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Association between vitamin B12 intake and EURRECA's prioritized biomarkers of vitamin B12 in young populations: a systematic review

Published online by Cambridge University Press:  13 September 2012

Iris Iglesia*
Affiliation:
GENUD (Growth, Exercise, Nutrition and Development) Research Group, Health Sciences Faculty, Cervantes Building, C/ Corona de Aragón, n° 42, 2nd floor, 50009 University of Zaragoza, Zaragoza, Spain
Rosalie AM Dhonukshe-Rutten
Affiliation:
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Silvia Bel-Serrat
Affiliation:
GENUD (Growth, Exercise, Nutrition and Development) Research Group, Health Sciences Faculty, Cervantes Building, C/ Corona de Aragón, n° 42, 2nd floor, 50009 University of Zaragoza, Zaragoza, Spain
Esmée L Doets
Affiliation:
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Adrienne EJM Cavelaars
Affiliation:
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Pieter van ‘t Veer
Affiliation:
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Mariela Nissenshohn
Affiliation:
Department of Clinical Sciences, Las Palmas de Gran Canaria University, Las Palmas de Gran Canaria, Spain
Vassiliki Benetou
Affiliation:
Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
María Hermoso
Affiliation:
Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig Maximilians University of Munich Medical Centre, Munich, Germany
Cristiana Berti
Affiliation:
Department of Clinical Sciences Hospital ‘L Sacco’ and Center for Fetal Research Giorgio Pardi, Unit of Obstetrics and Gynecology, University of Milan, Milan, Italy
Lisette CPGM de Groot
Affiliation:
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Luis A Moreno
Affiliation:
GENUD (Growth, Exercise, Nutrition and Development) Research Group, Health Sciences Faculty, Cervantes Building, C/ Corona de Aragón, n° 42, 2nd floor, 50009 University of Zaragoza, Zaragoza, Spain
*
*Corresponding author: Email iglesia@unizar.es
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Abstract

Objective

To review evidence on the associations between vitamin B12 intake and its biomarkers, vitamin B12 intake and its functional health outcomes, and vitamin B12 biomarkers and functional health outcomes.

Design

A systematic review was conducted by searching electronic databases, until January 2012, using a standardized strategy developed in the EURRECA network. Relevant articles were screened and sorted based on title and abstract, then based on full text, and finally included if they met inclusion criteria. A total of sixteen articles were included in the review.

Setting

Articles covered four continents: America (n 4), Europe (n 8), Africa (n 1) and Asia (n 3).

Subjects

Population groups included healthy infants, children and adolescents, and pregnant and lactating women.

Results

From the total number of 5815 papers retrieved from the initial search, only sixteen were eligible according to the inclusion criteria: five for infants, five for children and adolescents, and six for pregnant and lactating women.

Conclusions

Only one main conclusion could be extracted from this scarce number of references: a positive association between vitamin B12 intake and serum vitamin B12 in the infant group. Other associations were not reported in the eligible papers or the results were not provided in a consistent manner. The low number of papers that could be included in our systematic review is probably due to the attention that is currently given to research on vitamin B12 in elderly people. Our observations in the current systematic review justify the idea of performing well-designed studies on vitamin B12 in young populations.

Type
Nutrition and health
Copyright
Copyright © The Authors 2012 

Nutrition plays an important role in the programming of health across the lifespan, especially during the earliest periods, because of short- and long-term consequences in the absence of appropriate nutrition(Reference Roberts and McDonald1). There are biological substances which keep homeostasis to prevent adverse health outcomes like vitamin B12. In recent years, only a few studies have focused on the relationship between low vitamin B12 intake and cognitive function, megaloblastic anaemia or growth in young populations.

Across Europe, current reference values for vitamin B12 intake vary for infants from 0·3–0·5 to 1·5 μg/d depending on whether they are 3 or 9 months old, respectively(Reference Hermoso2), from 0·8 to 3·0 μg/d for children and adolescents(Reference Iglesia3) and from 1·5 to 4·0 μg/d for pregnant and lactating women(Reference Hall Moran, Lowe and Crossland4, Reference Berti, Decsi and Dykes5). The range of ages, values and terminology used for recommendations differ between European countries. However, the underlying concepts could be equivalent to: the RDA (Recommended Dietary Allowance, which is the daily dietary intake level of a nutrient considered sufficient to meet the requirements of nearly all (97–98 %) healthy individuals in each life stage and gender group), the AI (Adequate Intake, which is an estimation of the lowest intake level that seems sufficient for almost all people in a group) and the acceptable range (which is defined as the range of intakes high enough to avoid deficiency and low enough to avoid toxic effects). For vulnerable population groups such as those represented herein, nutrient requirements are generally obtained from data extrapolated from the adult ANR (Average Nutrient Requirement, which is the estimated average or median requirement of a specific nutrient in a population)(Reference Doets, de Wit and Dhonukshe-Rutten6).

In Western countries, the dietary intake of vitamin B12 among children, adolescents and adults is usually higher than the average requirement for vitamin B12. For instance, the Spanish study EnKid showed that the 2–24-year-old population had a mean daily vitamin B12 intake of 8·2 μg (males) and 6·8 μg (females)(Reference Serra-Majem and Aranceta Bartrina7). However, data from the Framingham Offspring Study suggest that suboptimal vitamin B12 status occurs at intakes exceeding the recommended intakes(Reference Tucker, Rich and Rosenberg8) and raise the question of whether the current recommended intakes for vitamin B12 are adequate to promote a normal vitamin B12 status(Reference Allen9) and influence the occurrence of several health outcomes(Reference Tucker, Rich and Rosenberg8, Reference Bor, Lydeking-Olsen and Moller10Reference Kwan, Bermudez and Tucker12).

The preferred approach to define the requirement takes into account the level of intake at which functioning is optimal. This implies that both preventing deficiencies as well as reducing the risk of developing other chronic disorders have to be taken into account(Reference Dhonukshe-Rutten, Timotijevic and Cavelaars13, Reference Ashwell, Lambert and Alles14).

In order to provide up-to-date and evidence-based micronutrient reference values across Europe, it is important to assess the micronutrient status for different population groups(Reference Atkinson and Koletzko15) through its preferred biomarkers or functional health outcomes(Reference King, Vorster and Tome16). The use of a biomarker that reflects changes in micronutrient status can facilitate the understanding of the relationships between dietary micronutrient intake and status or health outcomes (Fig. 1). The best tools to provide this information are dose–response and repletion–depletion studies, but they are rarely carried out.

Fig. 1 Intake–status–health relationships relevant for deriving reference values: 1 = intake–health relationship; 2 = intake–status relationship; 3 = status–health relationship

The aim of the present paper is to systematically review dose–response evidence from randomized controlled trials (RCT), prospective cohort and cross-sectional studies on the association of vitamin B12 with its main biomarkers, and also with its main health outcomes in infants, children, adolescents and pregnant and lactating women. The ultimate goal would be to provide micronutrient reference intake values for vitamin B12 in the aforementioned population groups.

Methods

The current systematic review on vitamin B12 in young populations and pregnant and lactating women was performed within the framework of EURRECA (www.eurreca.org) and has focused on one of the prioritized relationships set by the network(Reference Cavelaars, Doets and Dhonukshe-Rutten17) as illustrated in Fig. 1.

Search methods for identification of studies

To find the search strategy terms and the criteria for exclusion/inclusion papers, data on vitamin B12(Reference Cavelaars, Doets and Dhonukshe-Rutten17) were first reviewed. A multiple-database searching in MEDLINE, Embase (both on Ovid) and the Cochrane Library CENTRAL was carried out until 17 February 2009. The general search strategy included terms on study designs in humans AND (intake or status) AND (vitamin B12). The search terms included both MeSH terms and words to be found in the title or abstract. The initial search yielded 5815 references after exclusion of duplicates. Reference lists of six relevant review articles(Reference Dror and Allen18Reference Ray and Laskin23) were checked also to identify potentially relevant references that were not yet collected. This search did not yield any other references.

In January 2012 the search was repeated to retrieve other possible relevant papers. This search retrieved 596 new papers.

Criteria for the consideration of studies

Studies had to fulfill the following criteria to be included in the review:

  1. 1. Investigate the possible relationships between vitamin B12 intake, its biomarker levels or the selected health outcomes, following the structure available in Fig. 1;

  2. 2. Provide vitamin B12 from supplements, fortified foods or natural dietary sources;

  3. 3. Be observational studies (prospective cohort, nested case–control or cross-sectional, the latter for intake–status associations only) or intervention studies (only RCT);

  4. 4. Be performed in human subjects from birth to 18 years or pregnant or lactating women;

  5. 5. Include apparently healthy subjects.

