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Review

Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World

by
Rosemary A. Stamm
and
Lisa A. Houghton
*
Department of Human Nutrition, University of Otago, Dunedin 9016, New Zealand
*
Author to whom correspondence should be addressed.
Nutrients 2013, 5(10), 3920-3947; https://0-doi-org.brum.beds.ac.uk/10.3390/nu5103920
Submission received: 25 July 2013 / Revised: 3 September 2013 / Accepted: 3 September 2013 / Published: 30 September 2013
Versions Notes

Abstract

:
Folate is a B-vitamin with particular importance during reproduction due to its role in the synthesis and maintenance of DNA. Folate is well known for its role in preventing neural tube defects (NTDs) during the periconceptional period. There is also an increased need for folate throughout pregnancy to support optimal growth and development of the fetus and blood volume expansion and tissue growth of the mother. During lactation, women are at risk of folate deficiency due to increased demands to accommodate milk folate levels. Nutrient Intake Values (NIVs) for folate have been calculated to take into account additional needs during pregnancy and lactation. However, these values vary widely between countries. For example, the folate requirement that is set to meet the needs of almost all healthy women during pregnancy varies from 300 µg/day in the United Kingdom to 750 µg/day in Mexico. Currently, there is no accepted standardized terminology or framework for establishing NIVs. This article reviews country-specific NIVs for folate during pregnancy and lactation and the basis for setting these reference values.

1. Introduction

Folate is a B-vitamin involved in one-carbon transfer reactions and plays a fundamental role in nucleotide biosynthesis and methylation reactions [1]. During pregnancy and lactation, the demand for folate is increased to support both the normal physiological changes of the mother and optimal growth and development of the fetus and offspring [2,3]. Observational studies in the 1960s demonstrated higher rates of folate-related anemia (megaloblastic anemia) in unsupplemented pregnant and lactating mothers [4,5,6]. As a result, a number of countries recommended supplementation of folic acid during the prenatal period [7]. Years later, one of the better-known consequences of low folate status emerged with scientific evidence supporting the use of periconceptional folic acid supplementation for the prevention of neural tube defects (NTDs) [8]. While other pregnancy complications have been associated with folate deficiency, data are limited and the findings unclear. More recently, studies have suggested improved neurodevelopment outcomes in children of mothers with higher blood folate concentrations or mothers receiving prenatal folic acid supplements [9,10,11,12]. Thus, establishing nutrient intake recommendations to optimize folate status for pregnant women remains challenging. Moreover, the dietary contributors to folate intake have evolved since the first nutrient recommendations for folate, with an increasing number of countries mandating folic acid fortification of their food supply [8]. Limitations in our understanding of folate bioavailability make accurate interpretation of dietary intakes difficult.
Despite the challenges, most countries have established recommended folate intakes for their populations; however, requirements among countries vary considerably due to a lack of a standardized framework for deriving these standards. In 2005, the United Nations University’s Food and Nutrition Programme, in collaboration with the Food and Agriculture Organization (FAO), the World Health Organization (WHO) and UNICEF, assembled an international working group to establish a common approach for establishing nutrient intake recommendations. The umbrella term Nutrient Intake Values (NIVs) was proposed to refer to a set of specific nutrient standards and is synonymous with the U.S. and Canada Dietary Reference Intakes (DRIs) and the U.K. Dietary Reference Values (DRVs) among others [13,14].
In this paper, we will briefly review the approach used for deriving folate requirements, including considerations of the indicators used to establish adequate intakes, folate bioavailability and the potential influence of gene polymorphisms on requirements. The next section will compare current folate reference values from over 50 countries and describe the scientific foundation of the NIVs for non-pregnant, non-lactating (NPNL), pregnant, and lactating women.

2. Terminology

The terms Average Nutrient Requirement (ANR), Individual Nutrient Level (INLx) and the Upper Nutrient Level (UNL) will be used throughout the article as they are aligned with proposed common terminology of the international working group [14]. Table 1 provides a list of comparable terminology currently used by different countries and organizations. The ANR is synonymous with the U.S. and the U.K. Estimated Average Intake (EAR) or the European Community Average Requirement (AR). The ANR is derived from a statistical distribution of requirements for a criterion, and is the value that should be used for assessing the adequacy of population intakes and planning of group diets [15]. The ANR also serves as a basis for determining the INLx—the recommended intake level for all healthy individuals in the population. An INLx set at 2 standard deviations above the ANR would be INL98, covering 98% of the population nutrient requirement. This value is equivalent to the U.S. Recommended Dietary Allowance (RDA), and U.K. Recommended Nutrient Intake (RNI) and the European Community Population Reference Intake (PRI). The INLx should not be used for assessing the adequacy of population intakes; rather it should be used for planning individual’s intakes [15].
Table
Table 1. Sources of country Nutrient Intake Values and country specific terminology used for folate Nutrient Intake Values.
Table 1. Sources of country Nutrient Intake Values and country specific terminology used for folate Nutrient Intake Values.
CountryYearEquivalent Term Used for NIVs for FolateAdapted fromReference
NIVANRINL98SI
Australia and New Zealand2005NRVEARRDI−U.S.[16]
Austria, Germany, and Switzerland2000†−†−Own (DACH)[17]
Belgium2009−−PRI−EC[18]
Brazil2000−−IDR−WHO[19]
Bulgaria2005−−†−U.S.[20]
Central America 1 and Panama1994−−RDD−WHO/FAO 1988[21]
China2010DRIEARRNI−U.S.[22]
Colombia1988−−†−Own[23]
Croatia2004−−†−EC and U.S.[24]
Cuba2008−−DRI−U.S./WHO[25]
Denmark, Iceland and Sweden2004NNRARRI−Own (NNR)[26]
Estonia2006−−†−NNR[27]
European Community1993RDAARPRI−Own (EC)[28]
Finland2005NNRARRI−NNR[29]
France2001−−−ANCOwn[30]
Greece1993RDAARPRI−EC[31]
Hungary2005−−−†EC and U.S.[32]
India2010−−RDA−Own[33]
Ireland1999−−RDA−Own[34]
Italy2012LARNARPRI−U.S.[35]
Japan2005DRIEARRDA−Own[36]
Latvia2008−−†−Own[37]
Lithuania1999RPN−RP−Own[38]
Mexico2004VNRRNP−IDSU.S.[39]
Norway2005NNRARRI−NNR[40]
Poland2008−EARRDA−U.S.[41]
Republic of Macedonia2001−−†−EC[42]
Republica Srpska, Bosnia and Herzegovina2004−−†−WHO/FAO[43]
Russian Federation2008−−†−U.S.[44]
Slovakia1997−−OVD−Own and WHO/FAO[45]
Slovenia2004−−PVD−DACH[46]
South Korea2010KDRIEARRI−U.S.[47]
Southeast Asia Region 22005−−RDA−U.S.[48]
Spain2010−−IDR−Own and Ireland[49]
The Netherlands2003DRIEARRDA 3AI 4Own[50]
United Kingdom1991DRVEARRNI−Own[51]
United States and Canada1998DRIEARRDA−Own (U.S.)[52]
WHO/FAO2004−EARRNI−U.S.[53]
AI: adequate intake; ANC: apports nutritionnels conseillés; ANR: average nutrient requirement; AR: average requirement; DACH: Germany, Austria, and Switzerland; DRI: dietary reference intake; DRV: dietary reference value; EAR: estimated average requirement; EC: European community; FAO: Food and Agriculture Organization; IDR: ingestión diaria recomendada (Brazil); IDR: ingestas dietéticas de referencia (Spain); IDS: ingestión diaria sugerida; INL: individual nutrient level; KRDI: Korean Dietary Reference Intakes; LARN: livelli di assunzione di riferimento di nutrienti; NIV: nutrient intake value; NNR: Nordic nutrition recommendations; NRV: nutrient reference values; OVD: odporúčané výživové dávky; PRI: population reference intake; PVD: priporočeni dnevni vnosi; RI: recommended intake; RDA: recommended dietary allowance; RDD: recomendiaciones dietéticas diarias; RDI: recommended dietary intake; RNI: recommended nutrient intake; RNP: requerimiento nutrimental promedio; RP: rekomenduotinus paros poreikias; RPN: rekomenduojamos paros maistinių medžiagų ir energijos normos; SI: safe intake; VNR: valores nutrimentales de referencia; WHO: World Health Organization; † Equivalent terms are used; 1 inclusive of Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and the Dominican Republic; 2 inclusive of Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam; 3 for NPNL women; 4 for pregnant and lactating women.

3. Establishing Nutrient Intake Values for Folate

3.1. Selection of Model Indicators for Folate Adequacy

Selecting a reliable indicator for nutrient adequacy is a critical step in determining the ANR for a subpopulation. Ideally the indicator chosen should be reflective of a physiologic state representative of adequate intake in all individuals; resistant to short-term dietary intake changes and other environmental influences such as infection; easily measurable and non-invasive; elicit a dose-response relationship across a range of intakes; and be accepted worldwide to allow for harmonization of NIVs [13].
Folate requirements in most countries have been established based on concentrations of serum or erythrocyte folate known to be associated megaloblastic anemia—the clinical manifestation of folate deficiency. Several countries, namely Austria, Germany and Switzerland (abbreviated as the DACH countries) and France have chosen concentration of homocysteine (which increases when folate status is low) as an indicator of adequate intake on the basis of its association with CVD risk [17,30]. Although homocysteine concentration is considered a sensitive indicator, it is not specific for folate since it is influenced by nutritional status of other B-vitamins, one-carbon metabolism related nutrients and renal insufficiency [54]. Furthermore, a recent meta-analysis of randomized controlled trials found no significant effect of lowering homocysteine levels with folic acid supplementation on cardiovascular events [55]. In contrast, erythrocyte folate concentration appropriately fits the criteria as an indicator of adequacy. Erythrocyte folate concentration is a marker of long-term folate status (i.e., resistant to recent or transient changes in dietary folate intake), reflects tissue folate stores [56], and shows a dose-response relationship with intake. Erythrocyte folate cut-offs as an indicator of adequacy vary from country to country, ranging from 300 nmol/L to 327 nmol/L [26,28,50,51,52]. Conventionally, folate deficiency has been defined as a serum folate concentration <3 ng/mL (6.8 nmol/L) and an erythrocyte folate concentration <140 ng/mL (317 nmol/L), below which macrocytic anemia is most likely to appear (Folate cut-offs are originally reported in units of ng/mL. To obtain units in nmol/L values have been multiplied by 2.265). These cut-offs were based on data generated from folate depletion studies conducted in a small number of subjects [57,58,59], and erythrocyte folate concentration levels obtained from patients presenting with megaloblastic anemia [60,61]. In addition, the risk of uracil misincorporation into DNA and chromosomal breakage has shown to increase in individuals with erythrocyte folate concentrations below 317 nmol/L [62].
A major difficulty in establishing a scientific consensus for folate deficiency lies in the existence of a number of methodological issues related to the measurement of blood folate. The microbiologic assay is the method of choice for many research laboratories, however, changes in the assay protocol over time have resulted in substantial inter-laboratory differences in the quantification of folate, presenting challenges in data interpretation across studies [63,64,65]. Standardization of folate measurement is needed for accurate assessment of blood folate status. Recent development of sophisticated mass spectrometric techniques have led to the development of serum folate reference measurement procedures [66,67,68]; however, similar procedures for erythrocyte blood folate are still in development [69,70,71]. Once established, there will be a need for clinical trials that relate accurately measured folate biomarker data to clinical outcomes.

