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Home , Cyanocobalamin, Folate, Folate deficiency, Iron deficiency, Vitamin, Vitamin B12

Conclusions of a WHO Technical Consultation on and B12 deficiencies

All participants in the Consultation

Key words: Folate, The consultation agreed on conclusions in four areas: » Indicators for assessing the prevalence of folate and Preamble vitamin B12 deficiencies » Health consequences of folate and vitamin B12 defi- Folate and vitamin B12 deficiencies occur primarily as ciencies a result of insufficient dietary intake or, especially in » Approaches to monitoring the effectiveness of inter- the case of in the elderly, poor ventions absorption. Folate is present in high concentrations » Strategies to improve intakes of folate and vitamin B12 in , leafy green , and some fruits, so lower intakes can be expected where the staple consists of unfortified , , or , and when Indicators for assessing and monitoring the intake of legumes and folate-rich vegetables and vitamin status fruits is low. This situation can occur in both wealthy and poorer countries. Animal-source are the only Prevalence of deficiencies natural source of vitamin B12, so deficiency is prevalent when intake of these foods is low due to their high The recent review by WHO showed that the majority cost, lack of availability, or cultural or religious beliefs. of data on the prevalence of folate and vitamin B12 Deficiency is certainly more prevalent in strict vegetar- deficiencies are derived from relatively small, local ians, but lacto-ovo vegetarians are also at higher risk surveys, but these and national survey data from a for inadequate intakes. If the mother is folate-depleted few countries suggest that deficiencies of both of these during lactation, breastmilk concentrations of the may be a public health problem that could vitamin are maintained while the mother becomes affect many millions of people throughout the world. more depleted. In contrast, vitamin B12 concentrations Low concentrations of the vitamins occur across in breastmilk can be markedly lower in vitamin B12- population groups and in countries in various stages of depleted women. The impact of gene polymorphisms development. Inclusion of folate and vitamin B12 status on folate and vitamin B12 status and requirements assessment in more representative national surveys is in a population will vary depending on the underly- recommended, with standardization of the methods ing prevalence in that population. Although not well used to measure blood vitamin concentrations, and the understood, gene polymorphisms almost certainly application of universal cutoffs such as those proposed affect the risk of adverse outcomes. Folic in this Consultation. acid and vitamin B12 in synthetic form are absorbed at Inadequate intake of folate and vitamin B12 leads to about twice the efficiency as the forms, especially low serum or plasma concentrations of both vitamins, in lower doses. and elevated plasma . In addition, inad- equate folate intake causes low red blood folate, and elevated urinary or serum (MMA) occurs in vitamin B12 deficiency. Serum holotransco- Please direct queries to the corresponding author: Bruno balamin II is a more recently proposed additional de Benoist, Department of for Health and Devel- opment, World Health Organization, 20 Avenue Appia, measure of vitamin B12 status. Thus, several feasible CH-1211, Geneva 27, Switzerland; e-mail: debenoistb@ and reasonably good indicators of status are available who.int. for both vitamins.

S238 Food and Nutrition Bulletin, vol. 29, no. 2 (supplement) © 2008, The United Nations University. Conclusions of the Consultation S239