Results on adults and the elderly in studying these relationships are reported elsewhere.

Accepted dietary assessment methods to include the paper were: (i) validated FFQ/dietary history; and (ii) 24 h recall/food records/diary measures for at least 2 d.

Serum/plasma vitamin B12, methylmalonic acid (MMA) and holotranscobalamin (HoloTC)(Reference Hoey, Strain and McNulty24) were the biomarkers included as the most robust and sensitive biomarkers identified through earlier research activities in the EURRECA network(Reference Fairweather-Tait and Harvey25, Reference Hooper, Ashton and Harvey26).

The health outcomes chosen were those most relevant for the population group (based on public health reports and the scientific literature, i.e. current evidence of a relationship and the number of preliminary search hits from online databases) and not recently and thoroughly covered by a similar review. Health outcomes differed between population groups:

  1. 1. Neurodevelopment and megaloblastic anaemia for infants;

  2. 2. Megaloblastic anaemia, growth and cognitive function for children and adolescents;

  3. 3. Fetal malformations and fetal growth for fetuses;

  4. 4. Megaloblastic anaemia and pre-eclampsia for mothers.

Collection of papers

The results of the searches were combined in EndNote XII (Thompson Reuters). References were screened based on title and abstract. They were then sorted by population group: (i) infants, (ii) children and adolescents and (iii) pregnant and lactating women; and by relationship following the analytical model: (i) intake–health (I-H), (ii) intake–status (I-S), (iii) status–health (S-H) and (iv) intake–status–health (I-S-H).

Selection of studies

Once papers were screened based on title and abstract and sorted by population group, those selected were again screened based on full text by obtaining them electronically, as photocopies or reprints, according to the predefined criteria. The reasons for exclusion and the name of the reviewer were registered in the EndNote library. One hundred and seventeen potentially relevant references were considered for inclusion based on full text review; characteristics of the 101 references excluded are shown in Table 1. Figure 2 shows the flowchart of the selection steps for the populations reviewed herein. If language expertise existed in the review team, articles written in languages other than English could be included.

Table 1 Characteristics of excluded studies

RCT, randomized controlled trial; S, status; H, health; I, intake.

Fig. 2 Selection of studies for the current systematic review

Data extraction

Data from papers identified as relevant were extracted to characterize studies and to facilitate meta-analysis. Data were entered into an Access database specifically developed for EURRECA.

Quality check controls

For alignment and quality control, at the start of each step two independent reviewers screened 10 % of the references in duplicate. Any discrepancies at this step were discussed before proceeding with the rest of the references.

Assessment of risk of bias in included studies

To exclude major sources of bias, internal validity of the relevant studies was assessed. The criteria used were adapted from the Cochrane Handbook(27). The criteria for RCT were based on: method of sequence generation and allocation; blinding; potential funding bias; number of participants at start; drop-outs and reasons for dropping out; dose check; dietary intake data reported; and similarity of most and least exposed groups at baseline. For longitudinal studies the criteria were based on: drop-outs adequate and outcome data complete; funding; lack of other potential threats to validity; control for confounders; and assessment of exposure adequacy. For cross-sectional studies the criteria were based on: funding; lack of other potential threats to validity, such as those related to the specific study design used or related to differences in baseline characteristics of participants; confounders; and assessment of exposure adequacy.

Results

The systematic search retrieved sixteen relevant papers. Table 2 summarizes the characteristics and results of these studies.

Table 2 Main characteristics of the studies selected in the systematic review by study population group

IUGR, intra-uterine growth retardation; FA, folic acid supplement intake; IM, intramuscular(ly); SES, socio-economic status; RCT, randomized controlled trial; HoloTC, holotranscobalamin; MMA, methylmalonic acid; IQR, interquartile range; sem, standard error of measurement; SGA, small-for-gestational age; AOR, adjusted odds ratio.

Infants

Two out of five selected papers were RCT(Reference Bjorke-Monsen, Torsvik and Saetran28, Reference Worthington-White, Behnke and Gross29) and three were observational studies (one cross-sectional(Reference Jones, Ramirez-Zea and Zuleta30) and two longitudinal studies(Reference Hay, Johnston and Whitelaw31, Reference Dagnelie and van Staveren32)). In all these studies the association between intake and status (I-S) was reported, except for one longitudinal study(Reference Dagnelie and van Staveren32). In both RCT, the intervention groups(Reference Bjorke-Monsen, Torsvik and Saetran28, Reference Worthington-White, Behnke and Gross29) received vitamin B12 through intramuscular injection: once per month during the first 4 months (100 μg/month) in one study(Reference Worthington-White, Behnke and Gross29) and in the other(Reference Bjorke-Monsen, Torsvik and Saetran28) the injected amount was only once (400 μg). In the RCT from Worthington-White et al.(Reference Worthington-White, Behnke and Gross29), serum levels were significantly increased after the intervention (either with or without folate supplementation) at each point of the measurements. In that study, the dose–response association between injected vitamin B12 and levels of biomarkers was not estimated.

In the RCT from Bjorke-Monsen et al.(Reference Bjorke-Monsen, Torsvik and Saetran28), the intervention was the strongest predictor of changes for all blood indices (regression coefficient = 183 for serum vitamin B12 and regression coefficient = −0·70 for MMA). Four months after delivery, the median (range) of serum vitamin B12 was 421 (291–497) pmol/l and 240 (162–337) pmol/l for the intervention and placebo groups, respectively; corresponding values for MMA were 0·2 (0·15–0·43) pmol/l and 0·51 (0·23–1·55) pmol/l.

In the Guatemalan cross-sectional study(Reference Jones, Ramirez-Zea and Zuleta30), mean intake of vitamin B12 was 3·1 μg/d for mothers and 2·2 μg/d for infants at the age of 12 months and the accompanying mean (sd) plasma vitamin B12 concentration in mothers and infants was 114·4 (9·2) g/l and 262·2 (163·5) pmol/l, respectively. The plasma vitamin B12 concentrations of the infants were correlated with maternal concentrations and they were also positively associated with infant B12 intake from complementary foods (r = 0·16, P < 0·0001).

In the longitudinal study by Hay et al.(Reference Hay, Johnston and Whitelaw31), the results were divided between breast-fed (n 104) and non-breast-fed (n 115) infants: the mean intake of vitamin B12 was 1·4 (95 % CI 1·3, 1·6) μg/d for breast-fed infants excluding the intake from breast milk and 2·4 (95 % CI 2·1, 2·6) μg/d for the non-breast-fed infants. In that study, the selected biomarkers were measured at the age of 12 months. Mean (95 % CI) serum vitamin B12, HoloTC and MMA were 343 (319, 369) pmol/l, 54 (49, 60) pmol/l and 0·22 (0·20, 0·25) μmol/l, respectively, for breast-fed infants, and 397 (372, 424) pmol/l, 76 (70, 83) pmol/l and 0·20 (0·19, 0·22) μmol/l, respectively, for non-breast-fed infants. Infants who were breast-fed at the age of 12 months had significantly lower serum vitamin B12 and HoloTC and higher MMA than those who were not breast-fed at the same age. In that study, total vitamin B12 intake from complementary foods was positively associated with serum vitamin B12 (r = 0·15 and P = 0·030) and HoloTC (r = 0·25 and P = 0·001).

The longitudinal study by Dagnelie et al.(Reference Dagnelie and van Staveren32) was the only one studying the relationship between vitamin B12 intake and health, specifically psychomotor development, in spite of the status also being stated in the paper. However, they were not related with intakes or health outcomes. The results were divided between infants following a specified macrobiotic diet and those following an omnivorous one. Mean vitamin B12 intakes were significantly higher in the omnivorous group (2·9 (sd 1·3) μg/d) in comparison to the macrobiotic group (0·3 (sd 0·2) μg/d; P < 0·001). These differences could be also be shown in the scores obtained in the psychomotor development test in the areas of gross motor development (for which the mean difference in standard deviations between feeding groups was −0·48) and speech and language development (for which the mean difference in standard deviations between feeding groups was −0·42), with a P value of 0·04 and 0·03, respectively. Despite these differences in health outcomes obtained between feeding groups, the authors did not study an association between vitamin B12 intakes and differences in scores in psychomotor tests; for this reason, these results cannot be attributed only to the obtained difference in vitamin B12 intakes.