3.2. Consideration of Folate Bioavailability

Bioavailability is an important factor to consider when estimating folate requirements due to differences in the absorption of naturally occurring food folate and the more bioavailable synthetic folic acid used in supplements and fortified foods. A number of studies used to determine NIVs have been based on data obtained from folic acid supplement trials, causing uncertainties in determining the equivalent amount of the less bioavailable food folate required to maintain adequate folate status. The U.S. DRI process has recommended the use of dietary folate equivalents (DFEs) for planning and evaluating the adequacy of folate intake. DFEs are defined as the amount of naturally occurring food folate plus 1.7 times the amount of folic acid from fortified foods [52]. Several countries, including a number of European countries, India, South Korea, China, Australia and New Zealand have also expressed NIVs in units of DFEs (Table 1). While adjusting for differences in folate bioavailability is particularly important in countries where folic acid has been added to the food supply, the bioavailability estimate for food folate derived from the DFE equation remains questionable. A thorough review of folate bioavailability is presented elsewhere in this special issue [72]. In summary, there are fairly large discrepancies in the bioavailability of naturally occurring food folate with values ranging from 30% [73] to 98% [74] relative to folic acid. These differences are likely attributed to the use of different test foods, difficulties in quantifying the amount of folate in these foods, and metabolic differences in the physiologic response between naturally occurring food folate and the synthetic, fully oxidized, monoglutamate form of folic acid. It should also be noted that a number of trials have shown that [6S]-5-methyltetrahydrofolate in its monoglutamate form given as a supplement or microencapsulated in food results in a similar change in blood folate concentration to folic acid [75,76,77]. Further investigations are required to derive reasonably accurate and precise estimates of folate bioavailability. Recent efforts to scale up folic acid fortification in both developed and developing countries indicate that this should be a research priority.

3.3. Genetic Variation in Requirements

Recent advances in the field of genetics and nutrition have highlighted the importance of gene-diet interactions, and introduced the concept of applying genomic knowledge to population-based dietary recommendations. Currently NIVs for folate are targeted to the general and supposedly “normal” population. However, the identification of several genetic polymorphisms in folate metabolism has stimulated research on the impact of these variants on population health [78].
The C677T polymorphism in the enzyme methylenetetrahydrofolate reductase (MTHFR) is one of the most investigated genes in folate metabolism. For TT homozygous individuals, the polymorphism results in partial enzyme deficiency [78]. The distribution of the T allele varies substantially among ethnic groups, with a lower prevalence of the TT genotype among Sub-Saharan Africans (0%–2%), North American whites (8%–14%) and Northern Europeans (6%–14%) compared to Southern Europeans (15%–24%) and Hispanic populations (15%–35%) [78,79,80]. The TT genotype is associated with lower folate status by 10%–35% and elevated homocysteine concentrations [78]. Consequently folate requirements may be higher in persons with the TT genotype, although differences in indicators of folate status among genotype groups appear to be greater when folate status is low [78,81,82,83]. Moreover, data on variability and the magnitude of the effect of the TT genotype on requirements are lacking. Nonetheless, Mexico have set requirements based on the U.S. DRIs with an adjustment toward higher intake levels due to the increased frequency of the TT genotype in the Mexican population [39].
With the rapid pace of development in genome-wide technology, an increasing number of common genetic variants in folate metabolism will be identified and future research will continue to explore their link with common disorders. As a result, both the genetic and non-genetic variation in requirements within a population will need to be carefully considered in the future development of NIVs. Current evidence suggests that the allowance for variability used in setting INL98 levels may already act as a built-in safeguard for the presence of genetic variability within populations [84]. For example, Robitaille et al. [85] modeled the effect of MTHFR TT prevalence on the IOM RDA demonstrating that even when accounting for a large effect size of 50% (i.e., 50% higher requirement of dietary folate for individuals with a TT genotype), the RDA would only increase from 400 µg DFE to 436 µg DFE in a population with 20.3% TT genotyped individuals.

3.4. Estimating Variability in Requirements

Folate needs vary between individuals, yet information from which to obtain a reliable estimate of the variance or standard deviation of the ANR is limited. When the variance is not known for a nutrient, then a symmetrical distribution is assumed and a coefficient of variation (CV) can be applied—often this is equal to about 10%. For folate, CVs vary widely; 10% has been used in Japan, the U.S. and Canada, 15% in the DACH countries and the U.K., 20% in the European Community and Mexico, and 25% in the Netherlands and the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). Given the INLx is derived from the ANR and its distribution, these differences in the CV assumed has lead to some of the discrepancy in the INL98 set among countries. For example, both Japan and the Netherlands have set the same ANR value of 200 µg DFE, however Japan have assigned a CV of 10% [36], while the Netherlands have assigned a CV of 25% [50] leading to a discrepancy of 60 µg DFE in their INL98. In the face of limited data, the uncertainty surrounding the variation in requirements leads to the potential to over-estimate the proportion of inadequate intakes if the CV is set too low compared to the actual variability in requirements of a population, or under-estimate the proportion of inadequate intakes if set too high.
The traditional approach to determining nutrient requirements is to test a range of nutrient intakes (preferably from foods) in the same individuals using a controlled diet over a sufficient duration to elicit a response in the nutritional indices measured. Often participant numbers in these types of controlled metabolic-unit depletion/repletion and nutrient balance studies are small and consequently, inter-individual variation in requirements cannot be determined. Although challenging, rigorous large-scale controlled-diet studies on free-living subjects are needed to allow for a reasonable approximation of the variability in requirements and the distribution of intakes.

4. Nutrient Intake Values for Folate in Use around the World

NIVs for folate for NPNL, pregnant and lactating women by country are listed in Table 2. While several countries have established their own NIVs for folate, many others including the WHO have either shared or adopted values from other countries (Table 1). The most commonly adopted NIVs are those set by the IOM in 1998. Although folate NIVs for pregnant and lactating women are consistently higher than for NPNL women, NIVs vary among countries and the use of DFE units is inconsistent. Moreover, many countries have only specified a value equivalent to the INL98.
Table
Table 2. Nutrient intake values for non-pregnant, non-lactating (NPNL), pregnant, and lactating women by country.
Table 2. Nutrient intake values for non-pregnant, non-lactating (NPNL), pregnant, and lactating women by country.
CountryUnitsNPNLPregnantLactating
ANRINL98ANRINL98ANRINL98
Australia and New Zealand 1µg DFE320400520600450500
Austria, Germany, and Switzerland 1µg DFE−400−600−600
Austria, Germany, and Switzerland 1,2[86]µg DFE220300420550340450
Belgiumµg−200−400−350
Brazilµg−240−355−295
Bulgariaµg DFE−400−600−500
Central America 3 and Panamaµg−170−370–470−270
Chinaµg DFE320400520600450500
Colombiaµg−160−460−360
Croatiaµg DFE−200−600−500
Cubaµg DFE−400−600−500
Denmark, Iceland and Sweden 1µg 200400 5−500−500
Estoniaµg −400 5−500−500
European Communityµg140200−400−350
Finland 1µg200400 5−400−400
France 1µg−300 6−400 6−400 6
Greeceµg140200−400−350
Hungary 1µg−200 6, 400 6,7−400 6, 600 6,7−350 6, 500 6,7
Indiaµg DFE−200−500−300
Ireland 1µg−300−500−400
Italy 1µg DFE320400520600450500
Japanµg200240370440280340
Latviaµg−300−400−300
Lithuaniaµg−300−400−480
Mexicoµg DFE320460 6520750 6450650 6
Norway 1µg200400 4−400−400
Poland 1µg DFE320400520600450500
Republic of Macedoniaµg−200−400−500
Republica Srpska, Bosnia and Herzegovinaµg DFE−400−600−500
Russian Federationµg−400−600−500
Slovakiaµg−200−400−300
Sloveniaµg DFE−400−600−600
South Koreaµg DFE320400520600450550
Southeast Asia Region 4µg−400−600−500
Spain 1µg−300−500−400
The Netherlands 1µg DFE200300−400 6−400 6
United Kingdom 1µg150200−300−260
United States and Canada 1µg DFE320400520600450500
United States 1989 [87]µg−180−400−280 8, 260 9
United States 1980 [88]µg−400−800−500
United States 1974 [89]µg−400−800−600
United States 1968 [90]µg−400−800−500
WHO/FAOµg DFE320400520600450500
WHO/FAO 1988 [91]µg−170 6−370–400 6−270 6
NR: average nutrient requirement; DFE: dietary folate equivalents; FAO: Food and Agriculture Organization; INL: individual nutrient level; NPNL: non-pregnant, non-lactation; WHO: World Health Organization; 1 These countries recommend an additional intake of 400 µg folic acid per day from supplements and/or fortified foods for women who are capable of becoming pregnant or planning a pregnancy, or who have an unbalanced poor diet, or because women are unlikely to meet the NIV, for the prevention of neural tube defects. Poland does not specify a dosage for folic acid supplementation [16,34,50,52,86,92,93]. 2 Proposed values to be approved August 2013; 3 Inclusive of Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and the Dominican Republic; 4 Inclusive of Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam; 5 The Nordic recommendations presented are for women of reproductive potential; 6 the equivalent of a safe intake level is used rather than an INL98; 7 INL98 when cereals are supplemented; 8 1st 6 months; 9 2nd 6 months.