Biochemical and hematological indicators of status time for assessing the nutritional status of populations. They are derived from the US NHANES III (National Serum/plasma or erythrocyte concentrations of folate Health and Nutrition Examination Survey) [1], based and serum/plasma concentrations of vitamin B12 pro- on the plasma vitamin concentrations below which vide an accurate picture of a population’s status. The plasma metabolites become elevated ( homo- most practical and least expensive measurements at cysteine concentration for folate and MMA for vitamin the population level are serum or plasma folate and B12). In addition, these cutoffs are consistent with vitamin B12. data in the Institute of Medicine report [2] on recom- MMA and homocysteine assays have limitations in mended intakes of folate and vitamin B12, in which that they are more expensive, and the results can be blood vitamin concentrations were used to determine affected by poor renal function. Furthermore, inter- Estimated Average Requirements (EAR). pretation of homocysteine concentrations requires The concentrations suggested for defining folate and knowledge of both folate and vitamin B12 status as well vitamin B12 deficiencies based on metabolic indicators as that of and , since deficiencies are: of any of these vitamins can contribute to elevated < 10 nmol/L (4 ng/mL)* for serum folate and plasma homocysteine. < 340 nmol/L (151 ng/mL) for RBC folate. due to folate and vitamin B12 deficiency is relatively uncommon worldwide, but can best be < 150 pmol/L (203 pg/mL)** for plasma vitamin B . detected by elevated (MCV) 12 in a (CBC). It is important to note that deficiency tends to lower MCV more readily than it is raised by folate or vitamin B12 defi- Health consequences of folate and vitamin ciency, so high MCV may be a more sensitive measure B12 deficiencies of deficiency of these vitamins in populations where is less prevalent. Cutoff values that indicate deficiency There is strong evidence that folate deficiency causes The Consultation recognized the lack of universally . In regions where folate defi- accepted cutoffs to define deficiency of either vitamin, ciency is more common during pregnancy and lacta- and expressed the need for consensus on this issue. tion, a few studies have associated megaloblastic anemia There are several reasons for this situation. with prolonged lactation and multiple . Folate and vitamin B12 concentrations can differ depending on the method used for assessment, includ- Pregnancy outcomes ing various radioimmunoassays and microbiological There is strong evidence of an inverse association assays. Values frequently differ most in the lower range between blood folate concentrations and risk of low of concentrations where it is critical to have accurate birthweight. Folic acid supplementation increased and precise values. The microbiological assay is inex- birthweight in studies in Africa and India. This is an pensive but may be difficult to perfect initially. There is important issue for developing countries. a need for international reference materials and more There is some evidence of an inverse association interaction and communication among laboratories between blood folate concentrations during pregnancy regarding these analyses so that population preva- and the risks of and delivering lences of deficiency can be correctly determined and preterm or small-for-gestational-age infants. compared. The serum or plasma vitamin B cutoff 12 Birth defects used to diagnose vitamin B12 deficiency has gradually increased over time, because initially it was based on There is strong evidence of a causal association between detection of neurological consequences of deficiency, low maternal folate intake or lower folate status and then later on other indicators including elevated plasma increased risk of neural tube defects (NTD)—and homocysteine and MMA. However, the public health for a protective effect of folic acid supplementation significance of the impact of applying these cutoffs is or consumption of fortified foods, in the pericon- not fully understood, and requires further study. ceptional period, against NTD. This association has Appropriate cutoffs for pregnancy are uncertain, been confirmed in two randomized clinical trials, in since serum/plasma concentrations of both vitamins large-scale supplementation trials in China, and from decline over the course of pregnancy and recover at postfortification data available from countries such as delivery. Despite these caveats, the Consultation arrived at * Conversion factor used for folic acid: 2.265 [2]. a consensus on the cutoffs that should be used at this ** Conversion factor used for vitamin B12: 0.737 [2]. S240 All participants in the Consultation