The results of the four studies evaluating the I-S relationship showed that the status of vitamin B12 biomarkers is significantly and positively associated with vitamin B12 consumption (ingested or injected). The strength of this association was stated in almost all of the studies, with the exception of one RCT(Reference Worthington-White, Behnke and Gross29) in which the regression coefficient was not given. The limited availability of I-H data in infants did not allow for drawing any conclusions.

Children and adolescents

For the children and adolescents group, we identified four cross-sectional studies(Reference Papoutsakis, Yiannakouris and Manios33Reference Yeung, Cogswell and Carriquiry35, Reference Hay, Trygg and Whitelaw37) and one RCT(Reference Gewa, Weiss and Bwibo36). Two out of three cross-sectional studies were conducted with children(Reference Papoutsakis, Yiannakouris and Manios33, Reference Hay, Trygg and Whitelaw37), one study(Reference Steluti, Martini and Peters34) was carried out among adolescents and one(Reference Yeung, Cogswell and Carriquiry35) included both children and adolescents. In three cross-sectional studies(Reference Papoutsakis, Yiannakouris and Manios33Reference Yeung, Cogswell and Carriquiry35), vitamin B12 intake and plasma vitamin B12 was described. However, searching for an association between intake and status was not the purpose of the studies. Only in the study by Hay et al.(Reference Hay, Trygg and Whitelaw37), performed in Norwegian children, was vitamin B12 intake shown to be significantly and positively associated (r = 0·21, P < 0·05) with HoloTC. In that study, serum vitamin B12 and MMA were also measured; however, no association with them was found.

In the RCT by Gewa et al.(Reference Gewa, Weiss and Bwibo36), the targeted population group was children and the studied relationship was I-H. The authors discovered that children with a daily high intake of vitamin B12 gained a significant 0·24 more points in the Digit Span-forward test (as part of the entire cognitive test) than others with a low intake level, considering intakes of vitamin B12 predictors of the Digit Span-forward test.

Pregnant and lactating women

Regarding the pregnant and lactating women group, six prospective observational studies were included(Reference Baker, Wheeler and Sanders38Reference Takimoto, Hayashi and Kusama43). Four of them studied the relationship between status and health outcomes in the fetus (intra-uterine growth retardation (IUGR), small for gestational age (SGA) and growth in general)(Reference Baker, Wheeler and Sanders38, Reference Lindblad, Zaman and Malik40, Reference Muthayya, Kurpad and Duggan42, Reference Takimoto, Hayashi and Kusama43). In Lindblad et al.'s study(Reference Lindblad, Zaman and Malik40), the results suggested that in infants with normal birth weight, cord blood levels of vitamin B12 were correlated with maternal levels of serum vitamin B12. However these correlations were weaker when infants had IUGR. In the study by Baker et al.(Reference Baker, Wheeler and Sanders38), serum vitamin B12 levels in mothers were not associated with the risk of SGA infants. However, in Muthayya et al.'s study(Reference Muthayya, Kurpad and Duggan42) women in the lowest tertile for serum vitamin B12 concentration during each of the trimesters of pregnancy had significantly higher risk of delivering IUGR infants. In this last study, a correlation between vitamin B12 intake and status was also reported in all three trimesters. In Takimoto et al.'s study(Reference Takimoto, Hayashi and Kusama43), maternal vitamin B12 status, assessed in the third trimester of the pregnancy, was not associated with gestational weight, weight, length or head circumference of infants at delivery or at 1 month after delivery. Two studies(Reference Koebnick, Heins and Dagnelie39, Reference Morkbak, Ramlau-Hansen and Moller41) described longitudinal changes in vitamin B12 biomarkers through pregnancy, I-S being the main relationship examined. In one longitudinal study(Reference Koebnick, Heins and Dagnelie39), vitamin B12 intake in pregnant women was not associated with serum vitamin B12. In the study by Morkbak et al.(Reference Morkbak, Ramlau-Hansen and Moller41), which is the only selected study on pregnant women, in spite of there being three different supplementation groups, as there were no significant differences between them, results were presented for all three groups together. No change was observed in serum vitamin B12 throughout the study period, whereas a significant decrease was observed for HoloTC from baseline to the 9th month.

The observed I-S and S-H relationships were not consistent and further conclusions cannot be extracted.

Quality of included studies

Table 3 summarizes the method used to assess the quality of the included studies. Only three studies had a high risk of bias(Reference Worthington-White, Behnke and Gross29, Reference Papoutsakis, Yiannakouris and Manios33, Reference Gewa, Weiss and Bwibo36). Five studies had a moderate risk of bias(Reference Bjorke-Monsen, Torsvik and Saetran28, Reference Hay, Johnston and Whitelaw31, Reference Steluti, Martini and Peters34, Reference Yeung, Cogswell and Carriquiry35, Reference Baker, Wheeler and Sanders38) and eight studies reflect low risk of bias(Reference Jones, Ramirez-Zea and Zuleta30, Reference Dagnelie and van Staveren32, Reference Hay, Trygg and Whitelaw37, Reference Koebnick, Heins and Dagnelie39Reference Takimoto, Hayashi and Kusama43). The most repeated reason for risk of bias across the studies was an inadequate explanation about the drop-outs and an inadequate assessment of exposure (method to assess vitamin B12 intakes).

Table 3 Assessment of methodological quality of included randomized controlled trials, longitudinal and cross-sectional studies

Discussion

From 5815 identified papers, only sixteen were suitable to be included in the review according to EURRECA's eligibility criteria. From these, five papers focused only on descriptions of vitamin B12 intakes and biomarkers without any stated association. Because of the small number of eligible papers included in the review, only a few main conclusions can be drawn for the specific population groups studied.

Infants

In this population group, vitamin B12 (ingested or injected) was significantly and positively associated with vitamin B12 biomarkers. Serum vitamin B12 was investigated in all four studies. The evidence, however, was not sufficient for HoloTC (only one study(Reference Hay, Johnston and Whitelaw31)) or MMA (two studies(Reference Bjorke-Monsen, Torsvik and Saetran28, Reference Hay, Johnston and Whitelaw31), while in one study(Reference Hay, Johnston and Whitelaw31), associations were not found for MMA).

In this population group, the two included interventions were performed through injection of vitamin B12. Although injection could be a more reliable method of intervention, in general oral administration is better tolerated in the absence of neurological problems(Reference Duyvendak and Veldhuis44, Reference Rufenacht, Mach-Pascual and Iten45). Moreover, it should be noted that exposure to vitamin B12 via oral supplements or intramuscular injections is very different as e.g. bioavailability issues are different.

Children and adolescents

Among the four cross-sectional studies(Reference Papoutsakis, Yiannakouris and Manios33Reference Yeung, Cogswell and Carriquiry35, Reference Hay, Trygg and Whitelaw37) included in this population group, the only available finding was the positive association between children's intake of vitamin B12 and serum HoloTC in one of them. In that study, serum vitamin B12 and MMA were also investigated without any obtained association. The other three cross-sectional studies did not look for any association.

In the RCT of Gewa et al.(Reference Gewa, Weiss and Bwibo36), it was demonstrated that higher vitamin B12 intakes are associated with higher scores in one part of a cognitive test. However, only one study represents very limited data from which to extract a clear conclusion and in this respect, drawing conclusions may not be justified.

Pregnant and lactating women

Regarding the S-H relationships searched for in this group, as well as for I-S ones, no conclusions can be drawn due to the discrepancies in the results. One study(Reference Muthayya, Kurpad and Duggan42) showed an association between status and fetal growth and three(Reference Baker, Wheeler and Sanders38, Reference Lindblad, Zaman and Malik40, Reference Takimoto, Hayashi and Kusama43) showed no association. On the other hand, due to the heterogeneity shown in results regarding I-S relationships in all five included studies, it is possible to conclude that intake of vitamin B12 in pregnant and lactating women is not related to vitamin B12 concentration in their blood. This fact can be derived from the vitamin B12 gradient in the placenta, between the fetus and the mother. During pregnancy, vitamin B12 had been noted to decrease in mothers but not its transport molecules. Such an observation of the placenta facilitating the transport of a critical nutrient (as occurs with vitamin B12) for fetal growth and development when the mother is deficient is another revelation of how important the placenta is in maintaining the development of the fetus(Reference Schneider and Miller46, Reference Molloy, Mills and McPartlin47). In the other four studies(Reference Baker, Wheeler and Sanders38Reference Morkbak, Ramlau-Hansen and Moller41) there were no significant or relevant associations present.