4.1. Non-Pregnant, Non-Lactating (NPNL) Women

The INL98 for NPNL women varies between 200 µg and 460 µg DFE per day. Early work by Herbert in 1962 in one adult male and three adult females established that a minimum of 50 µg folic acid per day was required to recover normal hematology after a prolonged folate deficient diet [58,94]. The European Community have used this data to establish ANR for folate of 140 µg/day with the reasoning that the ANR would be somewhat higher than the minimum 50 µg folic acid/day—setting the value at 70 µg folic acid/day multiplied by a bioavailability correction factor of 2. Later work published by Sauberlich et al. in 1987 [95] and O’Keefe et al. in 1995 [96] generated from controlled metabolic studies, suggested higher intake levels of between 200 µg and 320 µg dietary folate/day were required to maintain status and prevent deficiency in NPNL women. The IOM (U.S. and Canada) and the Netherlands have considered much of the same data in determining NIVs for NPNL women, including the studies of Sauberlich et al. [95] and O’Keefe et al. [96] together with studies of Milne et al. [97] and Jacob et al. [98]. The IOM chose an ANR of 320 µg DFE/day, based primarily on data from the study of O’Keefe et al. [96], which demonstrated that at this intake level, 3 out of 5 women had an erythrocyte folate concentration below 305 nmol/L and serum folate below 7 nmol/L, and 2 out of 5 women had a homocysteine concentration greater than 16 nmol/L with another participant above 14 nmol/L. These data suggested that approximately half of women would have a normal erythrocyte folate level at an intake of 320 µg DFE/day [52]. In contrast, the Netherlands chose a lower ANR of 200 µg DFE/day, relying primarily on data from the depletion-repletion study of Sauberlich et al. [95], in which 200 µg of folate from food sources resulted in stabilization of plasma folate concentration in 2 out of 3 subjects [50,95]. Data from the study of Milne et al. [97] of adult men was also used to support the Netherland’s ANR of 200 µg DFE/day. Finally, the NIVs for folate set by the DACH countries are currently based on data from O’Keefe et al. [96], but are in the process of being revised toward lower NIVs on the basis of data from the studies of Sauberlich et al. [95] and Milne et al. [86,97].
The small study sample sizes of between 3 and 6 participants per test group, and the uncertainties surrounding folate bioavailability, particularly with the use of supplemental folic acid, leaves little confidence that these values are a true representation of the ANR. Another flaw of these studies is the inadequate duration to observe a plateau in erythrocyte folate response. The study of O’Keefe et al. [96] was conducted over 10 weeks (70 days) with subjects consuming a consistent diet, while the 13-week (91 day) study of Sauberlich et al. [95] involved a 4-week depletion diet followed by three 3-week repletion intervals whereby participants were provided with additional amounts of food folates along with graded doses of supplemental folic acid. Recent efforts to assess long-term blood folate responses to supplemental folic acid have shown that even with a relatively small daily intake of folic acid (140 µg/day) over a 40-week period, erythrocyte folate concentrations continued to increase [99]. Thus, the studies described above may have underestimated the biochemical response to controlled folate intakes and potentially overestimated folate requirements.
Interestingly, nutritional epidemiological evidence consistently demonstrates population intakes that are inconsistent with rates of folate deficiency. For example, most observational population studies have reported average dietary folate intakes ranging between 200 and 300 µg/day (Table 3); yet in a comprehensive review, Metz [100] found little evidence of anemia attributable to folate and vitamin B12 worldwide, with many studies showing no association between blood folate concentration and anemia even when the prevalence of low blood folate concentration is such that a significant association would be expected. It is conceivable that a discrepancy in the prevalence of low folate intakes, low folate status, and megaloblastic anemia exists due to measurement errors in dietary intake and laboratory assessment of folate status as well as a potential overestimation of folate requirements as previously noted.
To date, despite compelling evidence to support recommendations for women who are capable of becoming pregnant or who are planning a pregnancy to consume 400 µg of supplement folic acid/day for the prevention of NTDs, NIVs for women of reproductive potential in most countries are based on prevention of hematological abnormalities. A number of countries have established recommendations in addition their NIVs for the prevention of NTDs, recommending an additional 400 µg/day of folic acid from either supplements or a combination of supplements or fortified foods [16,34,50,52,86,92,93]. One exception is the Nordic countries, while still recommending an additional intake of 400 µg/day from supplemental folic acid [92,93], the Nordic countries have specifically set an INL98 of 400 µg/day for women of reproductive potential to reduce their chance of having an NTD-affected pregnancy versus the Nordic INL98 of 300 µg/day for adults [26]. Establishing an ANR for NPNL women on the basis of NTD prevention remains challenging, as there are a number of uncertainties surrounding the relationship among NTD risk, folate intake (natural food folate and folic acid), and erythrocyte folate concentration. The IOM considered data from two retrospective observational studies [101,102], showing a decrease in the risk of NTDs with increasing intake of dietary folate up to 400 µg DFE/day [52]. There were a number of limitations in these studies including relatively small participant sample size. At present, the minimum intake of folic acid to increase erythrocyte folate to concentrations associated with the lowest risk of NTDs is unknown [8,103].
Table
Table 3. Mean and median intakes of folate for women from population survey data by country.
Table 3. Mean and median intakes of folate for women from population survey data by country.
CountryYearMethodGroupNMeanMedianUnitsReference.
Australia199524 h RC19–24 year575233217µg[104]
25–44 year2385227210µg
Canada200424 h RC19–30 year1854415 1401 1µg DFE[105]
31–50 year2686423 1411 1µg DFE
Denmark19957 day DR19–24 year100244220µg[106]
25–34 year161266232µg
35–44 year158234239µg
Finland199724 h RC25–74 year325209 2,3 µg[107]
200748 h RC25–34 year180216 3 µg[108]
35–44 year211217 3 µg
48 h RC & 3 day EDR25–74 year641240 3,4230 3,4µg
310 2,3,4280 2,3,4µg
Germany1997–1999DH18–79 year2267 229µg[109]
238 2µg
2005–2006DH19–24 year510318257µg DFE[110]
25–34 year972311258µg DFE
35–50 year2694285255µg DFE
Ireland1997–19997 day DR18–35 year269247 2216 2µg[111]
36–50 year286267 2228 2µg
New Zealand199724 h RC19–24 year209202195µg[112]
25–44 year1205220213µg
Spain1992–199324 h RC & FFQ18–34 year431282257µg[113]
35–49 year323317291µg
Sweden1997–19987 day EDR25–34 year132209211µg[114]
35–44 year132206201µg
The Netherlands19922 day DR19–21 year107243236µg[115]
22–49 year1493234224µg
1993–1996FFQ20–65 year1160192 µg[116]
200324 h RC19–30 year398153 µg[117]
2007–201024 h RC19–30 year347 216µg DFE[118]
249 2µg DFE
31–50 year351 242µg DFE
282 2µg DFE
United Kingdom1986–19877 day WDR16–24 year189198194µg[119]
25–34 year253206198µg
35–49 year385220212µg
2000–20017 day WDR19–24 year104229225µg[120]
248 2232 2µg
25–34 year210233229µg
249 2233 2µg
35–49 year318255251µg
280 2258 2µg
2008–20104 day EDR19–64 year461232219µg[121]
264 2234 2µg
United States1988–199424 h RC20–39 year2260217178µg[122]
1999–200024 h RC20–39 year356294270µg[122]
2003–200624 h RC19–30 year914460 1 µg DFE[123]
645 1,2 µg DFE
31–50 year1350470 1 µg DFE
714 1,2 µg DFE
DFE: dietary folate equivalent; DH: diet history; DR: diet record; EDR: estimated diet record; FFQ: food frequency questionnaire; RC: recall; WDR: weighed diet record; 1 intake is measured following mandatory fortification of the food supply with folic acid; 2 inclusive of intake from supplements; 3 adjusted for folate losses in cooking; 4 excluding under-reporters.
Observational studies of dietary intake are subject to systematic errors that often lead to an underestimation of usual folate intakes due to underreporting of food intake and inaccuracies in food composition databases, secondary to methodological issues in analysis [52,124,125]. Furthermore folic acid intake from supplements and fortified foods, an important contributor to biochemical folate status, is not always considered in reports of dietary intake [125]. Thus determination of NIVs based on metabolic studies of controlled folate intake may result in higher values than those based on observational studies of dietary intake. The U.S. RDA for women for folate was lowered from 400 µg/day in the ninth edition (1980) to 180 µg/day in the tenth edition (1989) based on the recognition that observed population intakes of roughly 3 µg/kg maintained adequate folate status in approximately 90% of the population [87]. In 1998 the U.S. RDA was increased once again to 400 µg DFE/day based on data from controlled intake studies [52]. A number of countries have used observational data from population studies to set requirements including the UK, Belgium, France, and the Nordic countries.
The disparity between requirements based on studies of controlled folate intake versus observational survey data is prevalent and can be a significant hindrance to the way science informs and influences public health policymaking (e.g., food fortification programs). The ongoing development and validation of innovative dietary assessment methods (e.g., internet-based assessment, and the use of digital cameras and cellular phones), and improvements in analytical measurement of food and tissue folate levels will provide more accurate and meaningful data. Until then, caution is warranted in interpreting intake-status results from epidemiological studies.

4.2. Pregnant Women

Because of ethical considerations, depletion-repletion studies in pregnant women are lacking. Consequently, folate requirements for pregnant women are largely based on findings of population-based supplementation trials conducted in the 1960s [4,126,127,128] and a more recent controlled metabolic study aimed to evaluate the adequacy of the current folate requirements in a group of pregnant women [129]. Estimates generated from these earlier supplementation trials determined that the minimum daily requirement of supplemental folic acid in pregnant women was approximately 100 µg/day [4,126]; however, if megaloblastic anemia was more common in the population (i.e., in a population with suboptimal folate intake), a daily supplement of 300 µg folic acid/day was closer to the minimum requirement, particularly in late pregnancy [7,127,128]. Specifically, Hansen and Rybo [4] demonstrated that while supplementation with 50 µg folic acid/day taken in the last trimester of pregnancy was not sufficient to maintain maternal folate stores, 100 µg folic acid/day was found to be adequate to prevent against a decline in erythrocyte folate concentration, however 15% of study participants had serum folate levels below 2 ng/mL. Willoughby and Jewel [128] found that 100 µg folic acid/day was inadequate to prevent a serum folate concentration below 3 ng/mL in 33% of women compared to only 5% of women supplemented with 300 µg folic acid/day. Furthermore, none of the participants consuming 300 µg folic acid/day presented with megaloblastic anemia compared to 2% of the group supplemented with 100 µg folic acid/d. In a larger study of 3599 pregnant women, Willoughby [127] found that supplementation with 300 µg folic acid/d reduced the rate of megaloblastic anemia to 0.3% compared with 0.7% reported in a similar study of women (n = 350) supplemented with 100 µg/day. In contrast, Chanarin et al. [126] showed that supplementation with 100 µg folic acid/day was sufficient to maintain both serum and erythrocyte folate concentration during the last trimester of pregnancy in a group of 206 British women. The discrepancies in these findings may be explained by differences in dietary folate intakes. However, the dietary intakes of study participants were not assessed, with the exception of Chanarin et al., who determined an average baseline dietary folate intake of 676 µg of total folate/day [130]. This unexpectedly high value was derived from 24-h food collection obtained from a subsample of participants (16 of 206 women). Given that these studies were conducted prior to folic acid fortification of the food supply, usual dietary folate intakes were likely to be lower, ranging from 200 to 300 µg/day [131].
Caudill et al. conducted the only controlled metabolic study of folate intake [129]. Pregnant participants (n = 12) in their second trimester and non-pregnant controls were randomly assigned to supplemental folic acid intakes of either 330 or 730 µg/day, in addition to a diet containing 120 µg/day of dietary folate, for 12-weeks (84 days). No differences were detected in blood folate status between pregnant women and non-pregnant controls within the same supplementation group. Moreover, no women presented with a low serum (<13.6 nmol/L) or erythrocyte (<364 nmol/L) folate throughout the duration of the study. The authors concluded that 450 µg/day (dietary folate plus supplemental folic acid), equivalent to 600 µg DFE/day, was sufficient to maintain folate status in pregnant women. Using the equation for DFEs proposed by the IOM, this value is actually equivalent to 680 µg DFE/day. From these data along with the findings of the population studies, the IOM derived their ANR by adding 200 µg DFE to the ANR for NPNL women (320 µg/day DFE) to provide an ANR for pregnant women of 520 µg DFE/day. Assuming a CV of 10% and based on the support of the controlled metabolic study, the INL98 was set at 600 µg DFE/day [52]. Similarly, a number of other countries including the European Community, the DACH countries, and the Netherlands, have established NIVs based primarily on data from the population-based supplement trials with an addition of 200 µg folate added to their NIVs for NPNL women [28,50,86]; however differences in NIVs for pregnant women among these countries ranging from 400 to 600 µg/day have arisen directly from differences in NIVs set for NPNL women.
In contrast, several Nordic countries (Denmark, Sweden, and Iceland) have established a slightly lower recommendation of 500 µg/day [26] on the basis that requirements would not be as high as the minimum dose of 600 µg DFE/day in the study of Caudill et al. [129], particularly given the observed increase in erythrocyte folate status. India has also set their INL98 of 500 µg DFE/day although this value was based on the country-specific findings of a supplementation trial in 200 Indian pregnant women assigned to 60 mg of elemental iron with or without folic acid at levels of 100, 200, or 300 µg/day [132]. While a daily intake of 100 µg folic acid was sufficient to maintain erythrocyte folate concentrations, mean birth-weight was significantly higher in the 300 µg folic acid/day group versus the iron only group. A cross-sectional study of a group of unsupplemented women presented in the same article reported 23% and 64% of women had a serum folate below 3 ng/mL in the first and third trimester of pregnancy, respectively. Based on these findings, it was recommended that pregnant women would require an additional 300 µg DFE/day—although despite the use of DFE units, it does not appear that an adjustment for the bioavailability of supplemental folic acid was made. Finally, Finland and Norway adapted one of the lowest recommendations of 400 µg/day, with the reasoning that folate deficiency is rare and adoption of a higher level (as specified in the Nordic Nutrition Recommendations) would require the use of folic acid supplements during pregnancy and lactation [29].
Identification of alternative biomarkers of normal folate status that are sensitive to change and specific for folate inadequacy would be highly valuable in contributing to our understanding of the physiologic changes of pregnancy and the influence of dietary folate intake. Some researchers have proposed that the rate of urinary folate catabolite excretion reflects the role of folate in DNA biosynthesis and cellular turnover; therefore, urinary folate catabolites have been suggested as a potential indicator of folate requirements [133]. Specifically, McPartlin et al. [133] reported significantly greater urinary excretion of folate catabolites in the second and third trimester than in the first trimester, post-partum or NPNL state. Using a 50% bioavailability factor for dietary folate, the authors calculated an extra demand for dietary folate of about 200–300 µg/day during pregnancy. In contrast, the controlled metabolic unit study conducted by Caudill et al. [129,134], found no significant differences in mean folate catabolite excretion between pregnant women in the second trimester and non-pregnant controls; however catabolite excretion was significantly higher in pregnant and non-pregnant women consuming 850 versus 450 µg folate/day [134]. It was also noted that the pregnant women consuming 450 µg folate/day experienced a decline in urinary catabolite excretion from baseline compared to their non-pregnant counterparts. This decline in urinary folate catabolite excretion may reflect a decrease in supplemental folate intake rather than folate requirement. Prior to the study, 10 out of 12 pregnant women were consuming folic acid supplements between 400 and 1000 µg/day [129]. Whereas in the study of McPartlin et al. folate intake was only controlled up to 18 h before the collection of the 24-h urine sample and folic acid supplement use was not reported [133]. Current evidence cannot rule out whether the differences observed between these two studies are due to the different gestational periods of the women or are a reflection of prior supplemental intake. Additional work from metabolic controlled studies measuring changes in urinary folate catabolite excretion throughout pregnancy under conditions of inadequate folate intake to optimal intake levels are needed.
Other health outcomes related to maternal folate intake and status during pregnancy have been examined, with several studies finding a relation with birth weight and gestational age [135,136,137,138,139,140] whereas other have not [141]. In a recent meta-analysis, increased folate intake was found to be significantly associated with birth weight in a dose-dependent manner, but had no effect on placental weight or length of gestation [142]. Although data related to such perinatal outcomes are of potential interest, the inconsistent findings demonstrate the multi-factorial nature of these outcomes.

