Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies All participants in the Consultation Key words: Folate, vitamin B12 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 vitamin B12 deficiency in the elderly, poor ventions absorption. Folate is present in high concentrations » Strategies to improve intakes of folate and vitamin B12 in legumes, leafy green vegetables, and some fruits, so lower intakes can be expected where the staple diet consists of unfortified wheat, maize, or rice, 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 foods 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 vitamins 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 blood 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 pregnancy 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 food forms, especially low serum or plasma concentrations of both vitamins, in lower doses. and elevated plasma homocysteine. In addition, inad- equate folate intake causes low red blood cell folate, and elevated urinary or serum methylmalonic acid (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 Nutrition 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 (total 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 vitamin B6 and riboflavin, 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. Anemia 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 mean corpuscular volume (MCV) 12 in a complete blood count (CBC). It is important to note that iron 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 iron deficiency is less prevalent. Folate deficiency Hematology Cutoff values that indicate deficiency There is strong evidence that folate deficiency causes The Consultation recognized the lack of universally megaloblastic anemia. 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 pregnancies. 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 placental abruption 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 United States. 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 metabolism, 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. Child development 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