Use of biomarkers in studies

One of the currently open questions regarding vitamin B12 is to determine the best biomarker to assess its status. In the present review, data were insufficient to draw conclusions about the effectiveness of serum HoloTC or MMA as a biomarker of vitamin B12 status (only one study showed a positive association between vitamin B12 intakes and HoloTC in children(Reference Hay, Trygg and Whitelaw37)). However, MMA and HoloTC are more sensitive markers for vitamin B12 deficiency than plasma vitamin B12(Reference Hvas and Nexo48) by reflecting sudden changes in vitamin B12 homeostasis, whereas plasma vitamin B12 seems to reflect the accumulation of vitamin B12(Reference Nexo, Hvas and Bleie49). On the other hand, they are extremely variable in these periods of life, making difficult their interpretation(Reference Hay, Johnston and Whitelaw31). Moreover, due to the ability of serum/plasma vitamin B12 to describe the status of vitamin B12 through time, without being influenced by punctual intake, serum/plasma vitamin B12 is the most common biomarker to assess vitamin B12 status.

Cognitive function

One of the constraints to the lack of data in the research on vitamin B12 intake and cognitive function is that even detailed examinations are not sufficiently accurate to detect developmental delays in young infants. However, reports on short- and long-term neurological effects related to vitamin B12 deficiency in young infants demonstrate the importance of an adequate vitamin B12 status during the first months of life(Reference Bjorke-Monsen, Torsvik and Saetran28). Vitamin B12 is also suggested to be related with neurocognitive function in school-aged children(Reference Villamor, Mora-Plazas and Forero50). In the present systematic review, two papers on this topic suggested this association (one in infants, the other in children). However, in the infants study(Reference Dagnelie and van Staveren32), the differences in scores in psychomotor tests were associated with type of diet (macrobiotic or omnivorous) and not with intake of vitamin B12 (however, the authors found significant differences in vitamin B12 intakes between diet groups).

Megaloblastic anaemia

Although being selected as a relevant health outcome for infants and children and adolescents, no paper on megaloblastic anaemia was finally included. However, some bibliography has reported megaloblastic anaemia as a typical symptom of vitamin B12 deficiency, usually as a consequence of previous maternal vitamin B12 deficiency(Reference Honzik, Adamovicova and Smolka51). Absence of included studies investigating this outcome suggests the low quality of reporting of the available studies, which were mostly old case reports.

No studies were found for megaloblastic anaemia in pregnant and lactating women. The explanation for no revealed hits could be that the literature about megaloblastic anaemia in this vulnerable group is linked mostly to intake and status of folate rather than the intake and status of vitamin B12(Reference Campbell52).

Growth

Of four papers focusing on fetal/infant growth (SGA, IUGR or general growth) in pregnant and lactating women, as only one has shown a positive association, no clear conclusion can be extracted in this regard.

Fetal malformations

The literature reveals that neural tube defects are the most common fetal malformation linked to deficiency of vitamin B12 in mothers(Reference Ray and Blom53). However, due to the strict inclusion criteria of the present systematic review, no studies on this topic were included.

Maternal pre-eclampsia

This health outcome was mentioned in only one of the longitudinal studies in the pregnant and lactating women group. However, there was no significant difference in vitamin B12 status among mothers who suffered pre-eclampsia compared with mothers without pre-eclampsia(Reference Lindblad, Zaman and Malik40). In another similar study, no significant differences were observed in both maternal and fetal serum vitamin B12 between a severe pre-eclampsia group v. mild pre-eclampsia and control groups(Reference Acilmis, Dikensoy and Kutlar54).

Conclusions

The current systematic review emphasizes a number of knowledge gaps in the field of vitamin B12 research for young populations and pregnant and lactating women, derived from the scarcity and the low quality of available studies.

One of the reasons for this scarce literature on vitamin B12 in young population groups could be that mild vitamin B12 deficiency is more prevalent among elderly people in association with a number of chronic diseases(Reference Selhub, Morris and Jacques55).

There is also evidence that vitamin B12 deficiency is uncommon in young populations, unless they belong to a vegan community, or live in a developing area, or have a congenital malabsorption syndrome(Reference Stabler and Allen56). However, the prevalence in younger groups may be higher than formerly recognized(Reference Bjorke-Monsen and Ueland57).

RCT with enough power and varying doses of dietary intakes and duration of supplementation are required in order to establish vitamin B12 recommendations for young populations. Further studies to correlate serum/plasma vitamin B12, MMA and HoloTC and also to explore vitamin B12 adequacy in young age groups are needed.

Acknowledgements

Sources of funding: The work reported herein has been carried out within the EURRECA Network of Excellence (www.eurreca.org) which is financially supported by the Commission of the European Communities, specific Research, Technology and Development (RTD) Programme ‘Quality of Life and Management of Living Resources’, within the Sixth Framework Programme, contract no. 036196. This report does not necessarily reflect the Commission's views or its future policy in this area. S.B.-S. was funded by a grant from the Aragon Regional Government (Diputación General de Aragón, DGA). Conflicts of interest: The authors declare no conflicts of interest. Authors’ contributions: A.E.J.M.C., P.v.V., L.C.P.G.M.d.G. and L.A.M. designed and directed the study; I.I., R.A.M.D.-R., S.B.-S., E.L.D., M.N., V.B., M.H. and C.B. conducted the research; I.I. wrote the manuscript; R.A.M.D.-R. and L.A.M. participated in data interpretation; I.I. had responsibility for the final content. I.I., R.A.M.D.-R., S.B.-S., E.L.D., M.N., V.B., M.H., C.B., A.E.J.M.C., P.v.V., L.C.P.G.M.d.G. and L.A.M. critically reviewed the manuscript. All authors read and approved the final manuscript.