4.3. Lactating Women

Unlike NIVs for NPNL and pregnant women that are based on maintenance of blood folate status, NIVs for lactating women are often calculated as the sum of folate requirements of NPNL women and the amount of folate lost in breast-milk, with adjustments made for bioavailability. In doing so, variation in NIVs among countries can be partly attributed to differences in NIVs for NPNL women, and partly to differences in bioavailability adjustment factors and estimations of human milk folate content and volume [143]. Finland, Norway and France have not set NIVs specifically for lactating women, and have assigned NIVs using the same rationale as for pregnant women.
Table 4 shows the data used and calculations made by a number of countries to determine folate NIVs for lactating women based on extrapolation of human milk folate concentrations. Due to analytical difficulties, early measurements of human milk folate content were underestimated [52]. The U.K. based its NIV for lactating women on the study of Ek [144] published in 1983 which demonstrated a steady rise in milk folate concentration from 6 µg/L at 0 months after parturition up to 55 µg/L at 3 months after parturition; however, higher average milk folate values (average of 85 µg/L) were reported by Smith et al. in 1985 [145]. Later studies published include those of: Brown et al. [146], which reported a mean concentration of 85.3 µg/L in 180 samples from 16 women; O’Connor et al. [147], which reported slightly higher values between 90 and 110 µg/L in samples from four women after optimizing sample pre-treatment; and Lim et al. [148], which reported a mean concentration of 86 µg/L in 84 human milk samples. These three studies are cited in the reports of the IOM and the Netherlands although it is unclear why the Netherlands used a lower milk folate concentration of 60 µg/L. Human milk folate concentrations ranging between 70 and 110 µg/L have been confirmed in more recent studies using appropriate sampling techniques and pretreatment protocols [149,150,151,152].
Table
Table 4. Data used to derive nutrient intake values (NIVs) for lactating women from breast-milk losses of folate by country 1.
Table 4. Data used to derive nutrient intake values (NIVs) for lactating women from breast-milk losses of folate by country 1.
CountryMilk Folate ConcentrationDaily Milk ProductionLosses Per DayAdjustment for BioavailabilityAddition in Requirement 2Added to ANR or INL98
Austria, Germany and Switzerland 380 µg/L750 mL/day60 µg/day50%120 µg DFE/dayANR
European Community50–100 µg/L750 mL/day37–75 µg/day50%150 µg/dayINL98
The Netherlands60 µg/L800 mL/day48 µg/day50%100 µg DFE/dayINL98
Denmark, Iceland and Sweden60–85 µg/L750 mL/daync50%100 µg/dayINL98
United Kingdom−−40 µg/day66%60 µg/dayINL98
United States and Canada85 µg/day780 mL/day66 µg/day50%130 µg DFE/dayANR
ANR: average nutrient requirement; DFE: dietary folate equivalents; INL: individual nutrient level; nc: not calculated in report; 1 NIVs are calculated as an additional requirement that is added to the NIV for NPNL women; 2 values may be rounded; 3 proposed values to be approved August 2013 [86].
The factorial approach used to determine NIVs for lactating women assumes that milk folate content can be used as a proxy for maternal folate adequacy. However, evidence indicates that adequate milk folate content is maintained during folate depletion states [5]. While there is some evidence to suggest that blood folate status of lactating women decreases as lactation progresses [153,154], further longitudinal studies are needed to confirm this observation. It has been suggested that folate status of the lactating mother in these study populations often declines merely due to the discontinuation of prenatal folic acid supplements [154]. A number of studies have been carried out on maintenance of blood folate status during lactation [76,152,155,156,157]; however, these studies have also been conducted in groups of women who had consumed high-dose folic acid supplements throughout pregnancy.
Lastly, NIVs for lactation do not account for the influence of birth spacing on maternal nutritional status. Short intervals between pregnancies have been associated with increased risk of preterm birth, low birth-weight, and small-for-gestational-age babies [158]. Although the cause of these poor reproductive outcomes among women with short birth spacing has been debated, one plausible hypothesis is that women with closely spaced births have insufficient time to restore the folate reserves needed to support optimal fetal growth and development in the subsequent pregnancy [159]. Folate supplementation during early and late pregnancy has been shown to reduce the association between short inter-pregnancy spacing and low-birth weight [160]. In populations where supplementation rates during pregnancy are low, it may be of benefit to achieve an intake level that maintains blood folate status during both pregnancy and lactation.

5. Conclusions

NIVs set by different countries for folate vary substantially. Among countries, the range of INL98 levels were 160–460 µg/day for NPNL women, 300–750 µg/day for pregnant women, and 260–650 µg/day for lactating women. Differences in the indicators selected, the criteria for adequacy, and the type of evidence and assumptions made to set recommendations are all likely to contribute to the variation; however, the lack of transparency in the decisions made ultimately hampers the understanding of the differences [161]. The need to standardize nutrient requirements has also been recognized by the EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence in 2007. Although funding for EURRECA ended in 2012, the primary aim of the initiative was to provide a harmonized approach to guide the process of deriving micronutrient requirements in the European populations. Activities included the development and dissemination of a framework outlining the ideal process for deriving dietary reference values in a transparent, systematic and scientific way [162]. Despite the WHO/FAO recommendations on establishing a common terminology for NIVs, it was felt for practical purposes that establishing a common European terminology may lead to miscommunication and misinterpretation of NIVs at a national level [162]. EURRECA have also established a list of priority nutrients for review on the basis of: the amount of new evidence available; public health relevance of the nutrient; and variation in current recommendations of different European countries [163]. Folate was ranked in the top ten nutrients prioritized, fulfilling all three criteria in all life-stage groups, except for infancy, for which folate did not meet the criteria of public health relevance. However, despite an ongoing accumulation of evidence linking folate status with health outcomes, undertaking a formal review of folate requirements may prove difficult. A recent systematic review performed to support revision of the NNR folate requirement concluded that there was insufficient quality evidence to question current folate recommendations [164]; regardless, revision of older NIVs, such as those set by the UK (1991), European Union (1993), and the IOM (1998), may be justified. There is a lack of evidence for differences in requirements of folate among countries for NPNL women, and pregnant and lactating women in well-nourished populations; therefore achieving consensus in NIVs supported by a wide evidence base should be a priority.
Although challenging, additional studies in these life-stage populations groups are urgently needed. Most of the evidence supporting folate NIVs has been limited by data from relatively small sample sizes and uncertainties in bioavailability factors. Issues regarding laboratory measurement of food folate and biochemical folate status still exist and will need to be resolved in order to accurately determine dietary intake and provide definitive conclusions on the extent of folate deficiency. Once these issues are resolved, further studies are needed to evaluate the metabolic consequences associated with inadequate folate intakes and the reversal of these changes with increased intake levels. Controlled-metabolic studies are not feasible in large samples nor for a period of time long enough to observe a plateau in blood folate response; however it is possible to set NIVs based on observational data if intake data are accurate and captured over a sufficient period of time to ensure the sample days are truly representative of usual intake. For NPNL women, long-term observational studies of dietary folate intake in relation to erythrocyte concentration should not only be adequately powered to provide a precise estimate of the average requirement, but also to determine the variation in requirements. Given the importance of folate in prevention of NTDs during preconception, a higher erythrocyte folate status may serve as a better indicator of adequacy in NPNL women than erythrocyte folate status required to prevent megaloblastic anemia.
For pregnant women, there is reasonably good evidence that an additional 100 µg folic acid/day above the requirement for NPNL women is adequate to prevent against a decline in blood folate in a population with adequate intakes and a low prevalence of megaloblastic anemia. Differences among countries NIVs for pregnant women are largely due to differences in NIVs of NPNL women. Studies of folate requirements in pregnant women designed to maintain optimal folate status will be confounded by the use of high-dose supplements in the range of 400–1000 µg folic acid during preconception and early pregnancy [76,129,152,165]. It is important to determine future requirements based on an optimal erythrocyte folate level rather than maintenance of status in such populations, and to consider the effect of high-dose supplements on subsequent folate requirements throughout pregnancy. Similarly, this confounding effect should also be considered when evaluating folate status data during lactation. The current approach for deriving folate requirements during lactation with use of breastmilk folate content as a proxy for maternal adequacy may be inappropriate. Further research designed to evaluate the relationship between folate intake and blood folate status or other indicators during lactation among previously un-supplemented women are required.