Canada, Chile, and the . increased risk of NTD. There is moderately strong evidence of an asso- Evidence for an association between maternal vita- ciation between the MTHFR 677C→T gene variant, min B12 status and other birth defects, such as orofacial which affects folate , and increased risk clefts and heart defects, is weaker than the evidence of NTD. However, it is probable that there are other for an association of these defects with maternal folate genotypes that are at special risk for adverse birth out- status. comes, yet which may respond positively to folic acid supplementation. Some evidence exists to support an association The importance of adequate vitamin B12 status between folate status and the risk of other birth defects for child development is clear. Children who suffer such as orofacial clefts and heart defects. developmental delays as a result of severe vitamin B12 deficiency tend not to fully recover. In severe Cognitive function deficiency, as seen in children who are raised under Evidence for an association between serum/plasma macrobiotic conditions,* all developmental milestones folate concentrations and cognitive function is weaker are delayed. in children than in adults. However, some studies have School-aged children with poor vitamin B12 status reported lower scores in schoolchildren with low folate had lower scores at school and lower cognitive per- status [3]. formance in the two studies on this question. In adults, there is moderate evidence that low folate status is associated with cognitive impairment and Neuropathy and sustained spinal cord degeneration some measures of , but evidence for a benefi- There is strong evidence that severe vitamin B12 cial effect of folic acid supplementation on cognitive deficiency causes neuropathy in cases of pernicious performance or dementia is inconsistent. In addition, anemia, and in medical conditions such as there is moderately convincing evidence that low serum and ileal resections. The clinical sequelae that lead to or folate concentrations are associated neurological damage in pernicious anemia are rarely with either a higher prevalence or a longer duration seen in cases of dietary B12 deficiency, except in young of . infants (particularly those exclusively breastfed by mothers who are strict vegetarians), nor are the serum concentrations of the vitamin B as low as are seen in Vitamin B12 deficiency 12 patients with pernicious anemia. Hematology Cognitive function There is little evidence that widespread vitamin B12 deficiency at the population level increases the preva- Severe vitamin B12 deficiencies cause and lence of anemia, either in the elderly or in people cognitive impairment at all ages. consuming low amounts of animal-source foods. In There is weak evidence of an association between contrast, megaloblastic anemia is common when vita- low blood vitamin B12 and cognitive function, although min B12 deficiency is more severe, such as in clinical inconsistent results among studies may be due to prob- cases of pernicious anemia (defined as vitamin B12 lems with assessment. Although studies to date have deficiency due to caused by absence of failed to show consistent positive effects of oral vitamin ) and in some infants exclusively breast- B12 supplementation on cognitive function, there is fed by mothers who are strict vegetarians. some evidence of improvement in status after vitamin B injections in both deficient adults and elderly. Pregnancy outcomes 12 There is inadequate information on the relation- Homocysteine ship between poor maternal vitamin B12 status and There is strong evidence that plasma homocysteine is adverse pregnancy outcomes. The observed association a predictor of folate and vitamin B12 status. between vitamin B12 deficiency and recurrent abortions There are strong associations between elevated may only apply to women with pernicious anemia. plasma homocysteine and adverse pregnancy outcomes There is a moderate level of evidence that maternal such as preeclampsia, placental abruption, preterm vitamin B12 status correlates with neonatal vitamin B12 delivery, and low birthweight, but there is uncertainty status, and strong evidence that maternal B12 status about the direction of effect. For example, the relation- affects concentrations of the vitamin in breastmilk.

Birth defects * Typically a consists of grain (mainly rice), vegetables, pulses (mainly soy), and sea veg- There is moderately convincing evidence that low etables, and only very small amounts of fruits and products maternal vitamin B12 status is associated with an of animal origin [4]. Conclusions of the Consultation S241 ship between higher risk of preeclampsia and elevated population. homocysteine is not understood, and may or may not Baseline data should be collected on the prevalence be explained by poor folate or vitamin B12 status. of NTD. The methods used to collect this information Elevated plasma homocysteine was correlated with must be documented, since the methods will affect the cognitive decline and cerebral atrophy in several stud- estimated prevalence values and the ability to compare ies, and predicted the subsequent development of them across populations. dementia in cognitively intact middle-aged and elderly individuals. Controlling for folate and vitamin B 12 Monitoring status in analysis of such trials may not be appropriate, since poor folate and vitamin B12 status may be acting Monitoring the impact of interventions through elevated plasma homocysteine. Evidence is After a predetermined period of at least 6 months after still needed on the specific benefits of lowering plasma the start of the intervention and preferably annually homocysteine by folic acid and vitamin B12 interven- tions in these conditions. thereafter, intake and status assessment need to be There is moderately convincing evidence of an repeated using the same indicators and methods as association between elevated plasma homocysteine at baseline. This will provide information on change and such conditions as cardiovascular , cer- in prevalence of deficiency and status over time, and ebrovascular disease, cognitive decline, and reflect whether changes in intake are stable over time. dysfunction. However, intervention trials to date have A change in the highest quintile of MCV and the not had sufficient power to demonstrate clear effects lowest quintile of folate or vitamin B12 can indicate of reducing homocysteine on prevalence of deficiency at baseline in populations overall, although there may be an effect on . More with a low prevalence of iron deficiency, and evaluate definitive results will require meta-analysis of the data response to intervention. from current and future trials. Monitoring the safety of interventions