References

1.Roberts, SB & McDonald, R (1998) The evolution of a new research field: metabolic programming by early nutrition. J Nutr 128, Suppl. 2, 400S.CrossRefGoogle ScholarPubMed
2.Hermoso, M (2010) The nutritional requirements of infants. Towards EU alignment of reference values: the EURRECA network. Matern Child Nutr 6, Suppl. 2, 5583.CrossRefGoogle ScholarPubMed
3.Iglesia, I (2010) Physiological and public health basis for assessing micronutrient requirements in children and adolescents. The EURRECA network. Matern Child Nutr 6, Suppl. 2, 8499.CrossRefGoogle Scholar
4.Hall Moran, V, Lowe, N, Crossland, Net al. (2010) Nutritional requirements during lactation. Towards European alignment of reference values: the EURRECA network. Matern Child Nutr 6, Suppl. 2, 3954.CrossRefGoogle ScholarPubMed
5.Berti, C, Decsi, T, Dykes, Fet al. (2010) Critical issues in setting micronutrient recommendations for pregnant women: an insight. Matern Child Nutr 6, Suppl. 2, 522.CrossRefGoogle ScholarPubMed
6.Doets, EL, de Wit, LS, Dhonukshe-Rutten, RAet al. (2008) Current micronutrient recommendations in Europe: towards understanding their differences and similarities. Eur J Nutr 47, Suppl. 1, 1740.Google ScholarPubMed
7.Serra-Majem, L & Aranceta Bartrina, J (2004) Nutrición infantil y juvenil. Estudio enKid. Barcelona: Masson.Google Scholar
8.Tucker, KL, Rich, S, Rosenberg, Iet al. (2000) Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr 71, 514522.CrossRefGoogle ScholarPubMed
9.Allen, LH (2008) Causes of vitamin B12 and folate deficiency. Food Nutr Bull 29, Suppl. 2, S20S34.CrossRefGoogle ScholarPubMed
10.Bor, MV, Lydeking-Olsen, E, Moller, Jet al. (2006) A daily intake of approximately 6 microg vitamin B-12 appears to saturate all the vitamin B-12-related variables in Danish postmenopausal women. Am J Clin Nutr 83, 5258.CrossRefGoogle ScholarPubMed
11.Vogiatzoglou, A, Smith, AD, Nurk, Eet al. (2009) Dietary sources of vitamin B-12 and their association with plasma vitamin B-12 concentrations in the general population: the Hordaland Homocysteine Study. Am J Clin Nutr 89, 10781087.CrossRefGoogle ScholarPubMed
12.Kwan, LL, Bermudez, OI & Tucker, KL (2002) Low vitamin B-12 intake and status are more prevalent in Hispanic older adults of Caribbean origin than in neighborhood-matched non-Hispanic whites. J Nutr 132, 20592064.CrossRefGoogle ScholarPubMed
13.Dhonukshe-Rutten, RA, Timotijevic, L, Cavelaars, AEet al. (2010) European micronutrient recommendations aligned: a general framework developed by EURRECA. Eur J Clin Nutr 64, Suppl. 2, S2S10.CrossRefGoogle ScholarPubMed
14.Ashwell, M, Lambert, JP, Alles, MSet al. (2008) How we will produce the evidence-based EURRECA toolkit to support nutrition and food policy. Eur J Nutr 47, Suppl. 1, 216.CrossRefGoogle ScholarPubMed
15.Atkinson, SA & Koletzko, B (2007) Determining life-stage groups and extrapolating nutrient intake values (NIVs). Food Nutr Bull 28, Suppl. 1, S61S76.CrossRefGoogle ScholarPubMed
16.King, JC, Vorster, HH & Tome, DG (2007) Nutrient intake values (NIVs): a recommended terminology and framework for the derivation of values. Food Nutr Bull 28, Suppl. 1, S16S26.CrossRefGoogle ScholarPubMed
17.Cavelaars, AE, Doets, EL, Dhonukshe-Rutten, RAet al. (2010) Prioritizing micronutrients for the purpose of reviewing their requirements: a protocol developed by EURRECA. Eur J Clin Nutr 64, Suppl. 2, S19S30.CrossRefGoogle ScholarPubMed
18.Dror, DK & Allen, LH (2008) Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev 66, 250255.CrossRefGoogle ScholarPubMed
19.Kuschel, CA & Harding, JE (2004) Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev issue 1, CD000343.CrossRefGoogle ScholarPubMed
20.Mathews, F (1996) Antioxidant nutrients in pregnancy: a systematic review of the literature. Nutr Res Rev 9, 175195.CrossRefGoogle ScholarPubMed
21.Molloy, AM, Kirke, PN, Brody, LCet al. (2008) Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull 29, Suppl. 2, S101S111.CrossRefGoogle ScholarPubMed
22.Ramakrishnan, U, Aburto, N, McCabe, Get al. (2004) Multimicronutrient interventions but not vitamin A or iron interventions alone improve child growth: results of 3 meta-analyses. J Nutr 134, 25922602.CrossRefGoogle ScholarPubMed
23.Ray, JG & Laskin, CA (1999) Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta 20, 519529.CrossRefGoogle ScholarPubMed
24.Hoey, L, Strain, JJ & McNulty, H (2009) Studies of biomarker responses to intervention with vitamin B-12: a systematic review of randomized controlled trials. Am J Clin Nutr 89, issue 6, S1981S1996.CrossRefGoogle ScholarPubMed
25.Fairweather-Tait, SJ & Harvey, LJ (2008) Micronutrient status methods: proceedings of the EURRECA workshop and working party on new approaches for measuring micronutrient status. Br J Nutr 99, S1.CrossRefGoogle Scholar
26.Hooper, L, Ashton, K, Harvey, LJet al. (2009) Assessing potential biomarkers of micronutrient status by using a systematic review methodology: methods. Am J Clin Nutr 89, issue 6, S1953S1959.CrossRefGoogle ScholarPubMed
27.Higgins J & Green S (editors) (2011) Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. The Cochrane Collaboration; available at www.cochrane-handbook.orgGoogle Scholar
28.Bjorke-Monsen, AL, Torsvik, I, Saetran, Het al. (2008) Common metabolic profile in infants indicating impaired cobalamin status responds to cobalamin supplementation. Pediatrics 122, 8391.CrossRefGoogle ScholarPubMed
29.Worthington-White, DA, Behnke, M & Gross, S (1994) Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity. Am J Clin Nutr 60, 930935.CrossRefGoogle ScholarPubMed
30.Jones, KM, Ramirez-Zea, M, Zuleta, Cet al. (2007) Prevalent vitamin B-12 deficiency in twelve-month-old Guatemalan infants is predicted by maternal B-12 deficiency and infant diet. J Nutr 137, 13071313.CrossRefGoogle ScholarPubMed
31.Hay, G, Johnston, C, Whitelaw, Aet al. (2008) Folate and cobalamin status in relation to breastfeeding and weaning in healthy infants. Am J Clin Nutr 88, 105114.CrossRefGoogle ScholarPubMed
32.Dagnelie, PC & van Staveren, WA (1994) Macrobiotic nutrition and child health: results of a population-based, mixed-longitudinal cohort study in The Netherlands. Am J Clin Nutr 59, Suppl. 5, S1187S1196.CrossRefGoogle ScholarPubMed
33.Papoutsakis, C, Yiannakouris, N, Manios, Yet al. (2006) The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender. Eur J Clin Nutr 60, 155162.CrossRefGoogle ScholarPubMed
34.Steluti, J, Martini, LA, Peters, BSet al. (2011) Folate, vitamin B6 and vitamin B12 in adolescence: serum concentrations, prevalence of inadequate intakes and sources in food. J Pediatr (Rio J) 87, 4349.Google ScholarPubMed
35.Yeung, LF, Cogswell, ME, Carriquiry, ALet al. (2011) Contributions of enriched cereal-grain products, ready-to-eat cereals, and supplements to folic acid and vitamin B-12 usual intake and folate and vitamin B-12 status in US children: National Health and Nutrition Examination Survey (NHANES), 2003–2006. Am J Clin Nutr 93, 172185.CrossRefGoogle ScholarPubMed
36.Gewa, CA, Weiss, RE, Bwibo, NOet al. (2009) Dietary micronutrients are associated with higher cognitive function gains among primary school children in rural Kenya. Br J Nutr 101, 13781387.CrossRefGoogle ScholarPubMed
37.Hay, G, Trygg, K, Whitelaw, Aet al. (2011) Folate and cobalamin status in relation to diet in healthy 2-y-old children. Am J Clin Nutr 93, 727735.CrossRefGoogle ScholarPubMed
38.Baker, PN, Wheeler, SJ, Sanders, TAet al. (2009) A prospective study of micronutrient status in adolescent pregnancy. Am J Clin Nutr 89, 11141124.CrossRefGoogle ScholarPubMed
39.Koebnick, C, Heins, UA, Dagnelie, PCet al. (2002) Longitudinal concentrations of vitamin B(12) and vitamin B(12)-binding proteins during uncomplicated pregnancy. Clin Chem 48, 928933.CrossRefGoogle Scholar