Acknowledgments

We thank Rosalind Gibson for her helpful discussions on the international harmonization efforts, which enhanced our understanding of approaches and methods used for the development of NIVs.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Stover, P.J. Folate Biochemical Pathways and Their Regulation. In Folate in Health and Disease, 2nd ed.; Bailey, L.B., Ed.; CRC Press: Boca Raton, FL, USA, 2010; pp. 49–74. [Google Scholar]
  2. Lamers, Y. Folate recommendations for pregnancy, lactation, and infancy. Ann. Nutr. Metab. 2011, 59, 32–37. [Google Scholar] [CrossRef]
  3. Tamura, T.; Picciano, M.F.; McGuire, M.K. Folate in Pregnancy and Lactation. In Folate in Health and Disease, 2nd ed.; Bailey, L.B., Ed.; CRC Press: Boca Raton, FL, USA, 2010; pp. 111–131. [Google Scholar]
  4. Hansen, H.; Rybo, G. Folic acid dosage in profylactic treatment during pregnancy. Acta Obstet. Gynecol. Scand. 1967, 46, 107–112. [Google Scholar] [CrossRef]
  5. Metz, J. Folate deficiency conditioned by lactation. Am. J. Clin. Nutr. 1970, 23, 843–847. [Google Scholar]
  6. Willoughby, M.L.; Jewell, F.J. Folate status throughout pregnancy and in postpartum period. Br. J. Med. 1968, 4, 356–360. [Google Scholar] [CrossRef]
  7. Committee on Maternal Nutrition; Food and Nutrition Board; National Research Council. Maternal Nutrition and the Course of Pregnancy; National Academy of Sciences: Washington, DC, USA, 1970. [Google Scholar]
  8. Berry, R.J.; Mulinare, J.; Hamner, H.C. Neural Tube Defect Risk Reduction—A Global Health Perspective. In Folate in Health and Disease, 2nd ed.; Bailey, L.B., Ed.; CRC Press: Boca Raton, FL, USA, 2010; pp. 179–204. [Google Scholar]
  9. Christian, P.; Murray-Kolb, L.E.; Khatry, S.K.; Katz, J.; Schaefer, B.A.; Cole, P.M.; Leclerg, S.C.; Tielsch, J.M. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA 2010, 304, 2716–2723. [Google Scholar] [CrossRef]
  10. Roth, C.; Magnus, P.; Schjøberg, S.; Stotenberg, C.; Surén, P.; McKeague, I.W.; Davey Smith, G.; Reichborn-Kjennerud, T.; Susser, E. Folic acid supplements in pregnancy and severe language delay in children. JAMA 2011, 306, 1566–1573. [Google Scholar] [CrossRef]
  11. Schmidt, R.J.; Tancredi, D.J.; Ozonoff, S.; Hansen, R.L.; Hartiala, J.; Allayee, H.; Schmidt, L.C.; Tassone, F.; Hertz-Picciotto, I. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am. J. Clin. Nutr. 2012, 96, 80–89. [Google Scholar] [CrossRef]
  12. Veena, S.R.; Krishnaveni, G.V.; Srinivasan, K.; Wills, A.K.; Muthayya, S.; Kurpad, A.V.; Yajnik, C.S.; Fall, C.H.D. Higher maternal plasma folate but not vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10-year old choldren in South India. J. Nutr. 2010, 140, 1014–1022. [Google Scholar] [CrossRef]
  13. King, J.C.; Garza, C. Harmonization of nutrient intake values. Food Nutr. Bull. 2007, 28, S3–S12. [Google Scholar]
  14. King, J.C.; Vorster, H.H.; Tome, D.G. Nutrient Intake Values (NIVs): A recommended terminology and framework for the derivation of values. Food Nutr. Bull. 2007, 28, S16–S26. [Google Scholar]
  15. Murphy, S.P.; Vorster, H.H. Methods for using Nutrient Intake Values (NIVs) to assess or plan nutrient intakes. Food Nutr. Bull. 2007, 28, S51–S60. [Google Scholar]
  16. National Health and Medical Research Council. Nutrient Reference Values for Australia and New Zealand; NHMRC: Canberra, Australia, 2006.
  17. German Nutrition Society; Austrian Nutrition Society; Swiss Society for Nutrition Research; Swiss Nutrition Association. Referenzwerte für die Nährstoffzufuhr, 1st ed.; Umschau/Braus: Frankfurt am Main, Germany, 2000. [Google Scholar]
  18. Superior Health Council. Voedingsaanbevelingen voor België; Superior Health Council: Brussels, Belgium, 2009. [Google Scholar]
  19. Agência Nacional de Vigilância Sanitária. Resolução RDC n. 269, de 22 de Setembro de 2005. Regulamento Técnico Sobre a Ingestão Diária Recomendada (IDR) de Proteína, Vitaminas E Minerais. In Diário Oficial da República Federativa do Brasil; Ministério da Saúde: Brasília, Brazil, 2005. [Google Scholar]
  20. Ministry of Health. Наредба № 23 от 19 Юли 2005 г. за Физиологичните Норми за Хранене на Населението; Ministry of Health: Sofia, Bulgaria, 2005.
  21. Torun, B.; Menchu, M.T.; Elias, L.G. Recomendaciones Dietéticas Diarias del INCAP; Instituto de Nutricíon de Centro América y Panamá (INCAP): Guatemala City, Guatemala, 1994. [Google Scholar]
  22. Chinese Nutrition Society. Chinese Dietary Reference Intakes; (in Chinese). China Light Industry Press: Beijing, China, 2010. [Google Scholar]
  23. Instituto Colombiano de Bienestar Familiar. Recomendaciones de Consumo Diario de Calorías y Nutrientes para la Población Colombiana; Instituto Colombiano Bienestar Familiar: Bogotá, Colombia, 1988. [Google Scholar]
  24. Ministry of Health and Social Welfare. Pravilnik o Hrani za Posebne Prehrambene Potrebe. In Narodne Novine; Narodne Novine d.d.: Zagreb, Croatia, 2004. [Google Scholar]
  25. Hernández-Triana, M.; Porrata, C.; Jiménez, S.; Rodriguez, A.; Carrillo, O.; García, A.; Valdés, L.; Esquivel, M. Dietary reference intakes for the cuban population, 2008. MEDICC Rev. 2009, 11, 9–16. [Google Scholar]
  26. Nordic Council of Ministers. Nordic Nutrition Recommendations 2004. Integrating Nutrition and Physical Activity, 4th ed.; Nordic Council of Ministers: Copenhagen, Denmark, 2005. [Google Scholar]
  27. Tervise Arengu Insitituut; Eesti Toitumisteaduse Selts (Estonian Nutrition Society). Eesti Toitumis-ja Toidusoovitused; Eesti Toitumisteaduse Selts (Estonian Nutrition Society): Tallinn, Estonia, 2006. [Google Scholar]
  28. Commission of the European Communities. Nutrient and Energy Intakes for the European Community. In Reports of the Scientific Committee for Food (Thirty-First Series); Commission of the European Communities, Directorate-General Telecommunications, Information Industries and Innovation: Luxembourg, Luxembourg, 1993. [Google Scholar]
  29. National Nutrition Council. Soumalaiset Ravitsemussuositukset Ravinto ja Liikunta Tasapainoon; Edita Publishing Oy: Helsinki, Finland, 2005. [Google Scholar]
  30. Martin, A. Apports Nutritionnels Conseillés pour la Population Française, 3rd ed.; Tec et Doc: Paris, France, 2000. [Google Scholar]
  31. Supreme Scientific Health Council; Ministry of Health and Welfare. Dietary guidelines for adults in Greece. Arch. Hell. Med. 1999, 16, 516–524. [Google Scholar]
  32. Rodler, I. Új Tápanyagtáblázat; Medicina Könyvkiadó: Budapest, Hungary, 2005. [Google Scholar]
  33. Indian Council of Medical Research; National Institute of Nutrition. Nutrient Requirements and Recommended Dietary Allowances for Indians: A Report of the Expert Group of the Indian Council of Medical Research; Indian Council of Medical Research: New Dehli, India, 2010. [Google Scholar]
  34. Food Safety Authority of Ireland. Recommended Dietary Allowances for Ireland 1999; Safety Authority of Ireland: Dublin, Ireland, 1999. [Google Scholar]
  35. Societá Italiana di Nutrizione Umana. LARN—Livelli di Assunzione di Riferimento di Nutrienti ed Energia per la Popolazione Italiana; Societá Italiana di Nutrizione Umana: Milan, Italy, 2012. [Google Scholar]
  36. The Scientific Committee of “Dietary Reference Intakes for Japanese—Recommended Dietary Allowance”. Dietary Reference Intakes for Japanese; Ministry of Health, Labour and Welfare: Tokyo, Japan, 2005. [Google Scholar]
  37. Veselības Ministrijas (Ministry of Health). Ieteicamās Enerģijas un Uzturvielu devas Latvajas Iedzīvotājiem; Ministry of Health: Riga, Latvia, 2008.
  38. Svelkatos Apsaugos Ministerija (Ministry of Health). Rekomenduojamos Paros Maistinių Medžiagų ir Energijos Normos; Valstybės žinios: Vilnius, Lithuania, 1999. [Google Scholar]
  39. Bourges, H.; Casanueva, E.; Rosado, J.L. Recomendaciones de Ingestión de Nutrimentos Para la Población Mexicana: Bases Fisiológicas: Vitaminas y Nutrimentos Inorgánicos; Editorial Médica Panamericana: Mexico City, Mexico, 2005. [Google Scholar]
  40. Helsedirektoratet. Norske Anbefalinger for Ernæring og Fysisk Aktivitet; Helsedirektoratet: Oslo, Norway, 2005. [Google Scholar]
  41. Bułhak-Jachymczyk, B.; Chabros, E. Normy Żywienia Człowieka; Wydawnictwo Lekarskie PZWL: Warsaw, Poland, 2008. [Google Scholar]
  42. Ministry of Health; Republic Institute of Health Protection. Nutrient Recommendations as Addition to Guidelines for Healthy Nutrition of the Population in Republic of Macedonia; Ministry of Health: Skopje, Republic of Macedonia, 2001.
  43. Stojisavljević, D.; Danojević, D.; Bojanić, J.; Jandrić, L. Vodič za Pravilnu Ishranu za Zdravstvene Profesionalce; Institut za Zaštitu Republike Srpske: Banja Luka, Bosnia and Herzegovina, 2004. [Google Scholar]
  44. Тутельян, В.А.; Батурин, А.К.; Гаппаров, М.Г.; Каганов, Б.С.; Конь, И.Я.; Мазо, В.К.; Баева, В.С.; Бессонов, В.В.; Васильев, А.В.; Волкова, Л.Ю.; et al. MP-08 2.3.1.2432-Нормы Физиологических Потребностей в Энергии и Пищевых Веществах для Различных Групп Населения Российской Федерации; Cheif Medical Officer of Russia: Moscow, Russia, 2008. [Google Scholar]