Vitamin B12 intake is assumed to be safe at any level, Recommendations for monitoring the but monitoring plasma levels of and efficacy and effectiveness of intervention programs levels of nonfunctional analogs of vitamin B12 in those who have very high plasma vitamin B12 levels from supplements, especially children, may be useful when Establishing baseline data cyanocobalamin intake is high. Homocysteine and At a minimum, on a random cohort of samples of the MMA are not useful for detecting excessive intakes. population groups of interest, appropriately stratified While stimulation of growth, suppression of by age, socioeconomic status, and other relevant fac- killer cell activity, reversal of antiepileptic effect, and unpredictable epigenetic and embryo rescue out- tors, usual dietary intakes of vitamin B12 and folate and their sources, and prevalence of inadequate intakes comes have been proposed as possible adverse effects of of vitamin B12 and folate (i.e., intake below the EAR) excessive folic acid exposure, none of these effects have should be assessed using methods described elsewhere reached a level of certainty so as to be recommended [5]. This is essential for predicting the potential impact for surveillance, except for cancer. of fortifying specific food vehicles, and the impact of Measurement of unmetabolized folic acid concen- the intervention on intake. trations in serum was proposed as a way of detect- Similarly, on a random cohort of blood samples col- ing whether folic acid is being consumed in excess lected from the population groups of interest, stratified of requirements, but so far this has not been used to by age, status, and other relevant factors, the prevalence monitor safety in any survey. of deficiency should be assessed by measuring folate Monitoring of interventions to control folate and/ in serum/plasma (or red blood cells) and vitamin B 12 or vitamin B deficiencies should include measure- concentrations in serum/plasma. 12 If possible, a complete blood count (CBC) should be ments of folic acid and vitamin B12 intake to make performed on the baseline samples for measurement sure that their consumption does not exceed the safe of mean corpuscular volume (MCV), the most sensi- upper level. The higher frequency of food-bound vitamin B tive hematological indicator of vitamin B12 and folate 12 deficiencies. absorption in the elderly will limit the ability of food Metabolic markers of folate and vitamin B12 defi- sources to improve their status. Persons with less severe ciency, homocysteine, and MMA, could be measured, deficiency are more likely to have normal vitamin B12 if feasible, at least on a representative subset of the absorption from food and supplements. S242 All participants in the Consultation