40.Lindblad, B, Zaman, S, Malik, Aet al. (2005) Folate, vitamin B12, and homocysteine levels in South Asian women with growth-retarded fetuses. Acta Obstet Gynecol Scand 84, 10551061.Google ScholarPubMed
41.Morkbak, AL, Ramlau-Hansen, CH, Moller, UKet al. (2007) A longitudinal study of serum cobalamins and its binding proteins in lactating women. Eur J Clin Nutr 61, 184189.CrossRefGoogle ScholarPubMed
42.Muthayya, S, Kurpad, AV, Duggan, CPet al. (2006) Low maternal vitamin B12 status is associated with intrauterine growth retardation in urban South Indians. Eur J Clin Nutr 60, 791801.CrossRefGoogle ScholarPubMed
43.Takimoto, H, Hayashi, F, Kusama, Ket al. (2011) Elevated maternal serum folate in the third trimester and reduced fetal growth: a longitudinal study. J Nutr Sci Vitaminol (Tokyo) 57, 130137.CrossRefGoogle ScholarPubMed
44.Duyvendak, M & Veldhuis, GJ (2009) Oral better than parenteral supplementation of vitamin B12. Ned Tijdschr Geneeskd 153, B485.Google ScholarPubMed
45.Rufenacht, P, Mach-Pascual, S & Iten, A (2008) Vitamin B12 deficiency: a challenging diagnosis and treatment. Rev Med Suisse 4, 22122214, 2216–2217.Google ScholarPubMed
46.Schneider, H & Miller, RK (2010) Receptor-mediated uptake and transport of macromolecules in the human placenta. Int J Dev Biol 54, 367375.CrossRefGoogle ScholarPubMed
47.Molloy, AM, Mills, JL, McPartlin, Jet al. (2002) Maternal and fetal plasma homocysteine concentrations at birth: the influence of folate, vitamin B12, and the 5,10-methylenetetrahydrofolate reductase 677C–>T variant. Am J Obstet Gynecol 186, 499503.CrossRefGoogle Scholar
48.Hvas, AM & Nexo, E (2005) Holotranscobalamin – a first choice assay for diagnosing early vitamin B deficiency? J Intern Med 257, 289298.CrossRefGoogle ScholarPubMed
49.Nexo, E, Hvas, AM, Bleie, Oet al. (2002) Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem 48, 17681771.CrossRefGoogle ScholarPubMed
50.Villamor, E, Mora-Plazas, M, Forero, Yet al. (2008) Vitamin B-12 status is associated with socioeconomic level and adherence to an animal food dietary pattern in Colombian school children. J Nutr 138, 13911398.CrossRefGoogle Scholar
51.Honzik, T, Adamovicova, M, Smolka, Vet al. (2010) Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency – what have we learned? Eur J Paediatr Neurol 14, 488495.CrossRefGoogle ScholarPubMed
52.Campbell, BA (1995) Megaloblastic anemia in pregnancy. Clin Obstet Gynecol 38, 455462.CrossRefGoogle ScholarPubMed
53.Ray, JG & Blom, HJ (2003) Vitamin B12 insufficiency and the risk of fetal neural tube defects. QJM 96, 289295.CrossRefGoogle ScholarPubMed
54.Acilmis, YG, Dikensoy, E, Kutlar, AIet al. (2011) Homocysteine, folic acid and vitamin B12 levels in maternal and umbilical cord plasma and homocysteine levels in placenta in pregnant women with pre-eclampsia. J Obstet Gynaecol Res 37, 4550.CrossRefGoogle ScholarPubMed
55.Selhub, J, Morris, MS, Jacques, PFet al. (2009) Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr 89, issue 2, S702S706.CrossRefGoogle ScholarPubMed
56.Stabler, SP & Allen, RH (2004) Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 24, 299326.CrossRefGoogle ScholarPubMed
57.Bjorke-Monsen, AL & Ueland, PM (2011) Cobalamin status in children. J Inherit Metab Dis 34, 111119.CrossRefGoogle ScholarPubMed
58.Monsen, AL, Refsum, H, Markestad, Tet al. (2003) Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years. Clin Chem 49, 20672075.CrossRefGoogle ScholarPubMed
59.Monsen, AL, Schneede, J & Ueland, PM (2006) Mid-trimester amniotic fluid methionine concentrations: a predictor of birth weight and length. Metabolism 55, 11861191.CrossRefGoogle ScholarPubMed
60.Casanueva, E, Viteri, FE, Mares-Galindo, Met al. (2006) Weekly iron as a safe alternative to daily supplementation for nonanemic pregnant women. Arch Med Res 37, 674682.CrossRefGoogle ScholarPubMed
61.Choudhry, VP, Saraya, AK & Ghai, OP (1972) Morphological changes in relation to haemopoietic nutrient deficiency in nutritional macrocytic anaemia in infancy and childhood. Indian J Med Res 60, 17641773.Google ScholarPubMed
62.Cikot, RJ, Steegers-Theunissen, RP, Thomas, CMet al. (2001) Longitudinal vitamin and homocysteine levels in normal pregnancy. Br J Nutr 85, 4958.CrossRefGoogle ScholarPubMed
63.Couto, FD, Moreira, LM, Dos Santos, DBet al. (2007) Folate, vitamin B12 and total homocysteine levels in neonates from Brazil. Eur J Clin Nutr 61, 382386.Google ScholarPubMed
64.Cornel, MC, de Smit, DJ & de Jong-van den Berg, LT (2005) Folic acid – the scientific debate as a base for public health policy. Reprod Toxicol 20, 411415.CrossRefGoogle ScholarPubMed
65.Czeizel, AE & Dudas, I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327, 18321835.CrossRefGoogle ScholarPubMed
66.Czeizel, AE & Medveczky, E (2003) Periconceptional multivitamin supplementation and multimalformed offspring. Obstet Gynecol 102, 12551261.Google ScholarPubMed
67.Dagnelie, PC, van Staveren, WA, Vergote, FJet al. (1989) Nutritional status of infants aged 4 to 18 months on macrobiotic diets and matched omnivorous control infants: a population-based mixed-longitudinal study. II. Growth and psychomotor development. Eur J Clin Nutr 43, 325338.Google ScholarPubMed
68.Dawson, EB, Evans, DR, Conway, MEet al. (2000) Vitamin B12 and folate bioavailability from two prenatal multivitamin/multimineral supplements. Am J Perinatol 17, 193199.CrossRefGoogle ScholarPubMed
69.van Dusseldorp, M, Schneede, J, Refsum, Het al. (1999) Risk of persistent cobalamin deficiency in adolescents fed a macrobiotic diet in early life. Am J Clin Nutr 69, 664671.CrossRefGoogle ScholarPubMed
70.Eilander, A, Muthayya, S, van der Knaap, Het al. (2010) Undernutrition, fatty acid and micronutrient status in relation to cognitive performance in Indian school children: a cross-sectional study. Br J Nutr 103, 10561064.CrossRefGoogle ScholarPubMed
71.Gomber, S, Bhawna, , Madan, Net al. (2003) Prevalence & etiology of nutritional anaemia among school children of urban slums. Indian J Med Res 118, 167171.Google ScholarPubMed
72.Gomber, S, Kumar, S, Rusia, Uet al. (1998) Prevalence & etiology of nutritional anaemias in early childhood in an urban slum. Indian J Med Res 107, 269273.Google Scholar
73.Gordon, BA & Carson, RA (1976) Methylmalonic acidemia controlled with oral administration of vitamin B12. CMAJ 115, 233236.Google ScholarPubMed
74.Graham, SM, Arvela, OM & Wise, GA (1992) Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants. J Pediatr 121, 710714.CrossRefGoogle ScholarPubMed
75.Haggarty, P, McCallum, H, McBain, Het al. (2006) Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. Lancet 367, 15131519.CrossRefGoogle ScholarPubMed
76.Haiden, N, Klebermass, K, Cardona, Fet al. (2006) A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity. Pediatrics 118, 180188.CrossRefGoogle ScholarPubMed
77.Haiden, N, Schwindt, J, Cardona, Fet al. (2006) Effects of a combined therapy of erythropoietin, iron, folate, and vitamin B12 on the transfusion requirements of extremely low birth weight infants. Pediatrics 118, 20042013.CrossRefGoogle ScholarPubMed
78.Hay, G, Clausen, T, Whitelaw, Aet al. (2010) Maternal folate and cobalamin status predicts vitamin status in newborns and 6-month-old infants. J Nutr 140, 557564.CrossRefGoogle Scholar
79.Hininger, I, Favier, M, Arnaud, Jet al. (2004) Effects of a combined micronutrient supplementation on maternal biological status and newborn anthropometrics measurements: a randomized double-blind, placebo-controlled trial in apparently healthy pregnant women. Eur J Clin Nutr 58, 5259.CrossRefGoogle ScholarPubMed