  45. Ministerstva Zdravotníctva Slovenskej Republiky. Odporúčané Výživové Dávky pre Obyvatel’stvo v Slovenskej Republike. Ministerstva Zdravotníctva Slovenskej Republiky: Bratislava, Slovakia, 1997. [Google Scholar]
  46. Debenjak, P.; Arbeitsgruppe Referenzwerte für die Nährstoffzufuhf. Referenčne Vrednosti za vnos Hranil, 1st ed.Ministrstvo za Zdrave: Ljubljana, Slovenia, 2004.
  47. The Korean Nutrition Society. Dietary Reference Intakes for Koreans(in Korea), 1st ed.; The Korean Nutrition Society: Seoul, Korea, 2010. [Google Scholar]
  48. Tee, E.-S.; Florentino, R.F. Recommended Dietary Allowances: Harmonization in Southeast Asia; International Life Sciences Institute: Singapore, Singapore, 2005. [Google Scholar]
  49. Federación Española de Sociedades de Nutrición Alimentación y Dietética (FESNAD). Ingestas Dietéticas de Referencia (IDR) para la Población Española; Ediciones Universidad de Navarra, S.A. (EUNSA): Navarra, Spain, 2010. [Google Scholar]
  50. Health Council of The Netherlands. Voedingsnormen: Vitamine B6, Foliumzuur en Vitamine B12; Health Council of The Netherlands: The Hague, The Netherlands, 2003. [Google Scholar]
  51. Department of Health, Dietary Reference Values for Food Energy and Nutrients for the United Kingdom: Report of the Panel on Dietary Reference Values of the Committee on Medical Aspects of Food Policy. In Report on Health and Social Subjects; HMSO: London, UK, 1991; Volume 41, pp. 109–112.
  52. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline; National Academies Press: Washington, DC, USA, 1998. [Google Scholar]
  53. World Health Organization; Food and Agriculture Organization. Vitamin and Mineral Requirements in Human Nutrition. In proceedings of the Joint FAO/WHO Expert Consultation, Bangkok, Thailand, 21–30 September 1998; World Health Organization: Geneva, Switzerland, 2004. [Google Scholar]
  54. Selhub, J. Homocysteine metabolism. Annu. Rev. Nutr. 1999, 19, 217–246. [Google Scholar] [CrossRef]
  55. Clarke, R.; Halsey, J.; Lewington, S.; Lonn, E.; Armitage, J.; Manson, J.E.; Bønaa, K.H.; Spence, J.D.; Nygård, O.; Jamison, R.; et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality. Arch. Intern. Med. 2010, 170, 1622–1631. [Google Scholar] [CrossRef]
  56. Wu, A.; Chanarin, I.; Slavin, G.; Levi, A.J. Folate deficiency in the alcoholic—Its relationship to clinical and haematological abnormalites, liver disease and folate stores. Br. J. Haematol. 1975, 29, 469–478. [Google Scholar] [CrossRef]
  57. Eichner, E.R.; Pierce, I.; Hillman, R.S. Folate balance in dietary-induced megaloblastic anemia. N. Engl. J. Med. 1971, 284, 933–938. [Google Scholar] [CrossRef]
  58. Herbert, V. Experimental folate deficiency in man. Trans. Assoc. Am. Physicians 1962, 75, 307–320. [Google Scholar]
  59. Herbert, V. Making sense of laboratory tests of folate status: Folate requirements to sustain normality. Am. J. Hematol. 1987, 26, 199–207. [Google Scholar] [CrossRef]
  60. Hoffbrand, A.V.; Newcombe, B.F.; Mollin, D.L. Method of assay of red cell folate activity and the value of the assay as a test for folate deficiency. J. Clin. Pathol. 1966, 19, 17–28. [Google Scholar] [CrossRef]
  61. Varadi, S.; Abbott, D.; Elwis, A. Correlation of peripheral white cell and bone marrow changes with folate levels in pregnancy and their clinical significance. J. Clin. Pathol. 1966, 19, 33–36. [Google Scholar] [CrossRef]
  62. Blount, B.C.; Mack, M.M.; Wehr, C.M.; MacGregor, J.T.; Hiatt, R.A.; Wang, G.; Wickramasinghe, S.N.; Everson, R.B.; Ames, B.N. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. USA 1997, 94, 3290–3295. [Google Scholar] [CrossRef]
  63. Gunter, E.W.; Bowman, B.A.; Caudill, S.P.; Twite, D.B.; Adams, M.J.; Sampson, E.J. Results of an international round robin for serum and whole-blood folate. Clin. Chem. 1996, 42, 1689–1694. [Google Scholar]
  64. Pfeiffer, C.M.; Fazili, Z.; Zhang, M. Folate Analytical Methodology. In Folate in Health and Disease; Bailey, L.B., Ed.; CRC Press: Boca Raton, FL, USA, 2010; pp. 517–574. [Google Scholar]
  65. Pfeiffer, C.M.; Zhang, M.; Lacher, D.A.; Molloy, A.M.; Tamura, T.; Yetley, E.A.; Picciano, M.F.; Johnson, C. Comparison of serum and red blood cell folate microbiologic assays for national population surveys. J. Nutr. 2011, 141, 1402–1409. [Google Scholar] [CrossRef]
  66. Fazili, Z.; Pfeiffer, C.M. Accounting for an isobaric interference allows correct determination of folate vitamers in serum by isotype dilution-liquid chromatography-tandem MS. J. Nutr. 2013, 143, 108–113. [Google Scholar] [CrossRef]
  67. Nelson, B.C.; Pfeiffer, C.M.; Margiolis, S.A.; Nelson, C.P. Affinity extraction combined with stable isotope dilution LC/MS for the determination of 5-methyltetrahydrofolate in human plasma. Anal. Biochem. 2003, 313, 117–127. [Google Scholar] [CrossRef]
  68. Pfeiffer, C.M.; Fazili, Z.; McCoy, L.; Zhang, M.; Gunter, E.W. Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay. Clin. Chem. 2004, 50, 423–432. [Google Scholar] [CrossRef]
  69. Fazili, Z.; Pfeiffer, C.M. Measurement of folates in serum and conventionally prepared whole blood lysates: Application of an automated 96-well plate isotope-dilution tandem mass spectrometry method. Clin. Chem. 2004, 50, 2378–2381. [Google Scholar] [CrossRef]
  70. Fazili, Z.; Pfeiffer, C.M.; Zhang, M.; Jain, R. Erythrocyte folate extraction and quantitative determination by liquid chromatography-tandem mass spectroemetry: Comparision of results with microbiologic assay. Clin. Chem. 2005, 51, 2318–2325. [Google Scholar] [CrossRef]
  71. Fazili, Z.; Pfeiffer, C.M.; Zhang, M.; Jain, R.; Koontz, D. Influence of 5,10-methylenetetrahydrofolate reductase polymorphism on whole-blood folate concentration measured by LC-MS/MS, microbiologic assay, and bio-rad radioassay. Clin. Chem. 2008, 54, 197–201. [Google Scholar]
  72. Ohrvik, V.E.; Witthoft, C.M. Human folate bioavailability. Nutrients 2011, 3, 475–490. [Google Scholar] [CrossRef]
  73. Hannon-Fletcher, M.P.; Armstrong, N.C.; Scott, J.M.; Pentieva, K.; Bradbury, I.; Ward, M.; Strain, J.J.; Dunn, A.A.; Molloy, A.M.; Kerr, M.A.; et al. Determining bioavailability of food folates in a controlled intervention study. Am. J. Clin. Nutr. 2004, 80, 911–918. [Google Scholar]
  74. Brouwer, I.A.; van Dusseldorp, M.; West, C.; Meyboom, S.; Thomas, C.M.G.; Duran, M.; van het Hof, K.H.; Eskes, T.K.A.B.; Hautvast, G.A.J.; Steegers-Theunissen, R.P.M. Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J. Nutr. 1999, 129, 1135–1139. [Google Scholar]
  75. Green, T.; Liu, Y.; Dadgar, S.; Li, W.; Böhni, R.; Kitts, D.D. Wheat rolls fortified with microencapsulated l-5-methyltetrahydrofolic acid or equimolar folic acid increase blood folate concentrations to a similar extent in healthy men and women. J. Nutr. 2013, 143, 867–871. [Google Scholar] [CrossRef]
  76. Houghton, L.A.; Sherwood, K.L.; Pawlosky, R.; Ito, S.; O’Connor, D.L. [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. Am. J. Clin. Nutr. 2006, 83, 842–850. [Google Scholar]
  77. Pentieva, K.; McNulty, H.; Reichert, R.; Ward, M.; Strain, J.J.; McKillop, D.J.; McPartlin, J.M.; Connolly, E.; Molloy, A.; Kramer, K.; et al. The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acd are equivalent in men. J. Nutr. 2004, 134, 580–585. [Google Scholar]
  78. Christensen, K.E.; Rozen, R. Genetic Variation. Effect on Folate Metabolism and Health. In Folate in Health and Disease, 2nd ed.; Bailey, L.B., Ed.; CRC Press: Boca Raton, FL, USA, 2010; pp. 75–110. [Google Scholar]
  79. Guéant-Rodriguez, R.-M.; Guéant, J.-L.; Debard, R.; Thirion, S.; Hong, L.X.; Bronowicki, J.-P.; Namour, F.; Chabi, N.W.; Sanni, A.; Anello, G.; et al. Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: A comparative study in Mexican, West African, and European populations. Am. J. Clin. Nutr. 2006, 83, 701–707. [Google Scholar]
  80. Wilcken, B.; Bamforth, F.; Li, Z.; Zhu, H.; Ritvanen, A.; Redlund, M.; Stoll, C.; Alembik, Y.; Dott, B.; Czeizel, A.E.; et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): Findings from over 7000 newborns from 16 areas world wide. J. Med. Genet. 2003, 40, 687–693. [Google Scholar]
  81. De Bree, A.; Verschuren, W.M.M.; Bjørke-Monsen, A.L.; van der Put, N.M.J.; Heil, S.G.; Trijbels, F.J.M.; Blom, H.J. Effect of the methylenetetrahydrofolate reductased 677C→T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample. Am. J. Clin. Nutr. 2003, 77, 687–693. [Google Scholar]
  82. Nagele, P.; Meissner, K.; Francis, A.; Födinger, M.; Saccone, N.L. Genetic and environmental determinants of plasma total homocysteine levels: Impact of population-wide folate fortification. Pharmacogenet. Genomics 2011, 21, 426–431. [Google Scholar] [CrossRef]
  83. Yang, Q.-H.; Botto, L.D.; Gallagher, M.; Friedman, J.M.; Sanders, C.L.; Koontz, D.; Nikolova, S.; Erickson, J.D.; Steinberg, K. Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: Findings from the third National Health and Nutrition Examination Survey DNA Bank. Am. J. Clin. Nutr. 2008, 88, 232–246. [Google Scholar]
  84. Gibney, M.J.; Gibney, E.R. Diet, genes and disease: Implications for nutrition policy. Proc. Nutr. Soc. 2004, 63, 491–500. [Google Scholar]