Strategies to improve folate and vitamin daily intake is 2.4 µg/day, many elderly persons appear B12 intakes to require supplement doses many times higher to achieve optimum vitamin B12 status, probably due to General introduction limited absorption. The supplements can be given daily, or as a larger dose less frequently, e.g., 0.4 mg folic acid The overarching and long-term strategy recommended daily versus 5 mg once weekly. They can be provided as for the control of folate and B12 deficiency is the con- tablets or in powdered form with other . sumption of a diet that meets the recommended intakes The intervention must cover a large proportion of the of these vitamins. However, in populations where it is targeted population to assure a significant public health unlikely that diet will provide recommended intakes of impact. To be successful, supplementation interven- these , strategies such as supplementation and tions require sustained and strong education programs fortification should be considered. for health providers and the general public, social mar- For safety reasons, when deciding the best way of keting, social mobilization, and advocacy efforts. delivering additional folic acid and/or vitamin B12— The advantages of a supplementation program are either by supplementation or by fortification—the main the ability to target at-risk population groups, cost- criterion to be taken into consideration is the need to effectiveness, and the possibility of its being nested target the population group to be reached. into an already existing program. On the other hand, Furthermore, programs to increase the consump- such programs require additional costs for promotion, tion of folate among women of reproductive age to education, and advocacy, and their success relies on 400 µg/day may benefit countries where the NTD rate a well-functioning health care system to deliver the has been determined to be higher than 0.6/1,000 live supplements. Furthermore, the sustainability of supple- births based on surveillance methods that can detect mentation programs may be dependent on the ability of most NTD cases. Such programs should collect data on the target population to pay for the supplements, which both folate and vitamin B12 status, and monitor NTD may not be possible in some populations, in which case rates during the selected interventions. their cost must be defrayed by local or international These conclusions do not consider the potential institutions. The greatest limitations of supplementa- benefits of lowering homocysteine through folate or tion programs may be lack of compliance and unac- vitamin B12. ceptability of the supplements due to cultural factors, if motivation programs are ineffective or not sustained. Currently available approaches Prior to embarking on a supplementation program, it is important to document through appropriate social Diet marketing studies that the proposed motivation pro- The best strategy to improve folate and vitamin B12 grams are effective in the community of interest. intakes is to promote the consumption of foods rich in folate and vitamin B12. Advocacy programs will facilitate identification of local food sources of the The criteria for fortification strategies are 1) a high vitamins and promote their use. However, where foods prevalence of inadequate folate and/or vitamin B12 rich in folate and vitamin B12 are not affordable or intakes; 2) evidence of deficiency; 3) a high burden of available, supplementation and/or fortification may deficiency-related disease such as NTD; 4) absence of be considered. circumstances that would make targeted supplementa- tion likely to be successful; and 5) a widely available Supplementation and highly consumed food vehicle that can be pro- Before selecting a supplementation strategy, it is recom- duced centrally. In many countries there are ongoing mended that clear goals and target populations be set, food-fortification programs to which folic acid and e.g., reduction in the prevalence of folate and/or vita- vitamin B12 may be added, or their content adjusted to min B12 deficiency, NTD rates, megaloblastic anemia, become adequate for the intended purpose. However, and adverse pregnancy outcomes. In situations where the effective amount needed for vitamin B12 has not other ongoing supplementation programs exist, the been satisfactorily defined, because availability may incorporation of folic acid and vitamin B12 in the sup- be affected by poor absorption, especially among the plements can avoid duplication of costs and efforts. elderly. Furthermore, food-fortification programs Criteria for considering supplementation programs are passive interventions that are cost-effective, self- should include the existence of other supplementation sustaining, and do not require extensive social mar- programs, an effective health system, and a strong keting and promotion. However, there is no assurance public education component. that all target groups will receive adequate amounts of The usual recommendation for supplemental folic the fortificants. Where food fortification is universal, acid is 0.4 mg/day. The ideal amount of supplemental which may be the case in industrialized countries, vitamin B12 is less clear. Although the recommended there may be concern about the benefits and safety of Conclusions of the Consultation S243 fortified food, as unfortified foods are not likely to be anemia is a medical condition and should be treated as available. such, and will not be responsive to the low vitamin B12 The level of folic acid or vitamin B12 that should be doses in supplements or most fortification programs. added to food can be calculated based on the preva- There is some evidence that there is a potential lence of inadequate intakes in a sample of the target harmful effect of high folate intakes in people with low population(s). Details of how to formulate and regulate vitamin B12 status. fortified foods have been established by WHO/FAO [5]. Some elderly may need more vitamin B12 than is supplied by fortification of staples, but most can absorb Research needs the synthetic form of the vitamin. Causes and contributing factors