80.Hjelt, K & Krasilnikoff, PA (1990) The impact of gluten on haematological status, dietary intakes of haemopoietic nutrients and vitamin B12 and folic acid absorption in children with coeliac disease. Acta Paediatr Scand 79, 911919.CrossRefGoogle ScholarPubMed
81.Huemer, M, Simma, B, Fowler, Bet al. (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147, 469472.CrossRefGoogle ScholarPubMed
82.Järvenpää, J, Schwab, U, Lappalainen, Tet al. (2007) Fortified mineral water improves folate status and decreases plasma homocysteine concentration in pregnant women. J Perinat Med 35, 108114.CrossRefGoogle ScholarPubMed
83.Johnson, TE, Janes, SJ, MacDonald, Aet al. (2002) An observational study to evaluate micronutrient status during enteral feeding. Arch Dis Child 86, 411415.CrossRefGoogle ScholarPubMed
84.Knight, EM, Spurlock, BG, Edwards, CHet al. (1994) Biochemical profile of African American women during three trimesters of pregnancy and at delivery. J Nutr 124, Suppl. 6, S943S953.Google ScholarPubMed
85.Levy, R, Herzberg, GR, Andrews, WLet al. (1992) Thiamine, riboflavin, folate, and vitamin B12 status of low birth weight infants receiving parenteral and enteral nutrition. J Parenter Enteral Nutr 16, 241247.CrossRefGoogle ScholarPubMed
86.López de Romaña, G, Cusirramos, S, López de Romaña, Det al. (2005) Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants. J Nutr 135, issue 3, S646S652.CrossRefGoogle ScholarPubMed
87.Lovblad, K, Ramelli, G, Remonda, Let al. (1997) Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Pediatr Radiol 27, 155158.CrossRefGoogle ScholarPubMed
88.Lundgren, J & Blennow, G (1999) Vitamin B12 deficiency may cause benign familial infantile convulsions: a case report. Acta Paediatr 88, 11581160.CrossRefGoogle ScholarPubMed
89.Makedos, G, Papanicolaou, A, Hitoglou, Aet al. (2007) Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia. Arch Gynecol Obstet 275, 121124.CrossRefGoogle ScholarPubMed
90.Mamlok, RJ, Isenberg, JN, Rassin, DKet al. (1986) A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anemia. Neuropediatrics 17, 9499.CrossRefGoogle ScholarPubMed
91.Martin, I, Gibert, MJ, Pintos, Cet al. (2004) Oxidative stress in mothers who have conceived fetus with neural tube defects: the role of aminothiols and selenium. Clin Nutr 23, 507514.CrossRefGoogle ScholarPubMed
92.Mathan, VI, Baker, SJ, Sood, SKet al. (1979) WHO sponsored collaborative studies on nutritional anaemia in India. The effects of ascorbic acid and protein supplementation on the response of pregnant women to iron, pteroylglutamic acid and cyanocobalamin therapy. Br J Nutr 42, 391398.CrossRefGoogle ScholarPubMed
93.Maurage, C, Dalloul, C, Moussa, Fet al. (1995) Efficacy of oral administration of a micellaar solution of vitamin K during the neonatal period. Arch Pediatr 2, 328332.CrossRefGoogle ScholarPubMed
94.Masalha, R, Afawi, Z, Mahajnah, Met al. (2008) The impact of nutritional vitamin B12, folate and hemoglobin deficiency on school performance of elementary school children. J Pediatr Neurol 6, 243248.Google Scholar
95.McCoy, H, Kenney, MA, Kirby, Aet al. (1984) Nutrient intakes of female adolescents from eight southern states. J Am Diet Assoc 84, 14531460.CrossRefGoogle ScholarPubMed
96.McGrath, N, Bellinger, D, Robins, Jet al. (2006) Effect of maternal multivitamin supplementation on the mental and psychomotor development of children who are born to HIV-1-infected mothers in Tanzania. Pediatrics 117, e216e225.CrossRefGoogle ScholarPubMed
97.McNulty, H, Eaton-Evans, J, Cran, Get al. (1996) Nutrient intakes and impact of fortified breakfast cereals in schoolchildren. Arch Dis Child 75, 474481.CrossRefGoogle ScholarPubMed
98.Mena, PN, Pittaluga, EP, Blanco, Aet al. (2001) B12 vitamin does not change the evolution of the anemia in preterm babies. Rev Chil Pediatr 72, 3439.CrossRefGoogle Scholar
99.Merialdi, M, Caulfield, LE, Zavaleta, Net al. (2004) Randomized, controlled trial of prenatal zinc supplementation and fetal bone growth. Am J Clin Nutr 79, 826830.CrossRefGoogle ScholarPubMed
100.Metcalf, R, Dilena, B, Gibson, Ret al. (1994) How appropriate are commercially available human milk fortifiers? J Paediatr Child Health 30, 350355.CrossRefGoogle ScholarPubMed
101.Metz, J, Festenstein, H & Welch, P (1965) Effect of folic acid and vitamin B12 supplementation on tests of folate and vitamin B12 nutrition in pregnancy. Am J Clin Nutr 16, 472479.CrossRefGoogle ScholarPubMed
102.Mills, EJ, Wu, P, Seely, Det al. (2005) Vitamin supplementation for prevention of mother-to-child transmission of HIV and pre-term delivery: a systematic review of randomized trial including more than 2800 women. AIDS Res Ther 2, 4.CrossRefGoogle ScholarPubMed
103.Minet, JC, Bisse, E, Aebischer, CPet al. (2000) Assessment of vitamin B-12, folate, and vitamin B-6 status and relation to sulfur amino acid metabolism in neonates. Am J Clin Nutr 72, 751757.CrossRefGoogle ScholarPubMed
104.Miyake, Y, Sasaki, S, Tanaka, Ket al. (2006) Dietary folate and vitamins B12, B6, and B2 intake and the risk of postpartum depression in Japan: the Osaka Maternal and Child Health Study. J Affect Disord 96, 133138.CrossRefGoogle ScholarPubMed
105.Molloy, AM, Kirke, P, Hillary, Iet al. (1985) Maternal serum folate and vitamin B12 concentrations in pregnancies associated with neural tube defects. Arch Dis Child 60, 660665.CrossRefGoogle ScholarPubMed
106.Molloy, AM, Mills, JL, Cox, Cet al. (2005) Choline and homocysteine interrelations in umbilical cord and maternal plasma at delivery. Am J Clin Nutr 82, 836842.CrossRefGoogle ScholarPubMed
107.Monagle, PT & Tauro, GP (1997) Infantile megaloblastosis secondary to maternal vitamin B12 deficiency. Clin Lab Haematol 19, 2325.CrossRefGoogle ScholarPubMed
108.Moran, VH (2007) Nutritional status in pregnant adolescents: a systematic review of biochemical markers. Matern Child Nutr 3, 7493.CrossRefGoogle ScholarPubMed
109.Morkbak, AL, Hvas, AM, Milman, Net al. (2007) Holotranscobalamin remains unchanged during pregnancy. Longitudinal changes of cobalamins and their binding proteins during pregnancy and postpartum. Haematologica 92, 17111712.CrossRefGoogle ScholarPubMed
110.Msolla, MJ & Kinabo, JL (1997) Prevalence of anaemia in pregnant women during the last trimester. Int J Food Sci Nutr 48, 265270.CrossRefGoogle ScholarPubMed
111.Murphy, MM, Molloy, AM, Ueland, PMet al. (2007) Longitudinal study of the effect of pregnancy on maternal and fetal cobalamin status in healthy women and their offspring. J Nutr 137, 18631867.CrossRefGoogle ScholarPubMed
112.Mwanda, OW & Dave, P (1999) Megaloblastic marrow in macrocytic anaemias at Kenyatta National and M P Shah Hospitals, Nairobi. East Afr Med J 76, 610614.Google Scholar
113.Neiger, R, Wise, C, Contag, SAet al. (1993) First trimester bleeding and pregnancy outcome in gravidas with normal and low folate levels. Am J Perinatol 10, 460462.CrossRefGoogle ScholarPubMed
114.Nelen, WL, Blom, HJ, Steegers, EAet al. (2000) Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet Gynecol 95, 519524.Google ScholarPubMed
115.Neri, I, Allais, G, Schiapparelli, Pet al. (2005) Acupuncture versus pharmacological approach to reduce hyperemesis gravidarum discomfort. Minerva Ginecol 57, 471475.Google ScholarPubMed
116.Neuhouser, ML, Beresford, SA, Hickok, DEet al. (1998) Absorption of dietary and supplemental folate in women with prior pregnancies with neural tube defects and controls. J Am Coll Nutr 17, 625630.CrossRefGoogle ScholarPubMed
117.Neumann, CG & Harrison, GG (1994) Onset and evolution of stunting in infants and children. Examples from the Human Nutrition Collaborative Research Support Program. Kenya and Egypt studies. Eur J Clin Nutr 48, Suppl. 1, S90S102.Google ScholarPubMed
118.Niebyl, JR & Goodwin, TM (2002) Overview of nausea and vomiting of pregnancy with an emphasis on vitamins and ginger. Am J Obstet Gynecol 186, Suppl. 5, S253S255.CrossRefGoogle ScholarPubMed