  85. Robataille, J.; Hamner, H.C.; Cogswell, M.E.; Yang, Q. Doe the MTHFR 677C→T variant affect the Recommended Dietary Allowance for folate in the US population? Am. J. Clin. Nutr. 2009, 89, 1269–1273. [Google Scholar] [CrossRef]
  86. German Nutrition Society; Austrian Nutrition Society; Swiss Society for Nutrition Research; Swiss Nutrition Association. Referenzwerte für die Nährstoffzufuhr: Folat, 5th ed.; Neuer Umschau Buchverlag: Neustadt an der Weinstraße, Germany, 2013. [Google Scholar]
  87. Food and Nutrition Board. Recommended Dietary Allowances, 10th ed.; National Academy of Sciences: Washington, DC, USA, 1989. [Google Scholar]
  88. Food and Nutrition Board. Recommended Dietary Allowances, 9th ed.; National Academy of Sciences: Washington, DC, USA, 1980. [Google Scholar]
  89. Food and Nutrition Board. Recommended Dietary Allowances, 8th ed.; National Academy of Sciences: Washington, DC, USA, 1974. [Google Scholar]
  90. Food and Nutrition Board. Recommended Dietary Allowances, 7th ed.; National Academy of Sciences: Washington, DC, USA, 1968. [Google Scholar]
  91. Food and Agriculture Organization. Requirements of Vitamin A, Iron, Folate and Vitamin B12. Report of a Joint FAO/WHO Expert Consultation. In FAO Food and Nutrition Series No. 23; Food and Agriculture Organization of the United Nations: Rome, Italy, 1988. [Google Scholar]
  92. European Surveillance of Congenital Anomalies (EUROCAT). Special Report: Prevention of Neural Tube Defects by Periconceptional Folic Acid Supplementation in Europe. Part IIa: Country Specific Chapters (Austria to Ireland); European Surveillance of Congenital Anomalies: Newtonabbey, Ireland, 2009. [Google Scholar]
  93. European Surveillance of Congenital Anomalies (EUROCAT). Special Report: Prevention of Neural Tube Defects by Periconceptional Folic Acid Supplementation in Europe. Part IIb: Country Specific Chapters (Italy to UK); European Surveillance of Congenital Anomalies: Newtonabbey, Ireland, 2009. [Google Scholar]
  94. Herbert, V. Minimal daily adult folate requirement. Arch. Intern. Med. 1962, 110, 649–652. [Google Scholar] [CrossRef]
  95. Sauberlich, H.E.; Kretsch, M.J.; Skala, J.H.; Johnson, H.L.; Taylor, P.C. Folate requirement and metabolism in nonpregnant women. Am. J. Clin. Nutr. 1987, 46, 1016–1028. [Google Scholar]
  96. O’Keefe, C.A.; Bailey, L.B.; Thomas, E.A.; Hofler, S.A.; Davis, B.A.; Cerda, J.J.; Gregory, J.F. Controlled dietary folate affects folate status in nonpregnant women. J. Nutr. 1995, 125, 2717–2725. [Google Scholar]
  97. Milne, D.B.; Johnson, L.K.; Mahalko, J.R.; Sandstead, H.H. Folate status of adult males living in a metabolic unit: Possible relationships with iron nutriture. Am. J. Clin. Nutr. 1983, 37, 768–773. [Google Scholar]
  98. Jacob, R.A.; Wu, M.M.; Henning, S.M.; Swendseid, M.E. Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. J. Nutr. 1994, 124, 1072–1080. [Google Scholar]
  99. Houghton, L.A.; Gray, A.R.; Rose, M.C.; Miller, J.C.; Hursthouse, N.A.; Gregory, J.F. Long-term effect of low-dose folic acid intake: Potential effect of mandatory fortification on the prevention of neural tube defects. Am. J. Clin. Nutr. 2011, 94, 136–141. [Google Scholar] [CrossRef]
  100. Metz, J. A high prevalence of biochemical evidence of vitamin B12 or folate deficiency does not translate into a comparable prevalance of anemia. Food Nutr. Bull. 2008, 29, S74–S85. [Google Scholar]
  101. Shaw, G.M.; Schaffer, D.; Velie, E.M.; Morland, K.; Harris, J.A. Periconceptional vitamin use, dietary folate, and the occurance of neural tube defects. Epidemiology 1995, 6, 219–226. [Google Scholar]
  102. Werler, M.M.; Shapiro, S.; Mitchell, A.A. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 1993, 269, 1257–1261. [Google Scholar] [CrossRef]
  103. Crider, K.S.; Bailey, L.B.; Berry, R.J. Folic acid fortification—Its history, effect, concerns, and future directions. Nutrients 2011, 3, 370–384. [Google Scholar] [CrossRef]
  104. McLennan, W.; Podger, A. National Nutrition Survey. Nutrient Intakes and Physical Measurements Australia 1995; Australian Bureau of Statistics: Canberra, Australia, 1998. [Google Scholar]
  105. Health Canada; Statistics Canada. Canadian Community Health Survey Cycle 2.2, Nutrition (2004). Nutrient Intakes from Food. Provincial, Regional and National Summary Data Tables, Volume 2; Health Canada: Ottawa, Canada, 2008. [Google Scholar]
  106. Andersen, N.L.; Fagt, S.; Groth, M.V.; Harktopp, H.B.; Moller, A.; Ovesen, L.; Warming, D.L. Danskernes Kostvaner 1995: Hovedresultater; Levnedsmiddelstyrelsen: Saborg, Denmark, 1996. [Google Scholar]
  107. Alfthan, G.; Laurinen, M.S.; Valsta, L.M.; Pastinen, T.; Aro, A. Folate intake, plasma folate and homocysteine status in a ransom Finnish population. Eur. J. Clin. Nutr. 2003, 57, 81–88. [Google Scholar] [CrossRef]
  108. Paturi, M.; Tapanainen, H.; Reinivuo, H.; Pietinen, P. Finravinto 2007—Tutkimus. The National FINDIET 2007 Survey; National Public Health Insititute: Helsinki, Finland, 2008. [Google Scholar]
  109. Beitz, R.; Mensink, G.B.M.; Fisher, B.; Thamm, M. Vitamins—Dietary intake and intake from dietary supplements in Germany. Eur. J. Clin. Nutr. 2002, 56, 539–545. [Google Scholar] [CrossRef]
  110. Max Rubner-Institut; Bundesforschungsinstitut für Ernährung und Lebensmittel. Ergebnisbericht, Teil 2. Nationale Verzhrsstudie II. Die Bundesweite Befragung zur Ernährung von Jugendlichen und Erwachsenen; Max Rubner-Institut: Karlsruhe, Germany, 2008. [Google Scholar]
  111. OʼBrien, M.M.; Kiely, M.; Harrington, K.E.; Robson, P.J.; Strain, J.J.; Flynn, A. The North/South Ireland Food Consumption Survey: Vitamin intakes in 18–64-year-old adults. Public Health Nutr. 2001, 4, 1069–1079. [Google Scholar]
  112. Russell, D.G.; Parnell, W.; Wilson, N.C.; The Principle Investigators of the 1997 National Nutrition Survey. NZ Food: NZ People. Key Results of the 1997 National Nutrition Survey; Ministry of Health: Wellington, New Zealand, 1999.
  113. Serra Majem, L.; Ribas Barba, L.; Garcia Closas, R.; Ballart, J.F.; Guayta Escolier, R. Libre Blanc: Avaluació de L’estat Nutricional de la Població Catalana (1992–93): Avaluació dels Hábits Alimentaris, el Consum D'aliments, Energia i Nutrients i de Lʼestat Nutricional Mitjançant Indicadors Bioquímics i Antropomètrics; Generalidad de Catalunya: Barcelona, Spain, 1996. [Google Scholar]
  114. Becker, W.; Pearson, M. Riksmaten 1997–98. Kostvanor och Näringsintag i Sverige. Metodoch Resultatanalys; Livsmedelsverket: Uppsala, Sweden, 2002. [Google Scholar]
  115. Bausch-Goldbohm, R.A.; Hulshof, K.F.A.M.; Brants, H.A.M.; van den Berg, H.; Bouman, M. De Inneming van Foliumzuur Door Verschillende Bevolkingsgroepen in Nederland voor en na Verrijking van Bepaalde Voedingsmiddelen. Voedselconsumptiepeiling 1992; TNO Voeding: Zeist, The Netherlands, 1995. [Google Scholar]
  116. De Bree, A.; Verschuren, W.M.M.; Blom, H.J.; Kromhout, D. Association between B vitamin intake and plasma homocysteine concentration in the general Dutch population aged 20–65 year. Am. J. Clin. Nutr. 2001, 73, 1027–1033. [Google Scholar]
  117. Hulshof, K.F.A.M.; Ocké, M.C.; van Rossum, C.T.M.; Buurma-Rethans, E.J.M.; Brants, H.A.M.; Drijvers, J.J.M.M.; ter Doest, D. Resultaten van de Voedselconsumptiepeiling 2003; Rijksinstituut voor Volksgezondheid en Milieu: Bilthoven, The Netherlands, 2004. [Google Scholar]
  118. National Institure for Public Health and the Environmen; van Rossum, C.T.M.; Fransen, H.P.; Verkaik-Kloosterman, J.; Buurma-Rethans, E.J.M.; Ocké, M.C. Dutch National Food Consumption Survey 2007–2010. Diet of Children and Adults Aged 7 to 69 years; Colophon: Bilthoven, The Netherlands, 2011. [Google Scholar]
  119. Gregory, J.; Foster, K.; Tyler, H.; Wiseman, M. The Dietary and Nutritional Survey of British Adults; HMSO: London, UK, 1990.
  120. Henderson, L.; Irving, K.; Gregory, J.; Bates, C.J.; Prentice, A.; Perks, J.; Swan, G.; Farron, M. The National Diet & Nutrition Survey: Adults Aged 19 to 64 Years. Vitamin and Mineral Intake and Urinary Analytes; HMSO: London, UK, 2003.
  121. Bates, B.; Lennox, A.; Bates, C.; Swan, G. National Diet and Nutrition Survey: Headline Results from Years 1 and Years 2 (Combined) of the Rolling Programme 2008-9–2009-10; Department of Health: London, UK, 2011. [Google Scholar]
  122. Dietrich, M.; Brown, C.J.P.; 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, 4, 266–274. [Google Scholar]
  123. Bailey, R.L.; Dodd, K.W.; Gahche, J.J.; Dwyer, J.T.; McDowell, M.A.; Yetley, E.A.; Sempos, C.A.; Burt, V.L.; Radimer, K.L.; Picciano, M.F. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006. Am. J. Clin. Nutr. 2010, 91, 231–237. [Google Scholar] [CrossRef]
  124. Bailey, L.B. Folate Requirements and Dietary Recommendations. In Folate in Health and Disease; Bailey, L.B., Ed.; Marcel Dekker Inc.: New York, NY, USA, 1995. [Google Scholar]
  125. De Bree, A.; van Dusseldorp, M.; Brouwer, I.A.; van het Hof, K.H.; Steegers-Theunissen, R.P.M. Folate intake in Europe: Recommended, actual and desired intake. Eur. J. Clin. Nutr. 1997, 51, 643–660. [Google Scholar]
