • 73
    Azevedo DV, Sampaio HA. Consumo alimentar de gestantes adolescentes atendidas em serviço de assistência pré-natal. Rev Nutr. 2003;16(3):273-80.
  • 74
    Vitolo MR, Canal Q, Campagnolo PD, Gama CM. Factors associated with risk of low folate intake among adolescents. J Pediatr (Rio J). 2006;82(2):121-6.
  • 75
    Tomita LY, Cardoso MA. Avaliação da lista de alimentos e porções alimentares de Questionário Quantitativo de Freqüência Alimentar em população adulta. Cad Saúde Pública. 2002;18(6):1747-56.
  • 76
    Bernardi JR, De Cezaro C, Fisberg RM, Fisberg M, Rodrigues GP, Vitolo MR. Consumo alimentar de micronutrientes entre pré-escolares no domicílio e em escolas de educação infantil do município de Caxias do Sul (RS). Rev Nutr. 2011;24(2):253-61.
  • 77
    Boen TR, Soeiro BT, Pereira-Filho ER, Lima-Pallone JA. Folic acid and iron evaluation in Brazilian enriched corn and wheat flours. J Braz Chem Soc. [Internet]. 2008;19(1):53-9. Available from: http://www.scielo.br/pdf/jbchs/v19n1/ a09v19n1.pdf
    » http://www.scielo.br/pdf/jbchs/v19n1/ a09v19n1.pdf

Publication Dates

  • Publication in this collection
    Jul-Aug 2014

History

  • Received
    26 June 2013
  • Accepted
    26 July 2013
Creative Common - by-nc 4.0
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the original work is properly cited.
Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular R. Dr. Diogo de Faria, 775 cj 114, 04037-002 São Paulo/SP/Brasil, Tel. (55 11) 2369-7767/2338-6764 - São Paulo - SP - Brazil
E-mail: secretaria@rbhh.org
Acompanhe os números deste periódico no seu leitor de RSS