119.Nikolaus, E & Nikolaus, K (1979) Effect of a mixture of cyanocobalamin, glutamine and phosphoserine on performance and behavior of schoolchildren. Therapiewoche 29, 73537359.Google Scholar
120.Osganian, SK, Stampfer, MJ, Spiegelman, Det al. (1999) Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health. JAMA 281, 11891196.CrossRefGoogle ScholarPubMed
121.Patel, KD & Lovelady, CA (1998) Vitamin B12 status of east Indian vegetarian lactating women living in the United States. Nutr Res 18, 18391846.CrossRefGoogle Scholar
122.Ratan, SK, Rattan, KN, Pandey, RMet al. (2008) Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls. Pediatr Surg Int 24, 803808.CrossRefGoogle ScholarPubMed
123.Ronnenberg, AG, Goldman, MB, Aitken, IWet al. (2000) Anemia and deficiencies of folate and vitamin B-6 are common and vary with season in Chinese women of childbearing age. J Nutr 130, 27032710.CrossRefGoogle ScholarPubMed
124.Ronnenberg, AG, Goldman, MB, Chen, Det al. (2002) Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am J Clin Nutr 76, 13851391.CrossRefGoogle Scholar
125.Ronnenberg, AG, Goldman, MB, Chen, Det al. (2002) Preconception folate and vitamin B(6) status and clinical spontaneous abortion in Chinese women. Obstet Gynecol 100, 107113.Google ScholarPubMed
126.Ronnenberg, AG, Venners, SA, Xu, Xet al. (2007) Preconception B-vitamin and homocysteine status, conception, and early pregnancy loss. Am J Epidemiol 166, 304312.CrossRefGoogle ScholarPubMed
127.Rumbold, A, Middleton, P & Crowther, CA (2005) Vitamin supplementation for preventing miscarriage. Cochrane Database Syst Rev issue 2, CD004073.Google ScholarPubMed
128.Sachdeva, R & Mann, SK (1994) Impact of nutrition counselling and supplements on the mineral nutriture of rural pregnant women and their neonates. Indian Pediatr 31, 643649.Google ScholarPubMed
129.Scatliff, CE, Koski, KG & Scott, ME (2011) Diarrhea and novel dietary factors emerge as predictors of serum vitamin B12 in Panamanian children. Food Nutr Bull 32, 5459.CrossRefGoogle ScholarPubMed
130.Schneede, J, Dagnelie, PC, van Staveren, WAet al. (1994) Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets. Pediatr Res 36, 194201.CrossRefGoogle ScholarPubMed
131.Shih, VE, Coulombe, JT, Maties, Met al. (1976) Methylmalonic aciduria in the newborn. N Engl J Med 295, 13201321.Google ScholarPubMed
132.Siekmann, JH, Allen, LH, Bwibo, NOet al. (2003) Kenyan school children have multiple micronutrient deficiencies, but increased plasma vitamin B-12 is the only detectable micronutrient response to meat or milk supplementation. J Nutr 133, 11 Suppl. 2, 3972S3980S.CrossRefGoogle ScholarPubMed
133.Singla, PN, Gupta, HP, Ahuja, Cet al. (1982) Deficiency anaemias in preschool children – estimation of prevalence based on response to haematinic supplementation. J Trop Pediatr 28, 7780.CrossRefGoogle ScholarPubMed
134.Sivakumar, B, Nair, KM, Sreeramulu, Det al. (2006) Effect of micronutrient supplement on health and nutritional status of schoolchildren: biochemical status. Nutrition 22, 1 Suppl., S15S25.CrossRefGoogle ScholarPubMed
135.Smith Fawzi, MC, Kaaya, SF, Mbwambo, Jet al. (2007) Multivitamin supplementation in HIV-positive pregnant women: impact on depression and quality of life in a resource-poor setting. HIV Med 8, 203212.CrossRefGoogle Scholar
136.Sneed, SM, Zane, C & Thomas, MR (1981) The effects of ascorbic acid, vitamin B6, vitamin B12, and folic acid supplementation on the breast milk and maternal nutritional status of low socioeconomic lactating women. Am J Clin Nutr 34, 13381346.CrossRefGoogle ScholarPubMed
137.Sohrabvand, F, Shariat, M & Haghollahi, F (2006) Vitamin B supplementation for leg cramps during pregnancy. Int J Gynaecol Obstet 95, 4849.CrossRefGoogle ScholarPubMed
138.Steegers-Theunissen, RP, Boers, GH, Blom, HJet al. (1995) Neural tube defects and elevated homocysteine levels in amniotic fluid. Am J Obstet Gynecol 172, 14361441.CrossRefGoogle ScholarPubMed
139.Steen, MT, Boddie, AM, Fisher, AJet al. (1998) Neural-tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid. Prenat Diagn 18, 545555.3.0.CO;2-2>CrossRefGoogle ScholarPubMed
140.Strand, TA, Taneja, S, Bhandari, Net al. (2007) Folate, but not vitamin B-12 status, predicts respiratory morbidity in north Indian children. Am J Clin Nutr 86, 139144.CrossRefGoogle Scholar
141.Suarez, L, Hendricks, K, Felkner, Met al. (2003) Maternal serum B12 levels and risk for neural tube defects in a Texas–Mexico border population. Ann Epidemiol 13, 8188.CrossRefGoogle Scholar
142.Thomas, NE, Cooper, SM, Baker, JSet al. (2008) Homocyst(e)ine, folate, and vitamin B12 status in a cohort of Welsh young people aged 12–13 years old. Res Sports Med 16, 233243.CrossRefGoogle Scholar
143.Thompson, MD, Cole, DE & Ray, JG (2009) Vitamin B-12 and neural tube defects: the Canadian experience. Am J Clin Nutr 89, issue 2, S697S701.CrossRefGoogle ScholarPubMed
144.Thoradeniya, T, Wickremasinghe, R, Ramanayake, Ret al. (2006) Low folic acid status and its association with anaemia in urban adolescent girls and women of childbearing age in Sri Lanka. Br J Nutr 95, 511516.CrossRefGoogle ScholarPubMed
145.Thurlow, RA, Winichagoon, P, Green, Tet al. (2005) Only a small proportion of anemia in northeast Thai schoolchildren is associated with iron deficiency. Am J Clin Nutr 82, 380387.CrossRefGoogle Scholar
146.Valman, HB (1972) Late vitamin B12 deficiency following resection of the ileum in the neonatal period. Acta Paediatr Scand 61, 561564.CrossRefGoogle ScholarPubMed
147.Veena, SR, Krishnaveni, GV, Srinivasan, Ket al. (2010) 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 children in South India. J Nutr 140, 10141022.CrossRefGoogle ScholarPubMed
148.Verkleij-Hagoort, AC, van Driel, LM, Lindemans, Jet al. (2008) Genetic and lifestyle factors related to the periconception vitamin B12 status and congenital heart defects: a Dutch case–control study. Mol Genet Metab 94, 112119.CrossRefGoogle Scholar
149.Villamor, E, Mora-Plazas, M, Forero, Yet al. (2008) Vitamin B-12 status is associated with socioeconomic level and adherence to an animal food dietary pattern in Colombian school children. J Nutr 138, 13911398.CrossRefGoogle Scholar
150.Vinod Kumar, M & Rajagopalan, S (2008) Trial using multiple micronutrient food supplement and its effect on cognition. Indian J Pediatr 75, 671678.CrossRefGoogle ScholarPubMed
151.Vujkovic, M, Ocke, MC, van der Spek, PJet al. (2007) Maternal Western dietary patterns and the risk of developing a cleft lip with or without a cleft palate. Obstet Gynecol 110, 378384.CrossRefGoogle ScholarPubMed
152.Vujkovic, M, Steegers, EA, Looman, CWet al. (2009) The maternal Mediterranean dietary pattern is associated with a reduced risk of spina bifida in the offspring. BJOG 116, 408415.CrossRefGoogle ScholarPubMed
153.Wald, NJ, Hackshaw, AD, Stone, Ret al. (1996) Blood folic acid and vitamin B12 in relation to neural tube defects. Br J Obstet Gynaecol 103, 319324.CrossRefGoogle ScholarPubMed
154.Wright, ME (1995) A case–control study of maternal nutrition and neural tube defects in Northern Ireland. Midwifery 11, 146152.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1 Intake–status–health relationships relevant for deriving reference values: 1 = intake–health relationship; 2 = intake–status relationship; 3 = status–health relationship

Figure 1

Table 1 Characteristics of excluded studies

Figure 2

Fig. 2 Selection of studies for the current systematic review

Figure 3

Table 2 Main characteristics of the studies selected in the systematic review by study population group

Figure 4

Table 3 Assessment of methodological quality of included randomized controlled trials, longitudinal and cross-sectional studies