  126. Chanarin, I.; Rothman, D.; Ward, A.; Perry, J. Folate status and requirement in pregnancy. Br. Med. J. 1968, 2, 390–394. [Google Scholar] [CrossRef]
  127. Willoughby, M.L. An investigation of folic acid requirements in pregnancy. II. Br. J. Haematol. 1967, 13, 503–509. [Google Scholar] [CrossRef]
  128. Willoughby, M.L.; Jewell, F.J. Investigation of folic acid requirements in pregnancy. Br. Med. J. 1966, 2, 1568–1571. [Google Scholar] [CrossRef]
  129. Caudill, M.A.; Cruz, A.C.; Gregory, J.F.; Hutson, A.D.; Bailey, L.B. Folate status response to controlled folate intake in pregnant women. J. Nutr. 1997, 127, 2363–2370. [Google Scholar]
  130. Chanarin, I.; Rothman, D.; Perry, J.; Stratfull, D. Normal dietary folate, iron, and protein intake, with particular reference to pregnancy. Br. J. Med. 1968, 2, 394–397. [Google Scholar] [CrossRef]
  131. Moscovitch, L.F.; Cooper, B.A. Folate content of diets in pregnancy: Comparison of diets collected at home and diets prepared from dietary records. Am. J. Clin. Nutr. 1973, 26, 707–714. [Google Scholar]
  132. Iyengar, L. Folic acid requirements of Indian pregnant women. Am. J. Obstet. Gynecol. 1971, 111, 13–16. [Google Scholar]
  133. McPartlin, J.; Halligan, A.; Scott, J.M.; Darling, M.; Weir, D.G. Accelerated folate breakdown in pregnancy. Lancet 1993, 341, 148–149. [Google Scholar] [CrossRef]
  134. Caudill, M.A.; Gregory, J.F.; Hutson, A.D.; Bailey, L.B. Folate catabolism in pregnant and nonpregnant women with controlled folate intakes. J. Nutr. 1998, 128, 204–208. [Google Scholar]
  135. Bakker, R.; Timmermans, S.; Steegers, E.A.P.; Hofman, A.; Jaddoe, V.W.V. Folic acid supplements modify the adverse effects of maternal smoking on fetal growth and neonatal complications. J. Nutr. 2011, 141, 2172–2179. [Google Scholar] [CrossRef]
  136. Bergen, N.E.; Jaddoe, V.W.V.; Timmermans, S.; Hofman, A.; Lindemans, J.; Russcher, H.; Raat, H.; Steegers-Theunissen, R.P.M.; Steegers, E.A.P. Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: The Generation R Study. Br. J. Obstet. Gynaecol. 2012, 199, 739–751. [Google Scholar]
  137. Bodnar, L.M.; Himes, K.P.; Venkataramanan, R.; Chen, J.-Y.; Evans, R.W.; Meyer, J.L.; Simhan, H.N. Maternal serum folate species in early pregnancy and risk of preterm birth. Am. J. Clin. Nutr. 2010, 92, 864–871. [Google Scholar] [CrossRef]
  138. Relton, C.L.; Pearce, M.S.; Parker, L. The influence of erythrocyte folate and serum vitamin B12 status on birth weight. Br. J. Nutr. 2007, 93, 593–599. [Google Scholar] [CrossRef]
  139. Scholl, T.O.; Hediger, M.L.; Schall, J.I.; Khoo, C.S.; Fisher, R.L. Dietary and serum folate: Their influence on the outcome of pregnancy. Am. J. Clin. Nutr. 1996, 63, 520–525. [Google Scholar]
  140. Siega-Riz, A.M.; Savitz, D.A.; Zeisel, S.H.; Thorp, J.M.; Herring, A. Second trimester folate status and preterm birth. Am. J. Obstet. Gynecol. 2004, 191, 1851–1857. [Google Scholar] [CrossRef]
  141. Nilsen, R.M.; Vollset, S.E.; Monson, A.L.B.; Ulvik, A.; Haugen, M.; Meltzer, H.M.; Magnus, P.; Ueland, P.M. Infant birth size is not associated with maternal intake and status of folate during the second trimester in Norwegian pregnant women. J. Nutr. 2010, 140, 572–579. [Google Scholar] [CrossRef]
  142. Fekete, K.; Berti, C.; Trovato, M.; Lohner, S.; Dullemeijer, C.; Souverein, O.W.; 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. [Google Scholar] [CrossRef]
  143. Atkinson, S.; Koletzko, B. Determining life-stage groups and extrapolating Nutrient Intake Values (NIVs). Food Nutr. Bull. 2007, 28, S61–S77. [Google Scholar]
  144. Ek, J. Plasma, red call, and breast milk folacin concentrations in lactating women. Am. J. Clin. Nutr. 1983, 38, 929–935. [Google Scholar]
  145. Smith, A.M.; Picciano, M.F.; Deering, R.H. Folate intake and blood concentrations of term infants. Am. J. Clin. Nutr. 1985, 41, 590–598. [Google Scholar]
  146. Brown, C.M.; Smith, A.M.; Picciano, M.F. Forms of human milk folacin and variation patterns. J. Pediatr. Gastroenterol. Nutr. 1986, 5, 278–282. [Google Scholar]
  147. O’Connor, D.L.; Tamura, T.; Picciano, M.F. Pteroylpolyglutamates in human milk. Am. J. Clin. Nutr. 1991, 53, 930–934. [Google Scholar]
  148. Lim, H.S.; Mackey, A.D.; Tamura, T.; Wong, S.C.; Picciano, M.F. Measurable human milk folate is increased by treatment with α-amylase and protease in addition to folate conjugase. Food Chem. 1998, 63, 401–407. [Google Scholar] [CrossRef]
  149. Han, Y.-H.; Yon, M.; Han, H.-S.; Kim, H.-Y.; Tamura, T.; Hyun, T.H. Folate contents in human milk and casein-based and soya-based formulas, and folate status of Korean infants. Br. J. Nutr. 2009, 101, 1769–1774. [Google Scholar] [CrossRef]
  150. Houghton, L.A.; Yang, J.; O’Connor, D.L. Unmetabolized folic acid and total folate concentrations in breast milk are unaffacted by low-dose folate supplements. Am. J. Clin. Nutr. 2009, 89, 216–220. [Google Scholar] [CrossRef]
  151. Khambalia, A.; Latulippe, M.E.; Campos, C.; Merlos, C.; Villalpando, S.; Picciano, M.F.; O’Connor, D.L. Milk folate secretion is not impaired during iron deficiency in humans. J. Nutr. 2006, 136, 2617–2624. [Google Scholar]
  152. Mackey, A.D.; Picciano, M.F. Maternal folate status during extended lactation and the effect of supplemental folic acid. Am. J. Clin. Nutr. 1999, 69, 285–292. [Google Scholar]
  153. Hure, A.J.; Collins, C.E.; Smith, R. A longitudinal study of maternal folate and vitamin B12 status in pregnancy and postpartum, with the same infant markers at 6 months of age. Matern. Child Health J. 2012, 16, 792–801. [Google Scholar] [CrossRef]
  154. O’Connor, D.L.; Green, T.; Picciano, M.F. Maternal folate status and lactation. J. Mammary Gland Biol. Neoplasia 1997, 2, 279–289. [Google Scholar] [CrossRef]
  155. Keizer, S.; Gibson, R.S.; O’Connor, D.L. Postpartum folic acid supplementation of adolescents: Impact on maternal folate and zinc status and milk composition. Am. J. Clin. Nutr. 1995, 62, 377–384. [Google Scholar]
  156. Ramlau-Hansen, C.H.; Møller, U.K.; Henriksen, T.B.; Nexø, E.; Møller, J. Folate and vitamin B12 in relation to lactation: A 9-month postpartum follow-up study. Eur. J. Clin. Nutr. 2006, 60, 120–128. [Google Scholar] [CrossRef]
  157. Smith, A.M.; Picciano, M.F.; Deering, R.H. Folate supplementation during lactation: Maternal folate status, human milk folate content, and their relationship to infant folate status. J. Pediatr. Gastroenterol. Nutr. 1983, 2, 622–628. [Google Scholar] [CrossRef]
  158. Conde-Agudelo, A.; Rosas-Bermudez, A.; Kafury-Goeta, C. Birth spacing and risk of adverse perinatal outcomes: A meta-analysis. JAMA 2006, 295, 1809–1823. [Google Scholar] [CrossRef]
  159. Conde-Agudelo, A.; Rosas-Bermudez, A.; Castaño, F.; Norton, M.H. Effects of birth spacing on maternal, perinatal, infant, and child health: A systematic review of causal mechanisms. Stud. Fam. Plan. 2012, 43, 93–114. [Google Scholar] [CrossRef]
  160. Van Eijsden, M.; Smits, L.J.M.; van der Wal, M.F.; Bonsel, G.J. Association between short interpregnancy intervals and term birth weight: The role of folate depletion. Am. J. Clin. Nutr. 2008, 88, 147–153. [Google Scholar]
  161. Hermoso, M.; Tabacchi, G.; Iglesia-Altaba, I.; Bel-Serrat, S.; Moreno-Aznar, L.A.; García-Santos, Y.; García-Luzardo, M.R.; Santana-Salguero, B.; Peña-Quintana, L.; Serra Majem, L.; et al. The nutritional requirements of infants. Towards EU alignemet of reference values: The EURRECA network. Matern. Child Health J. 2010, 6, S55–S83. [Google Scholar]
  162. Van’t Veer, P.; Heseker, H.; Grammatikaki, E.; Benetou, V.; Grogoric, M.; Margaritis, I.; Raats, M.M.; Wijnhoven, T. EURRECA/WHO workshop report: Deriving micronutrient recommendations: Updating best practices. Ann. Nutr. Metab. 2013, 62, 63–67. [Google Scholar] [CrossRef]
  163. Cavelaars, A.E.J.M.; Doets, E.L.; Dhonukshe-Rutten, R.A.M.; Hermoso, M.; Fairweather-Tait, S.J.; Koletzko, B.; Gurinović, M.; Moreno, L.A.; Cetin, I.; Matthys, C.; et al. Prioritizing micronutrients for the purpose of reviewing their requirements: A protocol developed by EURRECA. Eur. J. Clin. Nutr. 2010, 64, S19–S30. [Google Scholar] [CrossRef]
  164. Nordic Council of Ministers. Folate—Nordic Nutrition Recommendations 2012—Draft Chapter for Public Consultation; Nordic Council of Ministers: Copenhagen, Denmark, 2012. [Google Scholar]
  165. Branum, A.M.; Bailey, R.; Singer, B.J. Dietary supplement use and folate status during pregnancy in the United States. J. Nutr. 2013, 143, 486–492. [Google Scholar] [CrossRef]

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MDPI and ACS Style

Stamm, R.A.; Houghton, L.A. Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World. Nutrients 2013, 5, 3920-3947. https://0-doi-org.brum.beds.ac.uk/10.3390/nu5103920

AMA Style

Stamm RA, Houghton LA. Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World. Nutrients. 2013; 5(10):3920-3947. https://0-doi-org.brum.beds.ac.uk/10.3390/nu5103920

Chicago/Turabian Style

Stamm, Rosemary A., and Lisa A. Houghton. 2013. "Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World" Nutrients 5, no. 10: 3920-3947. https://0-doi-org.brum.beds.ac.uk/10.3390/nu5103920

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