Specific issues » Examine potential role of bacterial overgrowth, -like conditions, and possibly Helico- Prevention of NTD bacter pylori as a cause of vitamin B12 deficiency. » Determine health/disease status of subjects volun- Programs to increase the consumption of folate among tarily consuming large amounts of oral folic acid or women of reproductive age to 400 µg/day may benefit vitamin B12 supplements. countries where the NTD rate is higher than 0.6/1,000 live births. To reduce the risk of NTD for women Assessment and monitoring of interventions capable of becoming pregnant, the recommendation is (efficacy/effectiveness and safety) to take 400 µg of folic acid daily from fortified foods, supplements, or both, in addition to consuming food » Further define the validity of chosen cutoffs adding folate from a varied diet beginning at least 1 month new status indicators as they are developed. prior to conception. » Determine and test criteria that define safe levels of The decision to choose between supplementa- folic acid intake, including avoidance of exceeding tion and fortification to deliver additional folic acid safe upper levels, and focusing attention on upper should be driven by the need to target women at risk deciles for folate and vitamin B12 status. for becoming pregnant. With that in mind, the main » Develop indicators of adverse functional conse- criteria to meet when considering a supplementation quences of folate and vitamin B12 deficiencies. program are a high rate (80%) of planned pregnancies, » Study folic acid accumulation and its consequences easy access to the health care system, a strong public in adults and children with high levels of folic acid health infrastructure capable of sustained promotional after fortification or supplementation. campaigns, and availability of social marketing inter- » Study accumulation of cyanocobalamin and non- ventions known to be effective in the targeted area. functional cobalamin analogs and their conse- Where the conditions to implement folic acid supple- quences in adults and children with high cobalamin mentation are not met, targeted fortification should levels after fortification or supplementation. be considered. » Assess effects of genetic polymorphisms on cutoff points for folate and vitamin B12 sufficiency and deficiency. Vitamin B12 deficiencies » Develop new analytic tools to fully explore gene– Population groups who consume low amounts of ani- and gene–gene interactions. mal-source foods, not just strict vegetarians, are at high » Establish objective criteria to assess early neuro- risk for vitamin B12 deficiency. Subgroups at special risk logical impairment caused by vitamin B12 deficiency for deficiency are pregnant or lactating women, infants, (e.g., neurophysiological measurements). and young children with low vitamin B12 intake. The elderly often have difficulty in absorbing vitamin B12 Health consequences from animal-source foods. There is evidence that most elderly can absorb synthetic vitamin B12 in supplements » Examine relationships between folate status and and in foods, but those with more severe malabsorption pregnancy outcomes, including birthweight, pla- may require higher amounts. cental abruption, prematurity, and small-for-gesta- Folic acid supplements or fortification programs can tional-age infants in both developed and developing mask the megaloblastic anemia of severe B12 deficiency countries. such that the condition is not detected through hema- » Examine relationships between folate status and risk tological changes, and neurological deterioration can of birth defects other than NTD, such as orofacial progress. Providing vitamin B12 as well as folic acid clefts and heart defects. can help to reduce this problem. However, pernicious » Assess effects of folate and vitamin B12 interventions S244 All participants in the Consultation

on risk of birth defects other than NTD. enhance microbial growth). » Assess persistent effects of folate and vitamin B12 » Determine the link between low folate and “mood” interventions during gestation on late-onset disease or depression, in terms of prevalence or duration. risk. » Determine whether poor folate and/or vitamin B12 » Examine folate and vitamin B12 metabolism and/ status increases the risk of preeclampsia via hyper- or status in relation to , HIV, and hemolytic homocysteinemia. anemia. » Assess the effect of folate and vitamin B12 status on » Examine the association between folate deficiency and cancer risk. and risk of megaloblastic and » Determine the link between low folate and/or vita- lactation, especially with prolonged lactation and min B12 status and cognitive impairment at all ages. multiple pregnancies in both developed and develop- » Examine interference of increased folic acid intake ing countries. on the efficacy of therapeutic (e.g., » Examine possible risk of related to high antimalarials, , ). vitamin B12 level (e.g., vitamin B12, which may

References

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